新辅助化疗是否可以免去乳腺癌患者的局部淋巴结照射 (12/31/2023)
Can regional lymph node irradiation be avoided in breast cancer patients following neoadjuvant chemotherapy
这是一项III期临床试验（NSABP B-51/RTOG 1304），该研究纳入了 1,641 名起初被诊断为淋巴结阳性, 非转移性乳腺癌的患者, 在新辅助化疗后淋巴结已无癌, 并且接受了乳房切除术或保乳手术。 患者被以 1:1 的比例随机分配到无局部淋巴结照射组（乳房切除术后观察或保乳手术后全乳腺照射）或局部淋巴结照射组（乳房切除术后胸壁照射加区域淋巴结照射, 或全乳切除术后观察）。 乳房照射加上保乳手术后的区域淋巴结照射）。
结果: 无论是否接受辅助区域淋巴结放疗, 可评估的患者 (n = 1,556) 都有相似的结果。无局部淋巴结照射组中 91.8% 的患者和局部淋巴结照射组中 92.7% 的患者在术后 5 年没有浸润性乳腺癌复发。 两组之间的远处复发率和总生存率也相似, 手术后 5 年，每组中 93.4% 的患者没有出现远处复发, 无局部淋巴结照射组中 94% 的患者和局部淋巴结照射组中 93.6% 的患者存活 5年后。
研究结果表明,: 通过新辅助化疗降低癌症阳性区域淋巴结的分期可以使一些患者跳过区域淋巴结放疗, 而不会对肿瘤学结果产生不利影响。 对患者长期结果的随访仍需继续,迄今为止,患者的乳腺癌复发率低于预期,影响了对复发次数的统计分析。
This is a phase III clinical trial (NSABP B-51/RTOG 1304) that enrolled 1,641 patients who were initially found to have node-positive, non-metastatic breast cancer, and became node negative following neoadjuvant chemotherapy. They had mastectomy or breast-conserving surgery. Patients were randomly assigned in a 1:1 ratio to the no regional lymph node irradiation group (observation after mastectomy or total breast irradiation after breast-conserving surgery) or regional lymph node irradiation group (chest wall irradiation plus regional nodal irradiation after mastectomy, or whole-breast irradiation plus regional nodal irradiation after breast-conserving surgery).
Results: Evaluable patients (n = 1,556) had similar outcomes regardless of whether they received adjuvant regional lymph node irradiation. A total of 91.8% of patients in the no regional lymph node irradiation group and 92.7% of patients in the regional lymph node irradiation group were free of invasive breast cancer recurrence 5 years after surgery. Distant recurrence and overall survival rates were also similar between the two groups, with 93.4% of patients in each group free from distant recurrence 5 years after surgery, and 94% of patients in the no regional lymph node irradiation group and 93.6% of patients in the regional lymph node irradiation group were alive after 5 years.
The findings suggest that downstaging cancer-positive regional lymph nodes with neoadjuvant chemotherapy may allow some patients to skip regional lymph node irradiation without adversely affecting oncologic outcomes. Long-term follow-up of outcome needs to continue, as so far, patients’ breast cancer recurrence rates are lower than expected, affecting the planned statistical analysis.
参考文献 Reference
Mamounas TP et al. 2023 San Antonio Breast Cancer Symp abstr GS-02-07
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奥希替尼联合或不联合化疗对EGFR突变的晚期非小细胞肺癌的中枢神经系统疗效 (12/30/2023)
CNS efficacy of osimertinib with or without chemotherapy in EGFR-mutated advanced NSCLC
这是一项III期临床试验（FLAURA2）, 评价一线奥希替尼联合化疗相比于奥希替尼单药治疗对表皮生长因子受体 (EGFR) 突变的晚期非小细胞肺癌 (NSCLC) 患者的中枢神经系统(CNS)疗效。
方法: 患者被随机分配接受奥希替尼联合铂类培美曲塞（联合组）或奥希替尼单药治疗, 直至疾病进展。 所有患者均在基线和进展时进行脑部扫描，并在预定评估时进行脑部扫描，直至基线CNS转移的患者出现进展; 扫描结果由神经放射科医生盲法独立中央审查进行评估。
结果: 根据基线 CNS评估，随机分配的 279 名患者中的 118 名（联合组）和 278 名患者中的 104 名（单药组）具有 ≥ 一个可测量和/或不可测量的 CNS 病变, 并被纳入 CNS 完整分析集; 118 例中的 40 例和 104 例中的 38 例具有 ≥ 一个可测量的目标 CNS 病变, 并被纳入事后 CNS 可评估响应集。 在CNS 完整分析集中，CNS 进展或死亡的风险比 (HR) 为 0.58（95% CI，0.33 至 1.01）。 在基线无 CNS 转移的患者中, CNS 进展或死亡的 HR 为 0.67（95% CI，0.43 至 1.04）。 在CNS 完整分析集中，CNS 客观响应率（95% CI）分别为 73%（联合治疗；64 至 81）与 69%（单一疗法；59 至 78）； 59% 和 43% 的患者获得中枢神经系统完全响应。 在CNS可评估响应集中，CNS 客观响应率 (95% CI) 分别为 88%（73 至 96）和 87%（72 至 96）； 48% 和 16% 的患者患有中枢神经系统完全响应。
结论: 与奥希替尼单药治疗相比，奥希替尼联合铂类培美曲塞可改善 CNS 疗效，包括延迟 CNS 进展, 无论基线 CNS 转移状态如何。 这些数据支持该组合作为 EGFR 突变晚期 NSCLC 患者（包括 CNS 转移患者）的新一线治疗方法。
This is a phase III clinical trial (FLAURA2) evaluating the central nervous system (CNS) efficacy of first-line osimertinib plus chemotherapy compared with osimertinib monotherapy in patients with epidermal growth factor receptor (EGFR) mutated advanced non-small cell lung cancer (NSCLC).
Methods: Patients were randomly assigned to receive osimertinib combined with platinum-based pemetrexed (combination group) or osimertinib monotherapy until disease progression. All patients had brain scans at baseline and at progression, and at scheduled assessments until progression for patients with baseline CNS metastases; scans were evaluated via blinded independent central review by neuroradiologists.
Results: Based on baseline CNS evaluation, 118 of 279 patients (combination group) and 104 of 278 patients (monotherapy group) randomized assigned patients had ≥ one measurable and/or non-measurable CNS lesion, and were included in the CNS full analysis set; 40 of 118 and 38 of 104 had ≥ one measurable target CNS lesion and were included in the post hoc CNS evaluable-for-response set.
In the CNS full analysis set, the hazard ratio (HR) for CNS progression or death was 0.58 (95% CI, 0.33 to 1.01). Among patients without CNS metastases at baseline, the HR for CNS progression or death was 0.67 (95% CI, 0.43 to 1.04). In the CNS full analysis set, CNS objective response rates (95% CI) were 73% (combination therapy; 64 to 81) versus 69% (monotherapy; 59 to 78); 59% versus 43% of patients achieved CNS complete response. In the CNS evaluable-for-response set, CNS objective response rates (95% CI) were 88% (73 to 96) and 87% (72 to 96), respectively; 48% and 16% of patients had a complete CNS response.
Conclusions: Osimertinib plus platinum pemetrexed improves CNS efficacy compared with osimertinib monotherapy, including delaying CNS progression, regardless of baseline CNS metastatic status. These data support this combination as a new first-line treatment for patients with EGFR-mutated advanced NSCLC, including those with CNS metastases.
参考文献 Reference
Jänne PA et al. J Clin Onc 2023; DOI: 10.1200/JCO.23.02219 Dec. 2, 2023.
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Enfortumab vedotin (EV) 联合派姆单抗相比于化疗第一线治疗局部晚期转移性尿路上皮癌 (12/24/2023)
Enfortumab vedotin in combination with pembrolizumab vs chemotherapy for untreated locally advanced metastatic urothelial carcinoma
这是一项全球性 III 期, 开放标签, 随机研究(EV-302/KEYNOTE-A39), 评估先前未经治疗的局部晚期转移性尿路上皮癌患者（有资格接受含顺铂或卡铂化疗的患者）。
方法: 患者（无论 PD-L1 表达情况）按 1:1 随机分配，接受每 3 周的第 1 天和第 8 天 EV（1.25 mg/kg；静脉）, 每 3 周的第 1 天派姆单抗（P, pembroliumab, 200 mg；静脉）l 或吉西他滨联合顺铂或卡铂。双重主要终点是无进展生存期和总生存期。次要终点包括总体响应率和安全性。
结果: 886 名患者（EV+P：442；化疗：444）被随机分组。 数据截止时, 中位随访时间为 17.2 个月。 与化疗相比, EV+P 的无进展生存期显著延长, 进展或死亡风险降低了 55%（中位无进展生存期分别为 12.5 个月相比于6.3 个月; HR 0.45 [95% CI: 0.38-0.54]；P <0.00001）。 与化疗相比, EV+P 的总生存期显著延长, 死亡风险降低了 53%（中位总生存期分别为 31.5 个月相比于16.1 个月; HR 0.47 [95% CI; 0.38-0.58]; P <0.00001）。 EV+P 组和化疗组的确认总体响应率分别为 67.7% 和 44.4%（P <0.00001）。
EV+P 组中 55.9% 发生 3 级以上 治疗相关的不良反应相比于化疗组中的 69.5% 。最常见的是 EV+P 中的斑丘疹 (7.7%)、高血糖 (5.0%) 和中性粒细胞减少症 (4.8%)，以及化疗中的贫血 (31.4%)、中性粒细胞减少症 (30.0%) 和血小板减少症 (19.4%)。 对 EV 最常见（≥5%）≥3 级治疗相关的不良反应包括皮肤反应（15.5%）、周围神经病变（6.8%）和高血糖（6.1%）。派姆单抗最常见 (≥5%) ≥3 级的不良反应包括严重皮肤反应 (11.8%)。
结论: EV+P 显著改善了先前未经治疗的局部晚期转移性尿路上皮癌患者的预后, 与化疗相比, 中位无进展生存期和总生存期几乎翻倍。 安全状况总体上是可控的，没有新的安全信号。 这些结果支持 EV+P 作为局部晚期转移性尿路上皮癌的新第一线治疗。
This is a global phase III, open-label, randomized study (EV-302/KEYNOTE-A39) evaluating patients with previously untreated locally advanced metastatic urothelial carcinoma who were eligible to receive cisplatin- or carboplatin-containing chemotherapy. patients.
Methods: Patients (regardless of PD-L1 expression) were randomly assigned 1:1 to receive EV (1.25 mg/kg; intravenously) on day 1 and 8 every 3 weeks, and pembrolizumab (P, pembrolizumab, 200 mg; intravenously) on day 1 of every 3 week cycle, vs chemotherapy (gemcitabine plus cisplatin or carboplatin). The dual primary endpoints were progression-free survival and overall survival. Secondary endpoints included overall response rate and safety.
Results: 886 patients (EV+P: 442; chemotherapy: 444) were randomized. At data cutoff, the median follow-up time was 17.2 months. Compared with chemotherapy, EV+P was associated with significantly longer progression-free survival and a 55% lower risk of progression or death (median progression-free survival, 12.5 months vs. 6.3 months, respectively; HR 0.45 [95% CI: 0.38-0.54]; P <0.00001). Compared with chemotherapy, EV+P resulted in significantly longer overall survival and a 53% lower risk of death (median overall survival, 31.5 months vs. 16.1 months; HR 0.47 [95% CI; 0.38-0.58]; P <0.00001). The confirmed overall response rates were 67.7% in the EV+P group and 44.4% in the chemotherapy group (P<0.00001).
Grade 3 or higher treatment-related adverse effects occurred in 55.9% of the EV+P group compared with 69.5% of the chemotherapy group. The most common were maculopapular rash (7.7%), hyperglycemia (5.0%), and neutropenia (4.8%) in EV+P group, and anemia (31.4%), neutropenia in chemotherapy group (30.0%) and thrombocytopenia (19.4%). The most common (≥5%) grade ≥3 treatment-related adverse effects in EV group included skin reactions (15.5%), peripheral neuropathy (6.8%), and hyperglycemia (6.1%). The most common (≥5%) grade ≥3 adverse effects with pembrolizumab included serious skin reactions (11.8%).
Conclusions: EV+P significantly improved outcome in patients with previously untreated locally advanced metastatic urothelial carcinoma, nearly doubling median progression-free survival and overall survival compared with chemotherapy. The safety prolife was generally controllable and there were no new security signals. These results support EV+P as a new first-line standard of care for locally advanced metastatic urothelial carcinoma.
参考文献 Reference
Powles TB et al. Annals of Oncol 2023: 34 (suppl_2)
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转移性高分化胃肠胰神经内分泌肿瘤的治疗：ASCO 指南 (12/23/2023)
Systemic therapy for tumor control in metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors: ASCO guideline
高分化转移性 1 级-2 级胃肠胰神经内分泌肿瘤的初始治疗方案的选择和进展后的治疗顺序应考虑患者和肿瘤特征, 如激素状态, 原发部位, 分级, 疾病范围和负担, 生长率, 合并症和生长抑素受体(SSTR, somatostatin receptor)阳性，并尽可能在多学科团队内进行讨论。
基线扫描: 使用 68Ga-DOTA 肽或 64Cu-DOTATATE 的 SSTR PET扫描评估患者的 SSTR 阳性情况。
转移性 1 级-2 级胃肠神经内分泌肿瘤的系统的第一线全身治疗 :
- 推荐生长抑素（somatostatin analogs, 奥曲肽或兰瑞肽）用于SSTR 阳性和/或功能性肿瘤。每 3-6 个月进行一次CT或MRI监测, 对于病情稳定者可延长至 6-12 个月，包括对于小体积肿瘤并且没有肿瘤负荷性症状, 或功能性肿瘤。对于骨转移的患者，建议采用SSTR-PET成像进行随访, 因为CT对这些转移的敏感性有限。支持生长抑素用于肿瘤控制的证据在低度或中低度 SSTR阳性肿瘤 (Ki-67 < 10%) 患者中最为有力。
- 对SSTR 阴性患者，依维莫司为一种全身治疗选择。
转移性 1 级-2 级胃肠神经内分泌肿瘤的二线或后期全身治疗:
- 肽受体放射性核素用于SSTR 阳性且在生长抑素治疗后病情进展的患者。对于功能性肿瘤, 除了肽受体放射性核素治疗外，建议继续使用生长抑素治疗。没有足够的疗效数据表明对于疾病进展的非功能性肿瘤患者应继续进行生长抑素。转移灶体积较小的患者应权衡肽受体放射性核素的益处与长期骨髓毒性的风险。
- 依维莫司推荐用于SSTR 阴性或SSTR 阳性的非功能性患者。该药物也可被视为功能性肿瘤的后期治疗。
转移性 1 级-2 级胰腺内分泌肿瘤的第一线全身治疗:
- 推荐生长抑素（奥曲肽或兰瑞肽）用于SSTR阳性和/或功能性肿瘤。
可以考虑每 3-6 个月进行一次CT 或 MRI, 对于疾病持续稳定的患者可延长至 6-12 个月, 包括对于小体积肿瘤并且没有肿瘤负荷性症状, 或功能性肿瘤.。 对于骨转移的患者，建议采用 SSTR-PET 成像进行随访, 因为CT对这些转移的敏感性有限。支持生长抑素用于肿瘤控制的证据在低度或中低度 SSTR 阳性肿瘤 (Ki-67 < 10%) 患者中最为有力。
- 对于体积较高和/或有与肿瘤负荷相关症状的患者建议化疗（例如卡培他滨和替莫唑胺 [capecitabine and temozolomide]）。在极少数情况下，对于具有较高体积和/或与肿瘤负荷相关的症状且不适合化疗的患者, 建议对SSTR阳性肿瘤患者进行肽受体放射性核素，或者舒尼替尼或依维莫司。
- 对SSTR阴性患者, 化疗（例如卡培他滨和替莫唑胺）,依维莫司或舒尼替尼可以为全身治疗选择。
转移性 1 级-2 级胰腺神经内分泌肿瘤的二线或后期全身治疗:
肽受体放射性核素用于 SSTR 阳性肿瘤, 二线或后期治疗推荐化疗（例如卡培他滨和替莫唑胺）, 依维莫司或舒尼替尼, 治疗选择取决于患者特征和治疗目标。对于功能性肿瘤, 除了肽受体放射性核素外，建议继续使用生长抑素治疗； 没有足够的疗效数据表明对疾病进展的非功能性肿瘤患者应继续进行生长抑素。 转移灶体积较小的患者应权衡肽受体放射性核素 的潜在益处与长期骨髓毒性的潜在风险。在选择治疗方法时应考虑合并症； 舒尼替尼不推荐用于未控制的高血压患者, 依维莫司不推荐用于未控制的糖尿病患者。
转移性 3 级胃肠胰腺神经内分泌肿瘤的系统治疗建议:
先前针对1 级-2 级神经内分泌肿瘤的建议选项可推荐用于分化良好的3级胃肠胰腺肿瘤。
3级胃肠胰腺肿瘤是神经内分泌肿瘤中较新定义的类别, 包括广泛的 Ki-67 增殖指数范围（即 >20%）。
在某些病例（即 SSTR 阳性、疾病体积较小, 肿瘤相关症状低, 生长速度较慢）中，单独的生长抑素可以被视为一线治疗。 对于 SSTR 阳性患者, 肽受体放射性核素联合或不联合生长抑素都是一种潜在的治疗选择, 这些患者具有生长速度较慢, 仅接受生长抑素 治疗后病情进展较小等特点。 化疗对于具有较高增殖指数/有丝分裂率, 快速生长和体积大等特征的患者可能特别有效。 化疗对于胰腺神经内分泌肿瘤有效的证据最为有力。
For patients with well-differentiated metastatic grade 1-2 gastroenteropancreatic neuroendocrine tumorsselection of initial treatment regimen and sequence of treatments after progression should consider patient and tumor characteristics such as hormonal status, primary site, grade, disease extent and burden, growth rate, comorbidities, and somatostatin receptor (SSTR)status and cases be discussed within the multidisciplinary team whenever possible.
Baseline Scan: SSTR PET scan using 68Ga-DOTA peptide or 64Cu-DOTATATE to assess patients for SSTR positivity.
Systemic first-line systemic therapy for metastatic grade 1-2 gastrointestinal neuroendocrine tumors:
- Somatostatin analogs (octreotide or lanreotide) are recommended for SSTR-positive and/or functional tumors.
CT or MRI monitoring is performed every 3-6 months, and can be extended to 6-12 months for patients with consistently stable disease, can be considered in small-volume tumors without tumor burden symptoms, or functional tumors. For patients with bone metastases, SSTR-PET imaging is recommended for follow-up because CT has limited sensitivity for these metastases. The evidence supporting the use of somatostatin for tumor control is strongest in patients with low- or low- to moderate-grade SSTR-positive tumors (Ki-67 < 10%).
- For SSTR-negative patients, everolimus is a systemic treatment option.
Second-line or late-stage systemic therapy for metastatic grade 1-2 gastrointestinal neuroendocrine tumors:
- Peptide receptor radionuclides therapy is used in patients with SSTR-positive disease who have progressed after somatostatin therapy.
For functional tumors, it is recommended to continue somatostatin therapy in addition to peptide receptor radionuclide therapy. There are insufficient efficacy data to suggest that somatostatin should be continued in patients with nonfunctional tumors whose disease has progressed. Patients with small metastases should weigh the potential benefits of peptide receptor radionuclides therapy against the potential risk of long-term bone marrow toxicity.
- Everolimus is recommended for SSTR-negative or SSTR-positive non-functional patients.
The drug may also be considered as a late-stage treatment for functional tumors.
First-line systemic therapy for metastatic grade 1-2 pancreatic endocrine tumors:
- Somatostatin (octreotide or lanreotide) is recommended for SSTR-positive and/or functional tumors.CT or MRI may be considered every 3-6 months, extending to 6-12 months for patients with persistently stable disease, can be considered in small-volume tumors without tumor burden symptoms, or for functional tumors.
For patients with bone metastases, SSTR-PET imaging is recommended for follow-up because CT has limited sensitivity for these metastases. The evidence supporting the use of somatostatin for tumor control is strongest in patients with low- or low- to moderate-grade SSTR-positive tumors (Ki-67 < 10%).
- Chemotherapy (e.g., capecitabine and temozolomide) is recommended for patients with high tumor volume and/or symptoms related to tumor burden.
In rare cases, peptide receptor radionuclides therapy, or sunitinib or everolimus, are recommended for patients with SSTR-positive tumors who have high tumor volume and/or symptoms related to tumor burden and are not candidates for chemotherapy.
- For SSTR-negative patients, chemotherapy (e.g., capecitabine and temozolomide), everolimus, or sunitinib may be systemic treatment options.
Second-line or late-stage systemic therapy for metastatic grade 1-2 pancreatic neuroendocrine tumors:
Peptide receptor radionuclides therapy is used for SSTR-positive tumors. Chemotherapy (e.g., capecitabine and temozolomide), everolimus, or sunitinib are recommended for second-line or later-line treatment. Treatment choice depends on patient characteristics and treatment goals.
For functional tumors, it is recommended that somatostatin therapy be continued in addition to peptide receptor radionuclide therapy; there are insufficient efficacy data to suggest that somatostatin should be continued in patients with non-functional tumors whose disease has progressed. Patients with small metastases should weigh the potential benefits of peptide receptor radionuclide therapy against the potential risks of long-term bone marrow toxicity. Comorbidities should be considered when selecting treatment; sunitinib is not recommended in patients with uncontrolled hypertension, and everolimus is not recommended in patients with uncontrolled diabetes.
Systemic treatment recommendations for metastatic grade 3 gastroenteropancreatic neuroendocrine tumors:
Previously suggested options for grade 1-2 neuroendocrine tumors may be recommended for well-differentiated grade 3 gastroenteropancreatic tumors. Grade 3 gastroenteropancreatic tumors are a relatively newly defined category of neuroendocrine tumors and include a broad range of Ki-67 proliferation indices (i.e., >20%).
In certain cases (i.e., SSTR-positive, small disease volume, low tumor-related symptoms, slow growth rate), somatostatin alone may be considered first-line therapy.
Peptide receptor radionuclide therapy with or without somatostatin is a potential treatment option for SSTR-positive patients who have slow growth rates and slow disease progression after somatostatin treatment alone. Chemotherapy may be particularly effective in patients with characteristics such as high proliferation index/mitotic rate, rapid growth, and large size. The evidence for the effectiveness of chemotherapy is strongest for pancreatic neuroendocrine tumors.
参考文献 Reference
Del Rivero J et al. J Clin Onc 2023; 41: 5049
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个性化 mRNA 癌症疫苗与pembrolizumab联合用于黑色素瘤辅助治疗 (12/17/2023)
Personalized mRNA vaccine in combination with pembrolizumab in melanoma adjuvant therapy
mRNA-4157/V940 是一种基于mRNA 的个性化癌症疫苗，由编码多达 34 种新抗原的单一合成 mRNA 组成，该疫苗是根据患者 DNA 序列的独特突变设计的。 注入体内后，衍生的 RNA 编码的新抗原序列会进行内源翻译，并经历自然细胞抗原加工和呈递。
KEYNOTE-942 是一项正在进行的随机, 开放标签 IIb 期试验，入组了 157 名 III/IV 期黑色素瘤患者。 患者在肿瘤完全切除后被随机分配接受 mRNA-4157/V940（总共 9 剂 mRNA-4157）和 pembrolizumab（每三周 200 毫克，最多 18 个周期[约一年]）或单独接受 pembrolizumab约一年, 直至疾病复发或出现不可接受的毒性。 主要终点是无复发生存期，次要终点包括无远处转移生存期和安全性。
该试验达到了主要疗效终点: 与 pembrolizumab 单药辅助治疗相比，mRNA-4157/V940 与 pembrolizumab 联合治疗，将复发或死亡风险降低 44%（HR =0.56 [95% CI, 0.31-1.08]；单侧 p 值 =0.0266）。
在 KEYNOTE-942 中观察到的 mRNA-4157/V940 不良事件与之前在 1 期临床试验中报告的不良事件一致。Pembrolizumab 的安全性与之前报道的研究中观察到的结果一致。 接受 mRNA-4157/V940 和 pembrolizumab 联合治疗的患者中有 14.4% 发生严重的治疗相关不良事件，而单独接受 pembrolizumab 治疗的患者为 10%。
编者按：2023年5月13日，本专栏报道了个性化RNA新抗原疫苗可以刺激胰腺癌中的T细胞
mRNA-4157/V940 is a personalized, mRNA-based cancer vaccine composed of a single synthetic mRNA encoding up to 34 neoantigens, designed based on unique mutations in a patient’s DNA sequence. Once injected into the body, the derived RNA-encoded neoantigen sequences undergo endogenous translation and undergo natural cellular antigen processing and presentation.
KEYNOTE-942 is an ongoing, randomized, open-label phase IIb trial enrolling 157 patients with stage III/IV melanoma. Following complete resection, patients were randomly assigned to receive either mRNA-4157/V940 (nine doses of mRNA-4157 in total) and pembrolizumab (200 mg every three weeks for up to 18 cycles [approximately one year]) or pembrolizumab alone for one year until disease relapse or unacceptable toxicity. The primary endpoint is recurrence-free survival, and secondary endpoints include distant metastasis-free survival and safety.
The trial met its primary efficacy endpoint: mRNA-4157/V940 in combination with pembrolizumab reduced the risk of relapse or death by 44% compared with pembrolizumab alone (HR =0.56 [95% CI, 0.31-1.08]; one sided p-value=0.0266). The adverse events observed with mRNA-4157/V940 in KEYNOTE-942 were consistent with those previously reported in phase 1 clinical trials. The safety profile of pembrolizumab was consistent with results observed in previously reported studies. Serious treatment-related adverse events occurred in 14.4% of patients who received the combination of mRNA-4157/V940 and pembrolizumab, compared with 10% of patients who received pembrolizumab alone.
Editor’s note: on 5/13/2023 this column reported personalized RNA neoantigen vaccine can stimulate T-cells in pancreatic cancer.
参考文献 Reference
https://investors.modernatx.com/news/news-details/2022/Moderna-and-Merck-Announce-mRNA-4157V940-an-Investigational-Personalized-mRNA-Cancer-Vaccine-in-Combination-with-KEYTRUDAR-pembrolizumab-Met-Primary-Efficacy-Endpoint-in-Phase-2b-KEYNOTE-942-Trial/default.aspx
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新辅助化疗加纳武单抗联合或不联合伊匹单抗治疗可手术非小细胞肺癌 (12/16/2023)
Neoadjuvant chemotherapy plus nivolumab with or without ipilimumab in operable NSCLC
这是一项II期平台试验 (NEOSTAR. NCT03158129)的两个组的结果和相关性, 测试新辅助(术前)nivolumab + 化疗 和 ipilimumab + nivolumab + 化疗，以主要病理响应作为主要终点。
Nivolumab + 化疗 组的主要病理响应率为 32.1% [7/22，80% 置信区间 (CI) 18.7–43.1%]，ipilimumab + nivolumab + 化疗组的主要病理响应率率为 50%（11/22，80% CI 34.6–61.1%）。 两组均达到了主要终点, 比单独化疗产生更高的病理响应率。
在没有已知肿瘤 EGFR/ALK 改变的患者中, nivolumab + 化疗 组和 ipilimumab + nivolumab + 化疗 组的主要病理响应率率分别为 41.2% (7/17) 和 62.5% (10/16)。 两组均未观察到新的安全信号。 单细胞测序和多平台免疫分析（探索性终点）强调了免疫细胞群和表型, 包括效应记忆 CD8+ T, B细胞和骨髓细胞以及三级淋巴结构标记物, 这些细胞群和表型在 ipilimumab + nivolumab + 化疗队列中优先增加 。 主要病理响应患者的基线粪便微生物群富含有益菌群, 如阿克曼氏菌，但促炎微生物和致病微生物丰度减少。
新辅助 ipilimumab + nivolumab + 化疗可增强病理响应，值得在可手术非小细胞肺癌中进行进一步研究。
This is a report of the outcome and correlation of two arms of a phase II platform trial (NEOSTAR. NCT03158129), testing neoadjuvant (preoperative) nivolumab + chemotherapy and ipilimumab + nivolumab + chemotherapy, with major pathologic response as the primary endpoint.
The major pathological response rate was 32.1% [7/22, 80% confidence interval (CI) 18.7–43.1%] in the nivolumab + chemotherapy group and 50% (11/22, 18.7–43.1%) in the ipilimumab + nivolumab + chemotherapy group. 80% CI 34.6–61.1%). Both groups met the primary endpoint, inducing higher pathological response rates than chemotherapy alone.
Among patients without known tumor EGFR/ALK alterations, major pathological response rates were 41.2% (7/17) in the nivolumab + chemotherapy group and 62.5% (10/16) in the ipilimumab + nivolumab + chemotherapy group. No new safety signals were observed in either group. Single-cell sequencing and multi-platform immunoassays (exploratory endpoints) highlighted immune cell populations and phenotypes, including effector memory CD8+T, B cells and myeloid cells as well as tertiary lymphoid structural markers, that were preferentially increased in ipilimumab+ nivolumab + chemotherapy cohort. Baseline fecal microbiota of patients with a primary pathological response was rich in beneficial texa, such as Akkermansia spp., but had a reduced abundance of pro-inflammatory and pathogenic microorganisms.
Neoadjuvant ipilimumab + nivolumab + chemotherapy enhances pathologic response and warrants further study in operable NSCLC.
参考文献 Reference
Cascone T et al. Nature Med 2023; 29:593
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围手术期 Atezolizumab 加氟尿嘧啶, 亚叶酸, 奥沙利铂和多西他赛治疗可切除食管胃腺癌 (12/10/2023)
Perioperative atezolizumab plus fluorouracil, leucovorin, oxaliplatin, and docetaxel for resectable esophagogastric adenocarcinoma
该试验评估将 PD-L1 抗体 atezolizumab 添加到标准护理氟尿嘧啶, 亚叶酸, 奥沙利铂和多西他赛 (FLOT) 中作为可切除食管胃腺癌患者的围手术期治疗。
方法:最初这是多中心, 随机 II 期试验(DANTE/IKF-s633), 随后转变为 III 期试验。 以下是第二阶段的结果, 重点是手术病理学和安全性结果。可切除食管胃腺癌（≥ cT2 或 cN+）的患者被分配接受 4 个术前和术后周期的 FLOT 联合atezolizumab，然后接受 8 个周期的atezolizumab维持（A 组）或单独 FLOT（B 组）。
结果: 295 名患者被随机分配（A组，146名；B组，149名），各组之间基线特征平衡。 23 名患者 (8%) 的肿瘤具有微卫星不稳定性，58% 的患者的肿瘤 PD-L1 综合阳性评分 (CPS) ≥1。 两组之间的与手术相关发病率（A组，45%；B组，42%）和 60 天死亡率（A组，3%；B组，2%）相当。 分期降级均有利A组相对于 B 组（ypT0，23% 相对于 15% [单侧 P = .044]；ypT0-T2，61% 相对于 48% [单侧 P = .015]；ypN0，68% 相对于 54 % [单侧 P = .012])。 FLOT 加atezolizumab后组织病理学完全消退率（病理完全响应）A组更高（24%相对于15%; 单侧 P = 0.032），并且这种差异在 PD-L1 CPS ≥ 10（33％相对于12％）和微卫星不稳定性（63％相对于27％）亚群更大。 两组的完全无切缘 (R0) 切除率都较高（96%相对于95%）。 两组不良事件的发生率和严重程度相似。
结论: 在数据探索性的限制内，在围手术期 FLOT 中添加atezolizumab是安全的，并且可以改善术后分期和组织病理学消退率。
The trial evaluated the addition of the PD-L1 antibody atezolizumab to standard of care fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) as a perioperative treatment for patients with resectable esophagogastric adenocarcinoma.
Methods: Initially this was a multicenter, randomized phase II trial (DANTE/IKF-s633), subsequently converted to a phase III trial. The following was the results from the phase II portion, focusing on surgical pathology and safety outcomes. Patients with resectable esophagogastric adenocarcinoma (≥ cT2 or cN+) were assigned to receive 4 preoperative and postoperative cycles of FLOT plus atezolizumab, followed by 8 cycles of atezolizumab maintenance (arm A) or FLOT alone (arm B).
Results: 295 patients were randomly assigned (group A, 146; group B, 149), and baseline characteristics were balanced between groups. Twenty-three patients (8%) had tumors with microsatellite instability, and 58% had tumors with a PD-L1 combined positivity score (CPS) ≥1. Surgical morbidity (group A, 45%; group B, 42%) and 60-day mortality (group A, 3%; group B, 2%) were comparable between the two groups. Downstaging favored group A (ypT0, 23% versus 15% [one-sided P = .044]; ypT0-T2, 61% versus 48% [one-sided P = .015]; ypN0, 68 % versus 54% [one-sided P = .012]). The rate of complete histopathological regression (pathological complete response) after FLOT plus atezolizumab was higher in Arm A (24% vs. 15%; one-sided P = 0.032), and this difference was even more pronounced in PD-L1 CPS ≥ 10 (33% vs. 12%) and microsatellite instability (63% vs. 27%) subpopulations. Complete margin-free (R0) resection rate was higher in both groups (96% vs. 95%). The incidence and severity of adverse events were similar in both groups.
Conclusions: Within the limitations of the exploratory nature of the data, the addition of atezolizumab to perioperative FLOT is safe and improved postoperative staging and histopathological regression.
参考文献 Reference
Lorenzen S et al. J Clin Onc 2023; DOI: 10.1200/JCO.23.00975
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Tucatinib 和 Trastuzumab Emtansine 治疗 HER2 阳性转移性乳腺癌 (12/9/2023)
Combination of Tucatinib and Trastuzumab Emtansine for HER2+ breast cancer with brain metastases
这是一项III期临床试验（HER2CLIMB-02）。 Tucatinib (图卡替尼)是 HER2 的小分子抑制剂, 可以延缓中枢神经系统的疾病进展。该试验入组了 463 名患有不可切除, 局部晚期或转移性 HER2 阳性乳腺癌的患者，并随机分配接受 tucatinib 加 T-DM1 (n = 228) 或安慰剂加 T-DM1 (n = 235）。 在这些患者中, 44.1% 在基线时患有脑转移。 图卡替尼组患者疾病进展或死亡的中位时间为 9.5 个月，安慰剂组患者为 7.4 个月。 在基线时患有脑转移的患者中, 图卡替尼组疾病进展或死亡的中位时间为 7.8 个月，安慰剂组为 5.7 个月，经过中位 24.4 个月的随访后, 总体生存数据仍不成熟。
图卡替尼组患者中与治疗相关的副作用, 特别是与肝脏和胃肠功能相关的副作用的发生率高于安慰剂治疗组, 导致剂量调整和治疗中断的发生率更高。
This is a phase III clinical trial (HER2CLIMB-02). Tucatinib is a small molecule inhibitor of HER2 that can delay disease progression in the central nervous system. The trial enrolled 463 patients with unresectable, locally advanced or metastatic HER2-positive breast cancer. Patients were randomized to receive tucatinib plus T-DM1 (n = 228) or placebo plus T-DM1 (n = 235). . Among these patients, 44.1% had brain metastases at baseline. The median time to disease progression or death was 9.5 months in the tucatinib group and 7.4 months in the placebo group. Among patients with brain metastases at baseline, the median time to disease progression or death was 7.8 months in the tucatinib group and 5.7 months in the placebo group. After a median follow-up of 24.4 months, overall survival data still not mature.
The incidence of treatment-related side effects, particularly those related to liver and gastrointestinal function, was higher in the tucatinib group than in the placebo group, resulting in a higher incidence of dose adjustments and treatment interruptions.
参考文献 Reference
Hurvitz S et al. 2023 San Antonio Breast Cancer Symposium abstr GS 01-10
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Datopotamab deruxtecan治疗ER+/HER2- 晚期乳腺癌 (12/3/2023)
Datopotamab deruxtecan for ER+/HER2- advanced stage breast caner
方法: Datopotamab deruxtecan (Dato-DXd) 是一种TROP-2 导向的抗体药物偶联物。临床试验 TROPION-Breast01 入组了 732 名无法手术或转移性激素受体阳性, HER2 阴性乳腺癌患者，她们在内分泌治疗中疾病进展或不再适合内分泌治疗, 并且之前接受过1-2线化疗。 患者被随机分配接受每 3 周 6 mg/kg 的 Dato-DXd 治疗或研究者选择的化疗方案（艾日布林, 长春瑞滨, 吉西他滨, 卡培他滨）。 主要终点是进展生存期和总生存期。 中位随访时间为 10.8 个月。
结果: 在数据截止时，与标准化疗相比，仍在接受 Dato-DXd 治疗的患者数量大约是标准化疗的三倍，Dato-DXd 组的中位无进展生存期为 6.9 个月，而化疗组为 4.9 个月（风险比 [HR] = 0.63；P < .0001），在所有亚组中观察到一致的获益。 9 个月时无进展的患者为37.5% 相对于 18.7%，12 个月时分别为 25.5% 相对于 14.6%。 Dato-DXd 的响应率为 36.4%相对于化疗组的 22.9%。 总体生存率尚未成熟，但观察到有利于 Dato-DXd（HR = 0.84）的趋势。
Dato-DXd 展示了可管理的安全状况，没有新的安全信号。与对照组相比，干预组 ≥ 3 级不良事件的发生率较低（21% vs 45%），治疗中断率较低（12% vs 25%）。 同样，Dato-DXd 的治疗中断率较低（12% vs 25%），口腔粘膜炎或口腔炎导致一名接受 Dato-DXd 治疗的患者停止治疗。接受 Dato-DXd 治疗的 9 名患者 (3%) 有药物相关的间质性肺疾病，其中 2 名 ≥ 3 级病例中的 1 名后来归因于疾病进展。 一起治疗相关死亡发生在化疗组, 继发于发热性中性粒细胞减少症。
结论：数据支持 Dato-DXd 作为转移性激素受体阳性, HER2 阴性乳腺癌患者的潜在新治疗。
编者注：Dato-DXd 用于三阴性乳腺癌的数据见6/25/2022
Methods: Datopotamab deruxtecan (Dato-DXd) is a TROP-2-directed antibody drug conjugate. The clinical trial TROPION-Breast01 enrolled 732 patients with inoperable or metastatic hormone receptor-positive, HER2-negative breast cancer who had disease progression on endocrine therapy or were no longer eligible for endocrine therapy and who had received 1-2 lines of prior chemotherapy. Patients were randomly assigned to receive Dato-DXd at 6 mg/kg every 3 weeks or investigator’s choice of chemotherapy (eribulin, vinorelbine, gemcitabine, capecitabine). The primary endpoints were progression survival and overall survival. Median follow-up was 10.8 months. Results: At the time of data cutoff, approximately three times as many patients were still receiving Dato-DXd compared with standard chemotherapy, with a median progression-free survival of 6.9 months in the Dato-DXd group compared with chemotherapy. A consistent benefit was observed across all subgroups at 4.9 months (hazard ratio [HR] = 0.63; P < .0001). Progression-free rates were 37.5% versus 18.7% at 9 months and 25.5% versus 14.6% at 12 months. The response rate for Dato-DXd was 36.4% versus 22.9% in the chemotherapy group. Overall survival has not yet matured, but a trend in favor of Dato-DXd (HR = 0.84) was observed. Dato-DXd demonstrates a manageable security posture with no new security signals. Compared with the control group, the intervention group had a lower incidence of grade ≥ 3 adverse events (21% vs 45%) and a lower rate of treatment discontinuation (12% vs 25%). Likewise, treatment discontinuation rates were lower with Dato-DXd (12% vs 25%), with oral mucositis or stomatitis leading to treatment discontinuation in one patient receiving Dato-DXd. Nine patients (3%) who received Dato-DXd had drug-related interstitial lung disease, with 1 of 2 grade ≥3 cases later attributed to disease progression. One treatment-related death occurred in the chemotherapy group, secondary to febrile neutropenia. Conclusions: Data support Dato-DXd as a potential new treatment for patients with metastatic hormone receptor-positive, HER2-negative breast cancer.
Editor’s Note: Data on Dato-DXd in triple-negative breast cancer are available on 6/25/2022
参考文献 Reference
Bardia A. et al Annals Onc 2023: 34 (suppl_2): S1254
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Domvanalimab, zimberelimab 和 FOLFOX 一线治疗晚期胃食管癌 (12/2/2023)
Combination of domvanalimab, zimberelimab and FOLFOX as first line treatment for advanced gastric, GE junction and esophageal cancer
背景： 在化疗中添加程序性细胞死亡蛋白 1 (PD-1) 抑制剂可为一线胃食管癌带来生存优势。 然而，长期结果仍然不佳。 PD-1 和抗 T 细胞免疫球蛋白和 ITM 结构域 (TIGIT) 双重阻断可增加肿瘤抗原特异性 CD8+ T 细胞的扩增，从而产生有效的抗肿瘤活性。 正在进行的多臂全球 EDGE-胃试验 (NCT05329766) 正在评估抗 TIGIT Fc 沉默单克隆抗体 domvanalimab 和抗 PD-1 抗体 zimberelimab 的各种组合的安全性和有效性。患有局部晚期不可切除或转移性胃/胃食管交界处/食管腺癌的患者。 该报导显示了一线组的结果。
方法： 既往未经治疗的胃/胃食管交界处/食管腺癌的患者每 4 周接受domvanalimab 1600 mg 静脉注射 + 每 4 周zimberelimab 480 mg 静脉注射 + 每 2 周FOLFOX（奥沙利铂 85 mg/m2 静脉注射，亚叶酸 400 mg/m2 静脉注射，氟尿嘧啶 400 mg /m2 静脉推注 + 2400 mg/m2 连续 46-48 小时 静脉输注）。 主要终点是根据 RECIST 1.1 的安全性和客观响应率。 次要终点包括 PD-L1 表达的客观响应率和无进展生存率。
结果： 截至数据截止（2023 年 6 月 5 日），已有 41 名患者入组，并有机会进行 ≥ 2 次影像学评估。 亚洲与世界其他地区的患者分布均匀，63% 的患者患有胃癌。 中位治疗时间为 23 周（1 至 40 周），31 名患者 (76%) 继续接受方案治疗，研究中没有死亡病例。 意向治疗客观响应率为 59%（95% CI 42 至 74）。在PD-L1高表达（n=15, > 5%）, PD-L1低表达（n =24, < 5%）和总患者（n =41）中，确认的总体响应率 (95% CI)分别为 67% (38 至 88), 46% (26至 67) 和54% (37, 至 69)；六个月的无进展生存率 (95% CI) 分别为93% (81至 100), 66% (41至 91) 和75% (58至 92)。
最常见的治疗引起的不良事件是中性粒细胞减少症（56% 的患者）、恶心（54%）和贫血（27%）。 10% 的患者观察到输注相关反应，但没有一个反应与 domvanalimab/ zimberelimab 相关。 66% 的患者发生≥3 级不良事件，其中 54% 和 12% 的患者分别有与 FOLFOX 和 domvanalimab/zimberelimab 相关的 ≥3 级不良事件。 24% 的患者发生严重不良事件：7% 的患者出现与 FOLFOX 相关的严重不良事件，没有患者出现与domvanalimab /zimberelimab 相关的严重不良事件。 13 例 (32%) 患者因不良事件相关 FOLFOX 停药，1 例患者因domvanalimab /zimberelimab 停药。
结论： 在 FOLFOX 中添加 domvanalimab/zimberelimab 显示出令人鼓舞的客观响应率和早期无进展生存率，特别是在患有 PD-L1 高肿瘤的患者中。 该方案具有良好的耐受性，与抗 PD-1+FOLFOX 具有相似的不良事件特征。
具有 Ig 和 ITIM 结构域的 T 细胞免疫受体 (TIGIT) 是在多种类型的淋巴细胞上表达的抑制性受体。在多种癌症中，TIGIT在肿瘤浸润性细胞毒性T细胞, 辅助性T细胞, 调节性T细胞和NK细胞上表达，其主要配体CD155在肿瘤浸润性骨髓细胞上表达，并在癌细胞上表达上调，有助于局部抑制免疫监视。TIGIT 抗体阻断在癌症免疫治疗中的功效目前在临床研究中得到广泛研究。
Background: Adding programmed cell death protein 1 (PD-1) inhibitors to chemotherapy confers a survival advantage in first-line gastroesophageal cancer. However, long-term outcomes remain poor. Dual blockade of PD-1 and anti-T cell immunoglobulin and ITM domains (TIGIT) increases the expansion of tumor antigen-specific CD8+ T cells, resulting in potent antitumor activity. The ongoing multi-arm global EDGE-gastric trial (NCT05329766) is evaluating the safety and efficacy of various combinations of the anti-TIGIT Fc-silencing monoclonal antibody domvanalimab and the anti-PD-1 antibody zimberelimab. Participants had locally advanced unresectable or metastatic gastric/gastroesophageal junction/esophageal adenocarcinoma. The report showed the results of the first-line group.
Methods: Patients with previously untreated gastric/gastroesophageal junction/esophageal adenocarcinoma received domvanalimab 1600 mg IV every 4 weeks + zimberelimab 480 mg IV every 4 weeks + every two weeks FOLFOX (oxaliplatin 85 mg/ m2 intravenous injection, leucovorin 400 mg/m2 intravenous injection, fluorouracil 400 mg/m2 intravenous bolus + 2400 mg/m2 continuous intravenous infusion for 46-48 hours). The primary endpoints were safety and objective response rate according to RECIST 1.1. Secondary endpoints included objective response rate by PD-L1 expression and progression-free survival.
Results: As of data cutoff (June 5, 2023), 41 patients were enrolled and had the opportunity for ≥ 2 imaging evaluations. Patients were evenly distributed between Asia and the rest of the world, with 63% of patients had gastric cancer. The median duration of treatment was 23 weeks (range 1 to 40 weeks), 31 patients (76%) continued on protocol, and there were no deaths on the study. The intention-to-treat objective response rate was 59% (95% CI 42 to 74). In PD-L1 high expression (n =15, > 5%), PD-L1 low expression (n=24, <5%), and overall patients (n =41), the confirmed overall response rate (95% CI) was 67% (38 to 88), 46% (26 to 67), and 54% (37, to 69), respectively; six-month progression-free survival (95% CI) was 93% (81 to 100), 66% (41 to 91) and 75% (58 to 92) respectively.
The most common treatment-emergent adverse events were neutropenia (56% of patients), nausea (54%), and anemia (27%). Infusion-related reactions were observed in 10% of patients, but none were associated with domvanalimab/zimberelimab. Grade ≥3 adverse events occurred in 66% of patients, with 54% and 12% of patients having grade ≥3 adverse events related to FOLFOX and domvanalimab/zimberelimab, respectively. Serious adverse events occurred in 24% of patients: 7% of patients experienced serious adverse events related to FOLFOX and no patients experienced serious adverse events related to domvanalimab/zimberelimab. Thirteen patients (32%) discontinued FOLFOX due to adverse events and 1 patient discontinued domvanalimab/zimberelimab.
Conclusions: The addition of domvanalimab/zimberelimab to FOLFOX showed encouraging objective response rates and early progression-free survival, particularly in patients with PD-L1-high tumors. The regimen was well tolerated with a similar adverse event profile to anti-PD-1+FOLFOX.
T cell immunoreceptors with Ig and ITIM domains (TIGIT) are inhibitory receptors expressed on multiple types of lymphocytes. In a variety of cancers, TIGIT is expressed on tumor-infiltrating cytotoxic T cells, helper T cells, regulatory T cells, and NK cells, and its main ligand CD155 is expressed on tumor-infiltrating myeloid cells and upregulated on cancer cells, which contributes to local suppression of immune surveillance. Efficacy of TIGIT antibody blockade in cancer immunotherapy is currently being studied extensively in clinical studies.
参考文献 Reference
Janjigian YY et al. J Clin Oncol 2023; 41: suppl 36, abstr 433248
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IDE161 用于治疗晚期或转移性 BRCA1/2 突变雌激素受体+ 乳腺癌 (11/26/2023)
IDE161 for advanced or metastatic BRCA1/2/ER-positive breast cancer
FDA 已授予 IDE161 快速通道资格，用于治疗携带 BRCA1/2 突变的晚期或转移性激素受体阳, HER2 阴性乳腺癌成年患者，这些患者至少接受过 1 种激素治疗 (CDK4/6 抑制剂和 PARP抑制剂)。
IDE161 是一种有效的选择性多聚（ADP-核糖）糖水解酶 (PARG) 抑制剂。PARG 在与 PARP 相同的生化途径中调节 DNA 修复，导致细胞死亡。 作为首次人体 I 期试验的一部分，该药物的安全性和早期疗效正在同源重组缺陷 (HRD) 实体瘤患者中进行研究 (NCT05787587)。 该研究剂量递增部分的早期发现表明，外周血中 PAR 蛋白的剂量依赖性药效学调节表明 IDE161 靶标参与。此外，在几名患者中也观察到了初步的肿瘤缩小，包括患有 BRCA1/ 2的患者突变的子宫内膜癌和结肠癌。数据支持将试验扩展到优先肿瘤适应症，其中包括 HRD 阳性相关乳腺癌和卵巢癌以及其他实体瘤。FDA 还授予 IDE161 快速通道资格，用于治疗具有种系或体细胞 BRCA1/2 突变, 铂类耐药且之前接受过抗血管生成和 PARP 抑制剂治疗的晚期或转移性卵巢癌成年患者。
该试验入组参考: 参加者必须年满 18 岁，患有晚期或转移性实体瘤，并有 HRD 基因改变。其他关键纳入标准包括至少接受过 1 种标准线治疗后疾病进展。对于第一阶段的扩展部分，乳腺癌患者要患有雌激素受体阳性/HER2阴性疾病和HRD阳性。排除标准包括患有原发性中枢神经系统肿瘤; 胃肠道功能受损或可能影响 IDE161 吸收的胃肠道疾病； 活动性, 不受控制的感染；临床上心脏异常。 患者不能在入组后 4 周内接受过大手, 在入组前 2 周内接受过放, 在入组后 4 周内接受过全身细胞毒化, 在入组后 6 周内接受过放射免疫治疗, 在入组后 4 周内接受过治疗性抗体, 或在治疗的 5 个半衰期或 2 周内接受抗癌小分子。在剂量递增阶段，患者每天一次接受不同剂量的口服 IDE161 治疗。 该研究的主要终点包括剂量限制性毒性、治疗引起的毒性和实验室异常。 在剂量扩展阶段，总体响应率作为主要终点。剂量递增期间的总体响应率和药代动力学是次要终点。
FDA has granted Fast Track Designation to IDE161 for the treatment of adult patients with BRCA1/2-mutated advanced or metastatic hormone receptor-positive, HER2-negative breast cancer. They had received at least one line of hormonal therapy (CDK4/6 inhibitors or PARP inhibitors).
IDE161 is a potent and selective inhibitor of poly(ADP-ribose)glycohydrolase (PARG). PARG regulates DNA repair in the same biochemical pathway as PARP, leading to cell death. The drug’s safety and early efficacy are being studied in patients with homologous recombination deficient (HRD) solid tumors as part of a first-in-human phase I trial (NCT05787587). Early findings from the dose-escalation portion of the study demonstrated dose-dependent pharmacodynamic modulation of PAR proteins in peripheral blood suggesting engagement of the IDE161 target. Additionally, preliminary results showed tumor shrinkage observed in several patients, including those with BRCA1/2-mutated endometrial and colon cancers. Data support expansion of the trial into priority oncology indications, which include HRD-positive associated breast and ovarian cancers and other solid tumors. FDA also granted Fast Track designation to IDE161 for the treatment of adult patients with advanced or metastatic ovarian cancer who had germline or somatic BRCA1/2 mutations, were platinum-resistant and had received prior anti-angiogenic and PARP inhibitor therapy.
For those who plan to enroll in this trial: Participants must be 18 years or older, have advanced or metastatic solid tumors, and have HRD gene alterations. Other key inclusion criteria include disease progression after at least one standard line of therapy. For the phase 1 extension, breast cancer patients are required to have estrogen receptor-positive/HER2-negative disease and be HRD-positive. Exclusion criteria include having a primary central nervous system tumor; impaired gastrointestinal function or gastrointestinal disease that may affect IDE161 absorption; active, uncontrolled infection; and clinical cardiac abnormalities. Patients must not have received surgery within 4 weeks after enrollment, radiotherapy within 2 weeks before enrollment, systemic cytotoxicity within 4 weeks after enrollment, or radioimmunotherapy within 6 weeks after enrollment, received a therapeutic antibody within 4 weeks of enrollment, or received an anti-cancer small molecule within 5 half-lives or 2 weeks of treatment. During the dose-escalation phase, patients received varying doses of oral IDE161 once daily. The study’s primary endpoints include dose-limiting toxicities, treatment-emergent toxicities, and laboratory abnormalities. In the dose expansion phase, overall response rate served as the primary endpoint. Overall response rate and pharmacokinetics during dose escalation were secondary endpoints.
参考文献 Reference
https://media.ideayabio.com/2023-09-27-IDEAYA-Biosciences-Receives-Fast-Track-Designation-for-IDE161-in-a-Second-Indication-for-the-Treatment-of-Pretreated,-Advanced-or-Metastatic-HR-,-Her2-,-BRCA1-2-mutant-Breast-Cancer
https://clinicaltrials.gov/study/NCT05787587
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派姆单抗加化疗与安慰剂加化疗治疗 HER2 阴性晚期胃癌的比较 (11/25/2023)
A randomized study to compare pembrolizumab plus chemo versus placebo plus chemo in HER2-negative advanced gastric cancer
方法：KEYNOTE-859 (NCT03675737)是一项多中心, 双盲, 安慰剂对照, 随机, III 期试验，在 33 个国家的 207 个医疗中心进行。 符合资格的参与者之前未经治疗，经组织学或细胞学证实为局部晚期或转移性 HER2 阴性胃或胃食管交界部腺癌。患者被随机分配（1:1）接受派姆单抗或安慰剂 200 mg，每 3 周静脉注射一次，最多 35 个周期。 所有参与者均接受研究者选择的氟尿嘧啶（静脉注射，每天 800 mg/m2）在每个 3 周周期的第 1-5 天连续给药，加上顺铂（静脉注射，80 mg/m2）在每个 3 周周期的第 1 天给药 或卡培他滨（口服，1000 mg/m2）在每个 3 周周期的第 1-14 天每天两次给药，加上奥沙利铂（静脉注射，130 mg/m2）在每个 3 周周期的第 1 天给药。 随机化是使用中央交互式语音应答系统进行的，并按地理区域、PD-L1 状态和化疗进行分层，排列的块大小为 4。 主要终点是总体生存率，在意向治疗人群、PD-L1 综合阳性评分 (CPS) 为 1 或更高, PD-L1 CPS 为 10 或更高的人群中进行评估。 在接受治疗的人群中评估了安全性，其中包括所有随机分配的接受至少一剂研究干预的参与者。 中期分析的结果报告如下。
结果：2018 年 11 月 8 日至 2021 年 6 月 11 日期间，2,409 名筛选参与者中的 1,579 名 (66%) 被随机分配接受派姆单抗加化疗（派姆单抗组；n =790）或安慰剂加化疗（安慰剂组；n =789）。 大多数参与者为男性（派姆单抗联合化疗组 790 名参与者中有 527 名参与者 [67%]；安慰剂加化疗组 789 名参与者中有 544 名参与者 [69%]）和白人（426 名参与者 [54%]；435 名参与者 [55%]）。 数据截止时的中位随访时间为 31.0 个月 (IQR 23.0-38.3)。 在意向治疗人群中，派姆单抗组的中位总生存期比安慰剂组更长（12.9 个月 [95% CI 11.9-14.0] vs 11.5 个月 [10.6-12.1]； 风险比 [HR] 0.78 [95% CI 0.70-0.87]； p <0.0001) 。PD-L1 CPS 为 1 或更高的参与者（13.0 个月 [11.6- 14.2] vs 11.4 个月 [10.5-12.0]；0.74 [0.65-0.84]；p <0.0001），以及 PD-L1 CPS 为 10 的参与者 或更长（15.7 个月 [13.8-19.3] 对比 11.8 个月 [10.3-12.7]；0.65 [0.53-0.79]；p <0.0001） 。
最常见的任何原因的 3-5 级不良事件是贫血（派姆单抗组 785 名参与者中的 95 名 [12%]，安慰剂组 787 名参与者中 76 名 [10%]）和中性粒细胞计数减少（10% vs 8%）。 派姆单抗组有 184 名（23%）名参与者和安慰剂组有 146 名（19%）名参与者发生了严重的治疗相关不良事件。 派姆单抗组有 8 名 (1%) 参与者和安慰剂组有 16 名 (2%) 参与者发生治疗相关死亡。 没有发现新的安全信号。
解释：与安慰剂加化疗组的参与者相比，派姆单抗加化疗组的参与者的总生存期有了显著且有临床意义的改善，且毒性可控。 因此，派姆单抗联合化疗可能是局部晚期或转移性 HER2 阴性胃或胃食管交界腺癌患者的一线治疗选择。
Methods: KEYNOTE-859 (NCT03675737) was a multicenter, double-blind, placebo-controlled, randomized, phase III trial conducted at 207 medical centers in 33 countries. Eligible participants had previously untreated, histologically or cytologically confirmed locally advanced or metastatic HER2-negative gastric or gastroesophageal junction adenocarcinoma. Patients were randomly assigned (1:1) to receive pembrolizumab or placebo 200 mg intravenously every 3 weeks for up to 35 cycles. All participants received investigator’s choice of fluorouracil (IV, 800 mg/m2 daily) administered continuously on days 1-5 of each 3-week cycle, plus cisplatin (IV, 80 mg/m2) on day 1 of each 3-week cycle or capecitabine (oral, 1000 mg/m2) administered twice daily on days 1-14 of each 3-week cycle, plus oxaliplatin (intravenously, 130 mg/m2) administered on Day 1 of each 3-week cycle. Randomization was performed using a central interactive voice-response system and stratified by geographic region, PD-L1 status, and chemotherapy in a permuted block size of 4. The primary endpoint was overall survival, assessed in the intention-to-treat population, and the population with a PD-L1 composite positivity score (CPS) of 1 or greater, and a PD-L1 CPS of 10 or greater. Safety was assessed in the as-treated population, which included all randomly assigned participants who received at least one dose of the study intervention. The results of the interim analysis are reported below.
Results: Between November 8, 2018, and June 11, 2021, 1,579 (66%) of 2,409 screened participants were randomized to receive pembrolizumab plus chemotherapy (pembrolizumab group; n =790) or placebo plus chemotherapy (placebo group; n =789). Most participants were male (527 of 790 [67%] in the pembrolizumab plus chemotherapy group; 544 of 789 [69%] in the placebo plus chemotherapy group) and White (426 participants [54%]; 435 participants [55%]). Median follow-up at data cutoff was 31.0 months (IQR 23.0-38.3). In the intention-to-treat population, median overall survival was longer with pembrolizumab compared with placebo (12.9 months [95% CI 11.9-14.0] vs 11.5 months [10.6-12.1], hazard ratio [HR] 0.78 [95% CI 0.70-0.87]; p <0.0001); in participants with a PD-L1 CPS of 1 or higher (13.0 months [11.6-14.2] vs. 11.4 months [10.5-12.0]; 0.74 [0.65-0.84]; p <0.0001); participants with a PD-L1 CPS of 10 or greater (15.7 months [13.8-19.3] vs. 11.8 months [10.3-12.7]; 0.65 [0.53-0.79]; p <0.0001).
The most common grade 3-5 adverse events of any cause were anemia (95 of 785 participants [12%] in the pembrolizumab group and 76 of 787 participants [10%] in the placebo group) and Decreased neutrophil count (10% vs 8%). Serious treatment-related adverse events occurred in 184 (23%) participants in the pembrolizumab group and 146 (19%) in the placebo group. Treatment-related deaths occurred in 8 (1%) participants in the pembrolizumab group and 16 (2%) in the placebo group. No new safety signals were discovered.
Interpretation: Participants in the pembrolizumab plus chemotherapy group experienced a significant and clinically meaningful improvement in overall survival with manageable toxicity compared with participants in the placebo plus chemotherapy group. Therefore, pembrolizumab combined with chemotherapy may be a first-line treatment option for patients with locally advanced or metastatic HER2-negative gastric or gastroesophageal junction adenocarcinoma.
参考文献 Reference
Rha SY et al. Lancet Onc 2023; 24:1181
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苯达莫司汀治疗对接受嵌合抗原受体 T 细胞 (CAR-T) 治疗的大 B 细胞淋巴瘤预后产生负面影响 (11/19/2023)
Negative impact of bendamustine on CAR-T therapy in diffuse large B-cell lymphoma (DLBCL)
淋巴瘤治疗指南建议在血浆分离术前避免使用苯达莫司汀(bendamustine)，但这项建议缺乏具体数据。
方法: 该研究包括来自七个欧洲站点的 CAR-T 细胞接受者。 根据血浆分离前苯达莫司汀暴露分析安全性、有效性和 CAR-T 细胞扩增动力学。 对清除期和苯达莫司汀剂量的影响进行了额外的研究。 对苯达莫司汀暴露患者和未接触过苯达莫司汀的患者之间的所有疗效比较进行了逆概率治疗权重 (IPTW) 和倾向评分匹配 (PSM) 分析。
结果: 该研究纳入了 439 名接受 CD19 靶向商业 CAR T 细胞输注的难治性/复发性 DLBCL患者，其中 80 名患者在血浆分离术前接受了苯达莫司汀治疗。 暴露的患者在进行单采时 CD3+ 细胞和血小板显著降低。 与从未接受过苯达莫司汀组相比, 这些患者的总体响应率较低（53% vs 72%；P < .01），无进展生存期较短（3.1 vs 6.2 个月；P = .04），总生存期较短（10.3 vs 23.5 个月；P = .01)。 对基线变量调整后，这些差异得以缓解。重点关注单采术前苯达莫司汀洗脱期的影响，近期（< 9 个月）接触过苯达莫司汀的患者 (N = 42) 表现出较低的总体响应率 (40% vs 72%；P < .01)、较短的无进展生存期 (1.3 vs 6.2 个月；P < .01) 和总生存期 (4.6 vs 23.5 个月；P < .01) 。 经过 IPTW 和 PSM 分析后，这些差异仍然显著。 相反，血浆分离术前苯达莫司汀的累积剂量并不影响 CAR-T 疗效结果。
结论: 在血浆分离术前近期接触过接触苯达莫司汀与 CD19 靶向 CAR-T 细胞治疗后的较差的治疗结果相关，因此在 CAR-T 细胞候选者中应避免使用。
Consensus guidelines recommend avoiding bendamustine before apheresis, but specific data are lacking in this setting.
Methods: The study included CAR-T cell recipients from seven European sites. Safety, efficacy, and CAR-T cell expansion kinetics were analyzed according to bendamustine exposure prior to apheresis. Additional studies were conducted on the effect of washout period and bendamustine dose. Inverse probability treatment weighting (IPTW) and propensity score matching (PSM) analyses were performed for all efficacy comparisons between bendamustine-exposed and bendamustine-naïve patients.
Results: The study included 439 patients with relapsed/refractory DLBCL who received infusions of CD19-targeted commercial CAR T cells, 80 of whom received bendamustine before apheresis. Exposed patients had significant decreases in CD3+ cells and platelets while undergoing apheresis. Compared with the bendamustine-naïve group, these patients had a lower overall response rate (53% vs 72%; P < .01), shorter progression-free survival (3.1 vs 6.2 months; P = .04) and shorter overall survival (10.3 vs 23.5 months; P = .01). These differences were mitigated after adjustment for baseline variables. Focusing on the impact of the bendamustine washout period before apheresis, patients with recent (< 9 months) exposure to bendamustine (n = 42) showed a lower overall response rate (40% vs 72%; P < .01), shorter progression-free survival (1.3 vs 6.2 months; P < .01) and overall survival (4.6 vs 23.5 months; P < .01). These differences remained significant after IPTW and PSM analyses. In contrast, the cumulative dose of bendamustine before apheresis did not affect CAR-T efficacy outcomes.
Conclusions: Recent exposure to bendamustine before apheresis is associated with negative treatment outcomes after CD19-targeted CAR-T cell therapy and should be avoided in CAR-T cell candidates.
参考文献 Reference
Jacoboni G et al. J Clin Onc 2023: DOI: 10.1200/JCO.23.01097
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一线治疗RET 融合阳性非小细胞肺癌: Selpercatinib 相对于化疗+/- pembrolizumab (11/18/2023)
First line selpercatinib vs chemotherapy +/- pembrolizumab in RET fusion-positive NSCLC
方法: 一项随机 III 期试验(NCT04194944)中，评估了一线 selpercatinib 与对照治疗的疗效和安全性，对照治疗由研究者自行决定铂类化疗联合或不联合派姆单抗。 主要终点是在意向治疗派姆单抗人群（即，如果患者被分配到对照组时，医生计划用派姆单抗治疗的患者）和总体意向治疗人群的无进展生存期 。 如果在接受对照治疗期间发生疾病进展，则允许从对照组交叉到selpercatinib组。
结果: 总共有 212 名患者在意向治疗派姆单抗人群中接受了随机分组。 在预先计划的中期疗效分析时，selpercatinib 组的中位无进展生存期为 24.8 个月（95% 置信区间 [CI]，16.9 至不可估计），而对照治疗组的中位无进展生存期为 11.2 个月（95% CI，8.8 至 16.8）。 进展或死亡的风险比，0.46；95% CI，0.31至0.70；P <0.001）。 Selpercatinib 组获得客观响应的患者比例为 84%（95% CI，76 至 90），对照治疗组为 65%（95% CI，54 至 75）。 影响中枢神经系统的进展时间的特定原因风险比为 0.28（95% CI，0.12 至 0.68）。 总体意向治疗人群（261 名患者）的疗效结果与意向治疗派姆单抗人群相似。 Selpercatinib 和对照治疗发生的不良事件与之前报道的一致。
结论: 在晚期 RET 融合阳性 NSCLC 患者中，与含或不含派姆单抗的铂类化疗相比，selpercatinib 治疗可显著延长无进展生存期。
Methods: This randomized phase III trial (ClinicalTrials.gov number, NCT04194944) evaluated the efficacy and safety of first-line selpercatinib versus control treatment with platinum-based chemotherapy with or without pembrolizumab at the investigator’s discretion. The primary endpoint was progression-free survival in the intention-to-treat pembrolizumab population (i.e., patients whose physicians had planned to treat them with pembrolizumab in the event that they were assigned to the control group) and the overall intention-to-treat population. Crossover from the control arm to the selpercatinib arm was allowed if disease progression occurred while receiving control treatment.
Results: A total of 212 patients underwent randomization in the intention-to-treat pembrolizumab population. At the time of the preplanned interim efficacy analysis, the median progression-free survival was 24.8 months (95% confidence interval [CI], 16.9 to not estimable) in the selpercatinib arm and 11.2 months in the control arm (95% CI, 8.8 to 16.8). Hazard ratio for progression or death, 0.46; 95% CI, 0.31 to 0.70; P <0.001). The proportion of patients who achieved an objective response was 84% (95% CI, 76 to 90) in the selpercatinib group and 65% (95% CI, 54 to 75) in the control group. The cause-specific hazard ratio for time to progression affecting the central nervous system was 0.28 (95% CI, 0.12 to 0.68). Efficacy results in the overall intention-to-treat population (261 patients) were similar to those in the intention-to-treat pembrolizumab population. Adverse events that occurred with selpercatinib and control treatments were consistent with those previously reported.
Conclusions: In patients with advanced RET fusion-positive NSCLC, treatment with selpercatinib significantly prolonged progression-free survival compared with platinum-based chemotherapy with or without pembrolizumab.
参考文献 Reference
Zhou C et al. N Engl J Med 2023; 389:1839
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从母乳中检测早期乳腺癌(11/12/2023)
Identifying circulating tumor DNA in breast milk
与其他乳腺癌相比，妊娠期和产后发生的乳腺癌通常在更晚的阶段被诊断出来，从而导致其预后恶化。研究者首次报道从乳腺癌患者收集的母乳中存在无细胞肿瘤 DNA (ctDNA)。使用NGS和液滴数字PCR两种技术分析了乳腺样本和血液样本。对母乳 ctDNA 进行分析，检测出 87% 病例中的肿瘤变异，而在 92% 的匹配血浆样本中仍未检测到变异。母乳 ctDNA 回顾性下一代测序分析概括了肿瘤变异，总体临床敏感性为 71.4%，特异性为 100%。 在两个病例中，在标准诊断前 18 个月和 6 个月收集的母乳中可检测到 ctDNA。 这项结果开辟了母乳作为产后发生的乳腺癌检测的潜在用途。
Breast cancers arising during pregnancy and postpartum are often diagnosed at a later stage than other breast cancers, leading to a wors prognosis. Researchers report for the first time the presence of cell-free tumor DNA (ctDNA) in breast milk collected from breast cancer patients. Blood and breast milk samples were analyzed using NGS and droplet digital PCR techniques. Analysis of breast milk ctDNA detected tumor variants in 87% of cases, while variants remained undetected in 92% of matched plasma samples. Retrospective next-generation sequencing analysis of breast milk ctDNA recapitulated tumor variants with an overall clinical sensitivity of 71.4% and specificity of 100%. In two cases, ctDNA was detectable in breast milk collected 18 and 6 months before standard diagnosis. The results opened up the potential use of breast milk as a test for breast cancer that occurs in the postpartum period.
参考文献 Reference
Saura C et al. Cancer Discovery 2023; 13:2180
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Patritumab Deruxtecan 用于EGFR突变的治疗后进展的非小细胞肺癌 (NSCLC) (11/11/2023)
Patritumab Deruxtecan in EGFR-mutated non-small-cell lung cancer (NSCLC) that progressed after target and chemotherapy
Patritumab deruxtecan 或 HER3-DXd 是一种抗体-药物缀合物，由人表皮生长因子受体(EGFR) 3 (HER3) 的单克隆抗体组成，通过可裂解接头连接到拓扑异构酶 I 抑制剂。 研究者评估了 HER3-DXd 对EGFR突变的NSCLC 患者的疗效和安全性。
方法: 这项 II 期研究（HETHENA-Lung01, NCT04619004）旨在评估HER3-DXd治疗先前接受 EGFR 酪氨酸激酶抑制剂 (TKI) 治疗和铂类化疗治疗的晚期 EGFR 突变 NSCLC 患者。 患者每 3 周静脉注射一次 HER3-DXd 5.6 mg/kg 或接受增量方案 (3.2 → 4.8 → 6.4 mg/kg)。 主要终点是客观响应率，基于历史数据的零假设为26.4%。
结果: 根据 I 期试验数据的预先指定的获益/风险评估，上调组的招募提前结束。 总共有 225 名患者每 3 周接受一次 HER3-DXd 5.6 mg/kg 治疗。 截至 2023 年 5 月 18 日，中位研究持续时间为 18.9 个月（范围 14.9-27.5）个月。响应率为 29.8%（95% CI，23.9 至 36.2）； 中位响应持续时间为 6.4 个月； 中位无进展生存期，5.5 个月； 中位总生存期为 11.9 个月。 既往接受过奥希替尼和铂类化疗治疗的患者亚组具有相似的结果。 在不同的治疗前肿瘤 HER3 膜表达水平和不同的 EGFR TKI 耐药机制中观察到了疗效。 在基线时未接受放射治疗的脑转移患者 (n = 30) 中，CNS客观响应率为 33.3%（95% CI，17.3 至 52.8）。
安全性是可管理和可容忍的，与之前的观察结果一致。
结论: 在 EGFR 突变 NSCLC 患者中采用 EGFR TKI 治疗和铂类化疗治疗肿瘤进展后，每 3 周一次的 HER3-DXd 证明了具有临床意义的疗效和持久反应，包括 CNS 转移。 一项针对 EGFR TKI 治疗后出现进展的 EGFR 突变 NSCLC 的 III 期试验正在进行。
Patritumab deruxtecan, or HER3-DXd, is an antibody-drug conjugate consisting of a monoclonal antibody to human epidermal growth factor receptor (EGFR) 3 (HER3) linked to a topoisomerase I inhibitor via a cleavable linker. Researchers evaluated the efficacy and safety of HER3-DXd in patients with EGFR-mutated NSCLC.
Methods: This phase II study (HETHENA-Lung01, NCT04619004) was designed to evaluate HER3-DXd in patients with advanced EGFR-mutant NSCLC previously treated with an EGFR tyrosine kinase inhibitor (TKI) and platinum-based chemotherapy. Patients received HER3-DXd 5.6 mg/kg intravenously every 3 weeks or received an incremental regimen (3.2 → 4.8 → 6.4 mg/kg). The primary endpoint was objective response rate, with the null hypothesis based on historical data being 26.4%.
Results: Enrollment in the up-titration arm ended early based on prespecified benefit/risk assessment of phase I trial data. A total of 225 patients received HER3-DXd 5.6 mg/kg every 3 weeks. As of May 18, 2023, the median study duration was 18.9 months (range 14.9-27.5) months. The response rate was 29.8% (95% CI, 23.9 to 36.2); the median duration of response, 6.4 months; the median progression-free survival, 5.5 months; and the median overall survival, 11.9 months. Similar results were seen in the subgroup of patients previously treated with osimertinib and platinum-based chemotherapy. Efficacy was observed across different pretreatment tumor HER3 membrane expression levels and diverse mechanisms of EGFR TKI resistance. Among patients with brain metastases who did not receive radiation therapy at baseline (n = 30), the objective CNS response rate was 33.3% (95% CI, 17.3 to 52.8). Safety was manageable and tolerable, consistent with previous observations.
Conclusions: HER3-DXd every 3 weeks demonstrated clinically meaningful efficacy and durable responses, including CNS metastases, after tumor progression with EGFR TKI therapy and platinum-based chemotherapy in patients with EGFR-mutated NSCLC. A phase III trial is ongoing in EGFR-mutated NSCLC that has progressed on EGFR TKI therapy.
参考文献 Reference
Yu HA et al J Clin Onc 2023; DOI: 10.1200/JCO.23.01476
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绝经前双侧卵巢切除术对身体衰老和慢性疾病的长期影响 (11/5/2023)
Impact of premenopausal bilateral oophorectomy on physical aging and chronic medical conditions
方法: 研究者招募了 274 名有绝经前双侧卵巢切除术（PBO）病史的女性(无论同时或之前进行了子宫切除术)，以及 240 名年龄在 55 岁及以上, 明尼苏达州居民的参考对象。 通过病历摘要评估慢性病。 认知诊断基于神经认知测试。 身体功能评估包括力量和活动能力的测量。 多变量回归模型比较了 PBO <46 岁女性、PBO 46-49 岁女性以及参照女性的特征，并调整了年龄和其他混杂因素。
结果: 中位临床就诊（中位年龄 67 岁）为 PBO 或索引日期后的22 年。 在 274 名有 PBO 病史的女性中，161 名 (59%) 的 PBO 年龄 <46 岁，113 名 (41%) 的年龄为 46-49 岁。 与参考对象相比，PBO病史 <46年的女性患关节炎（比值比[OR]，1.64；95%置信区间[CI]，1.06-2.55）、哮喘（OR，1.74；95% CI， 1.03–2.93）、阻塞性睡眠呼吸暂停（OR，2.00；95% CI，1.23–3.26）和骨折（OR，2.86；95% CI，1.17–6.98），以及 6 分钟步行平均距离较短 步行测试（b = -18.43；P = 0.034）。 与参考对象相比，46-49岁有PBO病史的女性患关节炎（OR，1.92；95% CI，1.16-3.18）和阻塞性睡眠呼吸暂停（OR，2.21；95% CI，1.33-3.66）的机率增加 ）。 与参照者相比，PBO 病史女性的认知状态没有显著差异。
结论: 与参考对象相比，有 PBO 病史的女性，尤其是年龄 <46 岁的女性，在中年后期患有更多慢性病。
Methods: Researchers recruited 274 women with a history of premenopausal bilateral oophorectomy (PBO) (either concomitant or prior hysterectomy) and 240 reference subjects who were Minnesota residents aged 55 years and older. . Chronic conditions were assessed through medical record abstracts. Cognitive diagnosis is based on neurocognitive testing. Physical function assessment includes measurements of strength and mobility. Multivariable regression models compared characteristics of women with PBO <46 years, women with PBO 46–49 years, and reference women, adjusting for age and other confounders.
Results: The clinical visits (median age, 67 years) were a median of 22 years after the PBO or index date. Among 274 women with a history of PBO, 161 (59%) had PBO aged <46 years and 113 (41%) were aged 46–49 years. Compared with reference subjects, women with a history of PBO <46 years were more likely to have arthritis (odds ratio [OR], 1.64; 95% confidence interval [CI], 1.06-2.55), asthma (OR, 1.74; 95% CI, 1.03– 2.93), obstructive sleep apnea (OR, 2.00; 95% CI, 1.23–3.26), and fractures (OR, 2.86; 95% CI, 1.17–6.98), as well as shorter mean 6-minute walking distance on the walk test (b = -18.43; P = 0.034). Compared with reference subjects, women aged 46 to 49 years with a history of PBO had arthritis (OR, 1.92; 95% CI, 1.16 to 3.18) and obstructive sleep apnea (OR, 2.21; 95% CI, 1.33 to 3.66). probability increases). There were no significant differences in cognitive status among women with a history of PBO compared with controls.
Conclusions: Women with a history of PBO, especially those aged <46 years, have more chronic medical conditions in late middle age compared with reference subjects.
参考文献 Reference
M Mielke et al. Menopause2 023; 30: 1090
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九周相对于一年曲妥珠单抗治疗早期HER 2 阳性乳腺癌：10 年随访结果 (11/4/2023)
Nine-week versus one-year trastuzumab for early HER2–positive breast cancer: 10-year update
这是 III 期非劣效性随机 ShortHER 试验的最终分析，该试验比较了HER2 阳性早期乳腺癌患者的 9 周与 1 年辅助曲妥珠单抗联合化疗。 患者被随机分配接受蒽环类-紫杉烷组合加 1 年曲妥珠单抗治疗（长臂）或 9 周曲妥珠单抗治疗（短臂）。 在这里，研究者报告了主要终点总生存期, 更新的无病生存期以及根据激素受体状态, 年龄和淋巴结状态的结果。
中位随访时间为 9 年，长臂和短臂的 10 年无病生存期分别为 77% 和 78%。 长臂和短臂的 10 年总生存率分别为 89% 和 88%。 根据淋巴结状态，长臂与短臂的 10 年无病生存率分别为 N0 (淋巴结阴性)81% 与 85%； N1-3 (1-3个淋巴结阳性)77% 对比 79%； N4+ (> 4个淋巴结阳性)63% 对 53%。 根据淋巴结状态，长臂与短臂的十年总生存率分别为 N0 89% 和 95%%； N1-3 92% 对比 89%； N4+ 84% 对 64%。
ShortHER 试验的最新分析表明，1 年曲妥珠单抗是 HER2+ 早期 BC 患者的标准治疗，因为不能声称非劣效性。 然而，从数字上看，低风险或中风险 (N0/N1-3) 患者的差异可以忽略不计，而 N4+ 患者使用 1 年曲妥珠单抗可明显受益。
This is the final analysis of the phase III non-inferiority randomized ShortHER trial, which compared 9 weeks with 1 year of adjuvant trastuzumab plus chemotherapy in patients with HER2-positive early breast cancer. Patients were randomly assigned to receive an anthracycline-taxane combination plus 1 year of trastuzumab treatment (long arm) or 9 weeks of trastuzumab treatment (short arm). Investigators reported the co-primary endpoints of overall survival, updated disease-free survival, and outcomes according to hormone receptor status, age, and nodal status.
With a median follow-up of 9 years, 10-year disease-free survival was 77% in the long arm and 78% in the short arm. The 10-year overall survival rates were 89% and 88% in the long arm and short arm, respectively. According to lymph node status, the 10-year disease-free survival rates in the long arm versus the short arm were 81% versus 85% for N0 (lymph node-negative); 77% versus 79% for N1-3 (1-3 positive lymph nodes); and 63% versus 53% for N4+ (> 4 positive lymph nodes) .
Ten-year overall survival rates based on nodal status were N0 89% in the long arm vs. 95% in the short arm; N1-3 92% vs. 89%; N4+ 84% vs. 64%.
Updated analysis of the ShortHER trial suggests that 1 year of trastuzumab is the standard of care for patients with HER2+ early-stage breast cancer because non-inferiority cannot be claimed. However, numerically, the difference was negligible in low- or intermediate-risk (N0/N1-3) patients, whereas N4+ patients clearly benefited from 1 year of trastuzumab.
参考文献 Reference
Conte P et al. J Clin Onc 2023; DOI: 10.1200/JCO.23.00790
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高剂量甲氨蝶呤是否可以作为高危性 B 细胞淋巴瘤的中枢神经系统预防 (10/31/2023)
Is high-dose methotrexate as CNS prophylaxis effective in high-risk B-cell lymphoma
这项研究旨在确定高剂量甲氨蝶呤 (HD-MTX) 是否能有效预防高危侵袭性 B 细胞淋巴瘤患者的中枢神经系统进展或复发。
方法 这项国际回顾性观察性研究纳入了年龄为 18-80 岁、患有侵袭性 B 细胞淋巴瘤且中枢神经系统进展风险较高的患者，他们接受了基于抗 CD20 的化学免疫疗法的治疗。
根据 HD-MTX 的使用计算 CNS 进展的具体原因风险比 (HR) 和累积风险，根据所有患者的诊断和完成一线系统性淋巴瘤诱导治疗计算 CNS 进展时间， 适用于化学免疫治疗完成后完全缓解的患者。
结果: 研究包括 2,418 名所有患者 (HD-MTX；n = 425) 和 1,616 名完全缓解患者 (HD-MTX；n = 356)。 CNS 国际预后指数在 83.4% 的受访者中为 4-6。 使用 HD-MTX 治疗的患者 CNS 进展风险较低（调整后 HR，0.59 [95% CI，0.38 至 0.90]；P = 0.014），但当仅限于完全缓解患者时，意义不保留（调整后 HR，0.74） [95% CI，0.42 至 1.30]；P = .29），5 年调整后风险差异为 1.6%（95% CI，–1.5 至 4.4；所有患者）和 1.4%（95% CI，–1.5-4.1; 完全缓解患者）。 亚组无力就 HD-MTX 在个别高风险临床情况中的疗效得出明确的结论； 然而，在任何高风险亚组中，HD-MTX 均未明显降低 CNS 进展风险 。
结论: 在这项大型研究中，接受 HD-MTX 的高危患者的 2 年 CNS 进展风险为 7.2%，与之前报道的高风险队列中的进展风险一致。使用 HD-MTX 与中枢神经系统进展风险的临床意义降低无关。
This study aimed to determine whether high-dose methotrexate (HD-MTX) is effective in preventing central nervous system progression or relapse in patients with high-risk aggressive B-cell lymphoma.
Methods: This international retrospective observational study included patients aged 18–80 years with aggressive B-cell lymphoma at high risk for central nervous system progression who were treated with anti-CD20-based chemoimmunotherapy.
Cause-specific hazard ratios (HRs) and cumulative risks of CNS progression were calculated based on HD-MTX use, with time to CNS progression calculated from diagnosis for all patients and from completion of frontline systemic induction therapy, for patients in completer remission at completion of chemoimmunotherapy.
Results: The study included 2,418 all patients (HD-MTX; n = 425) and 1,616 patients with complete responses (HD-MTX; n = 356).
The CNS International Prognostic Index was 4-6 in 83.4% of respondents. Patients treated with HD-MTX had a lower risk of CNS progression (adjusted HR, 0.59 [95% CI, 0.38 to 0.90]; P = 0.014), but significance was not retained when restricted to patients with complete responses (adjusted HR, 0.74) [95% CI, 0.42 to 1.30]; P = .29), with a 5-year adjusted risk difference of 1.6% (95% CI, –1.5 to 4.4; all patients) and 1.4% (95% CI, –1.5 to 4.1; patients in complete remission). Subgroups were underpowered to draw definite conclusions regarding the efficacy of HD-MTX in individual high-risk clinical situations; however, HD-MTX did not significantly reduce the risk of CNS progression in any of the high-risk subgroups.
Conclusions In this large study, the 2-year risk of CNS progression in high-risk patients receiving HD-MTX was 7.2%, consistent with previously reported risks of progression in high-risk cohorts. Use of HD-MTX was not associated with a clinically meaningful reduction in risk of CNS progression
参考文献 Reference
Lewis KL et al. J Clin Onc published Oct. 5, 2023. DOI: 10.1200/JCO.23.00365
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检查点抑制剂对 EGFR 突变肺癌疾病进展后的疗效 (10/22/2023)
Checkpoint inhibitor offered limited benefit in EGFR-mutated lung cancer following disease progression
ILLUMINATE 是一项 II 期试验，评估了抗 PD-L1 药物 durvalumab 与抗 CTLA-4 抗体 tremelimumab 双重检查点抑制, 用于患有转移性 EGFR 突变型肺癌的患者在接受 EGFR 酪氨酸激酶抑制剂治疗(TKI)后疾病进展，该组合并联合化疗。
中位随访 22 个月后，队列 1 的未经证实的客观响应率为 42%，队列 2 为 35%。确认的响应率分别为 31% 和 21%，疾病控制率分别为 88% 和 75%。 队列 1 的中位无进展生存期为 6.5 个月，队列 2 的中位无进展生存期为 4.9 个月。
在队列 1 中，PD-L1 表达≥ 50% 的患者的中位无进展生存期为 13.1 个月，而 PD-L1 表达< 50% 的患者的中位无进展生存期为 4.8 个月 (P = .0044)。 在队列 2 中，EGFR T790M 突变疾病患者的 PD-L1 表达没有显著差异。没有观察到根据 EGFR 突变类型的无进展生存期差异。
两个队列之间的 3 级或 4 级免疫相关不良事件也没有显著差异，
检查点抑制剂对于具有 EGFR 突变且在标准治疗中出现疾病进展的晚期非小细胞肺癌患者益处甚少
ILLUMINATE is a phase II trial evaluating dual checkpoint inhibition with the anti-PD-L1 durvalumab and the anti-CTLA-4 antibody tremelimumab in metastatic EGFR-mutant lung cancer patients who received EGFR tyrosine kinase inhibitors and had disease progression on TKI. The immunotherapy was combined with chemotherapy. The trial enrolled adults from 10 Australian and 6 Taiwanese sites. The patients had exhausted all EGFR TKI treatments. There were two groups of patients: Group 1 (n = 50): tissue and plasma EGFR exon 20 T790M negative; disease progression after first-line osimertinib treatment or single-line first- or second-generation TKI treatment; Group 2 (n = 50): tissue and/or plasma positive for EGFR exon 20 T790M; disease progression on third generation EGFR TKI (ie, osimertinib). Participants received four cycles of 1,500 mg durvalumab and 75 mg tremelimumab plus platinum/pemetrexed chemotherapy every 3 weeks, followed by 1,500 mg durvalumab and 500 mg/m2 pemetrexed every 4 weeks maintenance treatment until disease progression or intolerance to treatment. The primary endpoint was objective response rate. The majority of patients were female (64%), and the median patient age was 60 years. Most patients were Asian (77%) and never smoked (73%). EGFR exon 19 deletions were detected in 57% of tumors and exon 21 L858R deletions were detected in 42% of tumors. Forty-seven patients had PD-L1 status <50% and 12% had ≥50%.
After a median follow-up of 22 months, the unconfirmed objective response rate was 42% in cohort 1 and 35% in cohort 2. Confirmed response rates were 31% and 21%, respectively. Disease control rates were 88% and 75%, respectively. The median progression-free survival was 6.5 months in cohort 1 and 4.9 months in cohort 2. In cohort 1, patients with PD-L1 expression ≥50% had a median progression-free survival of 13.1 months, compared with 4.8 months in patients with PD-L1 expression <50% (P = .0044). In cohort 2, there was no significant difference in PD-L1 expression. Among patients with EGFR T790M mutant, no differences in progression-free survival according to EGFR mutation type were observed.
There was no significant difference in grade 3 or 4 immune-related adverse events between the two cohorts, and the safety profile was consistent with the known toxicities of chemoimmunotherapy for advanced lung cancer.
The trial showed that checkpoint inhibitors had little benefit in patients with advanced non-small cell lung cancer who have EGFR mutations and have progressed on standard treatments.
参考文献 Reference
Lee C et al.2023 World Conference on Lung Cancer. Abstract OA09.04.
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Pirtobrutinib用于共价 BTK 抑制剂后治疗慢性淋巴细胞白血病/小淋巴细胞淋巴瘤 (10/14/2023)
Pirtobrutini used after covalent BTK inhibitors in CLL/SLL
Pirtobrutinib 是一种高选择性, 非共价（可逆性）BTK 抑制剂，旨在重建 BTK 抑制。
方法: 这是一项 I-II 期试验(NCT03740529)，研究者报告了先前接受过 BTK 抑制剂的慢性淋巴细胞白血病(CLL)或小淋巴细胞淋巴瘤(SLL)患者的疗效结果以及所有 CLL 或 SLL 患者的安全性结果。 主要终点是经独立审查评估的总体响应（部分响应或更好）。 次要终点包括无进展生存期和安全性。
结果: 共有 317 名 CLL 或 SLL 患者接受了 pirtobrutinib，其中 247 名患者之前接受过 BTK 抑制剂治疗。 在这 247 名患者中，既往治疗次数中位数为 3 次（范围为 1 至 11 次），100 名患者 (40.5%) 还接受过 B 细胞淋巴瘤 2 (BCL2) 抑制剂，如venetoclax。 对Pirtobrutinib总体响应的患者百分比为 73.3%（95% 置信区间 [CI]，67.3 至 78.7），当包括淋巴细胞增多的部分响应时，该百分比为 82.2%（95% CI，76.8 至 86.7）。 中位无进展生存期为 19.6 个月（95% CI，16.9 至 22.1）。
在接受Pirtobrutinib治疗的所有 317 名 CLL 或 SLL 患者中，最常见的不良事件是感染（71.0%）、出血（42.6%）和中性粒细胞减少（32.5%）。 在中位治疗持续时间为 16.5 个月（范围为 0.2 至 39.9）时，一些通常与 BTK 抑制剂相关的不良事件发生相对较少，包括高血压（14.2% 的患者）、心房颤动或心房扑动（3.8%） 和大出血（2.2%）。 317 名患者中只有 9 名 (2.8%) 由于治疗相关不良事件而停用了Pirtobrutinib。
结论: 在这项试验中，pirtobrutinib 对接受过共价 BTK 抑制剂治疗的 CLL 或 SLL 患者显示出疗效。 最常见的不良事件是感染、出血和中性粒细胞减少。
Pirtobrutinib is a highly selective, non-covalent (reversible) BTK inhibitor designed to reestablish BTK inhibition.
Methods: This is a phase I-II trial (NCT03740529) reporting efficacy results in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who previously received a BTK inhibitor and all safety outcomes in all patients with CLL or SLL. The primary endpoint was overall response (partial response or better) as assessed by independent review. Secondary endpoints included progression-free survival and safety.
Results: A total of 317 patients with CLL or SLL received pirtobrutinib, 247 of whom had previously received a BTK inhibitor. Of the 247 patients, the median number of prior treatments was three (range, 1 to 11), and 100 patients (40.5%) had also received a B-cell lymphoma 2 (BCL2) inhibitor, such as venetoclax. The percentage of patients who responded to pirtobrutinib overall was 73.3% (95% confidence interval [CI], 67.3 to 78.7) and when including partial response with lymphocytosis, the percentage was 82.2% (95% CI, 76.8 to 86.7). Median progression-free survival was 19.6 months (95% CI, 16.9 to 22.1).
Among all 317 patients with CLL or SLL who received pirtobrutinib, the most common adverse events were infection (71.0%), bleeding (42.6%), and neutropenia (32.5%). Some adverse events commonly associated with BTK inhibitors occurred relatively rarely over a median treatment duration of 16.5 months (range, 0.2 to 39.9), including hypertension (14.2% of patients), atrial fibrillation, or atrial flutter (3.8%) and major bleeding (2.2%). Only 9 of 317 patients (2.8%) discontinued pirtobrutinib due to treatment-related adverse events.
Conclusions: In this trial, pirtobrutinib showed efficacy in patients with CLL or SLL who were previously treated with a covalent BTK inhibitor. The most common adverse events were infection, bleeding, and neutropenia.
参考文献 Reference
Mato AR et al. N Engl J Med 2023;389:33
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FDA 批准melphalan作为葡萄膜黑色素瘤的肝脏定向治疗 (10/8/2023)
FDA approves melphalan as a liver-directed treatment for uveal melanoma
2023年8月FDA批准含有美法仑（melphalan）的注射用美法仑/肝输送系统作为肝脏定向治疗，用于治疗患有不可切除肝转移的葡萄膜黑色素瘤成年患者 影响小于 50% 的肝脏且无肝外疾病，或肝外疾病仅限于适合切除或放射的骨、淋巴结、皮下组织或肺。
这是一项单臂、多中心、开放标签试验 (FOCUS, NCT02678572)，受试者为 91 名患有不可切除肝转移的葡萄膜黑色素瘤患者。主要排除标准是肝实质转移≥50%,
Child-Pugh B 级或 C 级肝硬化、或乙型或丙型肝炎感染。 主要疗效结果指标是客观响应率和响应持续时间。客观响应率为 36.3% (95% CI: 26.4, 47)，中位响应持续时间为 14 个月 (95% CI: 8.3, 17.7)。
美法仑通过肝输送系统给药，每 6 至 8 周输注至肝动脉，总共最多输注 6 次。
根据理想体重，推荐的马法兰剂量为 3 mg/kg，单次治疗期间最大剂量为 220 mg。 美法仑肝输送系统给药的处方信息对严重的围手术期并发症（包括出血、肝细胞损伤和血栓栓塞事件）有黑框警告。 处方信息还包含针对骨髓抑制导致的严重感染、出血或症状性贫血的黑框警告。 由于存在严重的围手术期并发症（包括出血、肝细胞损伤和血栓栓塞事件）的风险, 美法仑肝输送系统给药只能通过风险评估和缓解策略下的一项名为美法仑肝输送系统给药REMS 的限制计划获得。
最常见（≥20%）的不良反应或实验室异常是血小板减少, 疲劳, 贫血, 恶心, 肌肉骨骼疼痛, 白细胞减少, 腹痛, 中性粒细胞减少, 呕吐, 丙 氨酸转氨酶升高, 活化部分凝血活酶时间延长, 天冬氨酸转氨酶升高, 血液碱性增加
磷酸酶和呼吸困难。 它禁忌用于患有活动性颅内转移或有出血倾向的脑部病变的患者； 肝功能衰竭、门静脉高压或已知有出血风险的静脉曲张； 过去 4 周内接受过肝脏手术或药物治疗； 无法纠正的凝血病、无法安全进行全身麻醉，包括活动性心脏病，包括但不限于不稳定冠状动脉综合征（不稳定或严重心绞痛或心肌梗塞）、恶化或新发充血性心力衰竭、明显心律失常或严重瓣膜病 ; 有过敏史或已知对马法兰过敏； 对马法兰 套件中使用的成分或材料有过敏史或已知的超敏反应，包括对天然橡胶乳 胶过敏史； 对肝素过敏或超敏反应史或存在肝素诱导的血小板减少症； 对碘造影剂有严重过敏反应史，且术前使用抗组胺药和类固醇无法控制。
In August 2023, FDA approved the injectable melphalan/hepatic delivery system (HEPZATO KIT)as a liver-directed therapy for the treatment of adult patients with uveal melanoma with unresectable liver metastases affecting less than 50% of the liver.and no extrahepatic disease or extrahepatic disease limited to bone, lymph nodes, subcutaneous tissue, or lungs amenable to resection or radiation.
This was a single-arm, multicenter, open-label trial (FOCUS, NCT02678572) in which 91 patients with uveal melanoma with unresectable liver metastases.
The main exclusion criteria were liver parenchymal metastasis ≥50%, Child-Pugh class B or C cirrhosis, or hepatitis B or C infection. The primary efficacy outcome measures were objective response rate and duration of response. The objective response rate was 36.3% (95% CI: 26.4, 47), and the median duration of response was 14 months (95% CI: 8.3, 17.7).
Melphalan is administered via a hepatic delivery system and is infused into the hepatic artery every 6 to 8 weeks for a total of up to 6 infusions.
The recommended melphalan dose based on ideal body weight is 3 mg/kg, with a maximum dose of 220 mg during a single treatment session. The prescribing information for melphalan hepatic delivery system administration has a boxed warning for serious perioperative complications, including bleeding, hepatocellular injury, and thromboembolic events. The prescribing information also contains a boxed warning for serious infection, bleeding, or symptomatic anemia due to myelosuppression. Due to the risk of serious perioperative complications, including bleeding, hepatocellular damage, and thromboembolic events, HEPZATO KIT is available only through a restricted program under a Risk Evaluation and Mitigation Strategy called the HEPZATO KIT REMS.
The most common (≥20%) adverse reactions or laboratory abnormalities were thrombocytopenia, fatigue, anemia, nausea, musculoskeletal pain, leukopenia, abdominal pain, neutropenia, vomiting, increased alanine aminotransferase, partial activation
Prolonged thromboplastin time, increased aspartate aminotransferase, increased blood alkalinity phosphatase and dyspnea. It is contraindicated in patients with active intracranial metastases or brain lesions with a tendency to hemorrhage; liver failure, portal hypertension, or varicose veins with a known risk of bleeding; liver surgery or medical treatment within the past 4 weeks; Uncorrectable coagulopathy, inability to safely administer general anesthesia, including active cardiac disease, including but not limited to unstable coronary syndrome (unstable or severe angina or myocardial infarction), worsening or new-onset congestive heart failure, significant cardiac rhythm abnormal or severe valvular disease; History of allergy or known allergy to melphalan; history of allergy or known hypersensitivity to ingredients or materials used in melphalan kit, including a history of allergy to natural rubber latex; allergy or hypersensitivity to heparin; history of reaction or presence of heparin-induced thrombocytopenia; history of severe allergic reaction to iodinated contrast media that cannot be controlled by preoperative use of antihistamines and steroids.
参考文献 Reference
https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-melphalan-liver-directed-treatment-uveal-melanoma
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前瞻性队列研究早期血液检测多种癌症 (10/7/2023)
Prospective cohort study for multicancer early detection via blood-based tests
这是一项期前瞻性队列研究（PATHFINDE, NCT04241796），通过血液检测循环游离 DNA (cfDNA) 中的癌症信号。
方法: 该研究在美国七个健康网络的肿瘤科和初级保健门诊进行，50 岁或以上, 没有癌症体征或症状的成年人并同意接受 MCED 检测提供方便样本。血液采集后分析了 cfDNA，结果返回给参与者的医生。 如果检测到指示癌症的甲基化特征，则预测的癌症信号起源可为诊断评估提供信息。 主要结果是确认癌症是否存在所需的诊断测试的时间和程度。
发现: 2019年12月12日至2020年12月4日，共招募了6,662名参与者。 在 6621 名可分析结果的参与者中，4204 名 (63.5%) 为女性，2417 名 (36.5%) 为男性，6,071 名 (91.7%) 为白人。 在 6,621 名参与者中，有 92 名 (1.4%) 检测到癌症信号，并具有可分析的结果。 35 名 (38%) 参与者被诊断患有癌症（真阳性），57 名 (62%) 参与者没有诊断出癌症（假阳性）。诊断解决的中位时间为 79 天 (IQR 37-219)：真阳性为 57 天 (33-143)，假阳性为 162 天 (44-248) 。 大多数参与者都进行了实验室检查（33 名参与者中的 26 名 [79%] 为真阳性结果，57 名参与者中的 50 名 [88%] 为假阳性结果）和影像学检查（33 名参与者中的 30 名 [91%] 为真阳性结果，57 名参与者中的 53 名 [93%] 为假阳性结果）。 假阳性结果的参与者进行的诊断干涉（57 人中的 17 人 [30%]）少于真阳性结果（33 人中的 27 人 [82%]），并且很少接受手术（1 人出现假阳性结果，3 人出现真阳性结果）。
解释: 这项研究支持了早期血液检测癌症的可行性，需要进一步研究该测试的临床实用性。
This is a prospective cohort study (PATHFINDE, NCT04241796) to detect cancer signals by testing circulating cell-free DNA (cfDNA) in blood.
Methods: The study was conducted in oncology and primary care outpatient clinics across seven health networks in the United States. Participants aged 50 years or older with no signs or symptoms of cancer agreed to undergo testing and provided a convenience sample. The blood was collected and analyzed for cfDNA, while the results returned to the participant’s physician. If a methylation signature indicative of cancer was detected, predicted cancer signal origin(s) informed diagnostic assessment. The primary outcome was the time to, and extent of, diagnostic testing needed to confirm the presence or absence of cancer.
Findings: Between December 12, 2019 and December 4, 2020, a total of 6,662 participants were recruited. Of 6,621 participants with analyzable results, 4,204 (63.5%) were female, 2,417 (36.5%) were male, and 6,071 (91.7%) were white. Cancer signals were detected in 92 of 6,621 participants (1.4%) with analyzable results. Thirty-five (38%) participants were diagnosed with cancer (true positives) and 57 (62%) participants were not diagnosed with cancer (false positives). Median time to diagnostic resolution was 79 days (IQR 37-219): 57 days (33-143) for true-positives and 162 days (44-248) for false-positives. Most participants had laboratory tests (26 of 33 [79%] true-positive results and 50 of 57 [88%] false-positive results) and imaging studies (30 of 33 participants [91%] had true-positive results and 53 of 57 participants [93%] had false-positive results). Fewer procedures were done in participants with false-positive results (17 of 57 [30%]) than those with true-positive results (27 of 33 [82%]) and rarely underwent surgery (one with a false-positive result, and three with true-positive results).
Interpretation: This study supports the feasibility of early detection of cancer via blood test and further research is needed for its clinical utility.
参考文献 Reference
Shrag D et al. Lancet: 2023: October 07, 2023DOI:https://doi.org/10.1016/S0140-6736(23)01700-2
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晚期卵巢癌患者的细胞减灭手术+/-腹腔热腹化疗: 10 年随访的生存结果 (10/1/2023)
Cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy in advanced ovarian cancer: 10-year follow-up of overall survival
方法: 这是一项开放标签, 随机, 对照的 III 期试验(OVHIPEC-1, NCT00426257)，在荷兰和比利时的八个 HIPEC 中心招募了原发性上皮 III 期卵巢癌, 不适合初次细胞减灭术的患者, 患者年龄在 18-76 岁，在至少三个周期新辅助卡铂加紫杉醇内未出现进展，则符合入选资格。 患者被随机分配 (1:1) 接受间歇性细胞减灭术，不进行 HIPEC (腹腔热灌注化疗)（手术组）或进行 HIPEC（100 毫克/平方米 顺铂；手术加 HIPEC 组）。主要终点是无进展生存期，次要终点是总体生存期，在意向治疗人群（即所有随机分配的患者）中进行分析。
发现: 2007年4月1日至2016年4月30日期间，入组了245名患者，和10组患者，手术组（n =123）中位随访时间为10.1年（95% CI 8.4–12.9）, 手术加 HIPEC 组 (n =122) 中位随访时间为10.4 年 (95% CI 9.5–13.3)。 手术组有 114 名 (93%) 患者出现复发、进展或死亡（中位无进展生存期 10.7 个月 [95% CI 9.6–12.0]），而手术组有 109 名 (89%) 患者出现复发、进展或死亡。 手术加 HIPEC 组（中位无进展生存期14.3 个月 [12.0–18.5]；风险比 [HR] 0.63 [95% CI 0.48–0.83]，分层对数秩 p =0.0008）。 手术组有 108 名 (88%) 患者死亡（中位总生存期 33.3 个月 [95% CI 29.0–39.1]），手术加 HIPEC 组有 100 名 (82%) 患者死亡（中位总生存期 44.9 个月 [95% CI 38.6–55.1]；HR 0.70 [95% CI 0.53–0.92]，分层对数秩 p =0.011）。
解释: 这些更新的生存结果证实了 HIPEC 对接受细胞减灭术的原发性 III 期上皮性卵巢癌患者的长期生存益处。
Methods: This was an open-label, randomized, controlled phase III trial (OVHIPEC-1, NCT00426257) enrolling patients (age 18-76) with primary epithelial stage III ovarian cancer patients who were ineligible for primary cytoreduction. They were eligible if there was no progression upon at least three cycles of neoadjuvant carboplatin plus paclitaxel. Patients were randomly assigned (1:1) to undergo interval cytoreduction without HIPEC (hyperthermic intraperitoneal chemotherapy) (surgery group) or HIPEC (100 mg/m cisplatin; surgery plus HIPEC group). The primary endpoint was progression-free survival and the secondary endpoint was overall survival. The analysis was performed in the intention-to-treat population (i.e., all randomly assigned patients).
Findings: Between April 1, 2007 and April 30, 2016, 245 patients were enrolled. The median follow-up in the surgical group (n = 123) was 10.1 years (95% CI 8.4–12.9), and 10.4 years in the surgery plus HIPEC group (n =122) (95% CI 9.5–13.3). Recurrence, progression, or death occurred in 114 (93%) patients in the surgery group (median progression-free survival, 10.7 months [95% CI 9.6–12.0]), compared with 109 (89%) patients in the surgery plus HIPEC group (median progression-free survival 14.3 months ([12.0–18.5], hazard ratio [HR] 0.63 [95% CI 0.48–0.83], stratified log-rank p =0.0008). A total of 108 (88%) patients died in the surgery group (median overall survival 33.3 months [95% CI 29.0–39.1]) and 100 (82%) patients died in the surgery plus HIPEC group (median overall survival 44.9 months [95% CI 38.6–55.1]; HR 0.70 [95% CI 0.53–0.92], stratified log-rank p =0.011).
Interpretation: These updated survival results confirm the long-term survival benefit of HIPEC in patients with primary stage III epithelial ovarian cancer who undergoing interval cytoreductive surgery.
参考文献 Reference
Aronson SL et al. Lancet Onc 2023; DOI:https://doi.org/10.1016/S1470-2045(23)00396-0
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第一线瑞戈非尼联合纳武单抗和化疗治疗晚期食管癌, 胃癌或胃食管交界癌 (9/30/2023)
First-line regorafenib with nivolumab and chemotherapy in advanced esophageal, gastric or GEJ junction cancer
方法: 这是一项由研究者（美国纽约斯隆凯特琳癌症中心）发起的单组 2 期试验(NCT04757363)，受试者为先前未经治疗的 HER2 阴性转移性食管胃腺癌成年患者。FOLFOX 化疗（氟尿嘧啶 [400 毫克/平方米 推注，然后在第 1 天和第 15 天静脉注射 2400 毫克/平方米，持续 48 小时], 亚叶酸 [400 毫克/平方米] 和奥沙利铂 [85 毫克/平方米]）和纳武单抗 (240 毫克)，以及在 28 天周期的第 1-21 天口服瑞戈非尼 (regorafenib , 80 毫克)。 持续治疗直至疾病进展, 出现不可接受的毒性或撤回同意。 主要终点是 6 个月无进展生存期。 如果 35 名患者中至少有 24 名在 6 个月时无进展，则认为该方案值得进一步研究。 对接受至少一剂任何研究治疗的所有参与者进行安全性评估。
发现: 2021年2月11日至2022年5月4日期间，共有39名患者入组，接受了至少一剂研究药物，并纳入安全性分析。 35 名患者的 6 个月无进展生存期可进行评估。 中位年龄为 57 岁（IQR 52-66），9 名患者（26%）为女性，26 名患者（74%）为男性，28 名患者（80%）为白人，7 名患者（20%）为亚洲人。 数据截止时（2023 年 3 月 3 日），中位随访时间为 18.1 个月（IQR 12.7–20.4）。 试验达到了主要终点，35 名患者中有 25 名（71%；95% CI 54-85）在 6 个月时无进展。 35 名患者中有 9 名 (26%) 出现疾病进展，1 名 (3%) 患者死亡； 死亡与治疗无关。
任何级别中最常见的不良事件是疲劳（39 例中有 36 例 [92%]）。 最常见的 3 级或 4 级不良事件是中性粒细胞计数减少（18 [46%]）, 高血压（6 [15%]）, 皮肤干燥, 瘙痒或皮疹（5 [13%]）和贫血（4 10%]）。 10 名 (26%) 患者发生了严重的治疗相关不良事件，包括急性肾损伤（3 名 [8%]）, 肝毒性（2 名 [5%]）, 败血症（2 名 [5%]）, 皮肤干燥, 瘙痒 或皮疹（1 例 [3%], 恶心（1 例 [3%]）和胃穿孔（1 例 [3%]）。 没有出现与治疗相关的死亡。
解释: 瑞戈非尼可以安全地与纳武单抗和化疗联合使用，并在 HER2 阴性转移性食管胃癌中显示出良好的活性。 计划进行随机三期临床试验。
Methods: This was an investigator-initiated, single-arm, phase 2 trial (NCT04757363) at Sloan Kettering Cancer Center, New York, in adults with previously untreated HER2-negative metastatic esophagogastric adenocarcinoma. FOLFOX chemotherapy (fluorouracil [400 mg/m2 bolus followed by 2400 mg/m2 IV for 48 hours on days 1 and 15], leucovorin [400 mg/m2], and oxaliplatin [ 85 mg/m]) and nivolumab (240 mg), and oral regorafenib (80 mg) on days 1-21 of a 28-day cycle. Treatment was continued until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was 6-month progression-free survival. If at least 24 of 35 patients were progression-free at 6 months, the regimen was considered worthy of further study. Safety assessments were conducted on all participants who received at least one dose of any study treatment.
Findings: Between February 11, 2021, and May 4, 2022, a total of 39 patients were enrolled, and received at least one dose of study drug, and were included in the safety analysis. Six-month progression-free survival was evaluable in 35 patients. Median age was 57 years (IQR 52-66), 9 patients (26%) were female, 26 patients (74%) were male, 28 patients (80%) were white, and 7 patients (20%) were Asian. At data cutoff (3 March 2023), median follow-up was 18.1 months (IQR 12.7–20.4). The trial met its primary endpoint, with 25 of 35 patients (71%; 95% CI 54-85) progression-free at 6 months. Nine of 35 patients (26%) experienced disease progression and 1 (3%) patient died; the death was not related to treatment.
The most common adverse event of any grade was fatigue (36 of 39 [92%]). The most common grade 3 or 4 adverse events were decreased neutrophil count (18 [46%]), hypertension (6 [15%]), dry skin, pruritus or rash (5 [13%]), and anemia (4 [10%]). Serious treatment-related adverse events occurred in 10 (26%) patients, including acute kidney injury (3 [8%]), hepatotoxicity (2 [5%]), sepsis (2 [5%]), dry skin, itching, or rash (1 patient [3%]), nausea (1 patient [3%]), and gastric perforation (1 patient [3%]). There were no treatment-related deaths.
Interpretation: Regorafenib can be used safely in combination with nivolumab and chemotherapy and shows promising activity in HER2-negative metastatic esophagogastric cancer. A randomized phase 3 clinical trial is planned.
参考文献 Reference
Cytryn SL et al. Lancet Onc 2023; DOI:https://doi.org/10.1016/S1470-2045(23)00358-3
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帕尼单抗相比于贝伐珠单抗联合标准一线化疗治疗RAS 野生型左侧转移性结直肠癌 (9/24/2023)
Panitumumab vs bevacizumab plus standard first-line chemotherapy in RAS wild-type, left-sided metastatic colorectal cancer
参与者 2015 年 5 月至 2022 年 1 月在日本 197 个地点进行的随机, 开放标签 3 期临床试验(NCT02394795)，受试者为 823 名未经化疗的 RAS 野生型, 不可切除的转移性结直肠癌患者, 随机给予帕尼单抗 (n = 411) 或贝伐单抗 (n = 412) 加每 14 天一次改良氟尿嘧啶, L-亚叶酸和奥沙利铂 (mFOLFOX6)。 首先在左侧肿瘤的参与者中测试主要终点，即总体生存率，然后在总体人群中进行测试。 次要终点是无进展生存期, 响应率, 响应持续时间和治愈性（ R0 ）切除率。
结果: 在接受治疗的人群中（n = 802；中位年龄，66 岁；282 名 [35.2%] 女性），604 名 (75.3%) 患有左侧肿瘤。 中位随访时间为 61 个月。 左侧肿瘤受试者中，帕尼单抗组的中位总生存期为 37.9 个月，贝伐珠单抗组为 34.3 个月（死亡风险比 [HR]，0.82；95.798% CI，0.68-0.99；P = .03）; 在总体人群中, 中位总生存期分别为帕尼单抗组37.9 个月，贝伐单抗组 31.3 个月。（HR，0.84；95% CI，0.72-0.98；P = .03）。 对于左侧肿瘤患者，帕尼单抗与贝伐珠单抗的中位无进展生存期分别为 13.1 个月和 11.9 个月（HR，1.00；95% CI，0.83-1.20）；在总体人群中, 无进展生存期为 12.2 个月和 11.4 个月（HR，1.05；95%） 置信区间，0.90-1.24）。 对于左侧肿瘤，帕尼单抗与贝伐单抗的响应率分别为 80.2% 和 68.6%（差异为 11.2%；95% CI，4.4%-17.9%）; 在总体人群中, 响应率为 74.9% 与 67.3%（差异为 7.7%；95 % CI，1.5%-13.8%）。 帕尼单抗与贝伐单抗的中位响应持续时间对于左侧肿瘤分别为 13.1 个月和 11.2 个月（HR，0.86；95% CI，0.70-1.10），在总体人群中, 响应持续时间为 11.9 个月和 10.7 个月（HR，0.89；95% CI，0.74-1.06） 。 对于左侧肿瘤，帕尼单抗与贝伐珠单抗的治愈性切除率分别为 18.3% 和 11.6%； （差异6.6%；95% CI，1.0%-12.3%）; 在总体人群中, 16.5% vs 10.9%（差异5.6%；95% CI，1.0%-10.3%）。
常见的治疗引起的不良事件是痤疮样皮疹（帕尼单抗：74.8%；贝伐单抗：3.2%）、周围感觉神经病变（帕尼单抗：70.8%；贝伐单抗：73.7%）和口腔炎（帕尼单抗：61.6%；贝伐单抗：40.5%）。
结论和相关性: 在 RAS 野生型转移性结直肠癌患者中，与贝伐珠单抗相比，在标准一线化疗中添加帕尼单抗可显著改善左侧肿瘤患者和总体人群的总生存期。
This was a randomized, open-label phase 3 clinical trial (NCT02394795) conducted at 197 sites in Japan from May 2015 to January 2022. A total of 823 patients with chemotherapy-naïve RAS wild-type, unresectable metastatic colorectal cancer patients were randomized to receive panitumumab (n = 411) or bevacizumab (n = 412) plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) every 14 days. The primary endpoint, overall survival, was tested first among participants with left-sided tumors and then in the overall population. Secondary endpoints were progression-free survival, response rate, duration of response and curative (R0) resection rate.
Results: Among those treated (n = 802; median age, 66 years; 282 [35.2%] women), 604 (75.3%) had left-sided tumors. Median follow-up was 61 months. Among participants with left-sided tumors, median overall survival was 37.9 months in the panitumumab group vs. 34.3 months in the bevacizumab group (hazard ratio [HR] for death, 0.82; 95.798% CI, 0.68- 0.99; P = .03); in the overall population, the median overall survival was 37.9 months in the panitumumab group vs. 31.3 months in the bevacizumab group. (HR, 0.84; 95% CI, 0.72-0.98; P = .03). For patients with left-sided tumors, the median progression-free survival was 13.1 months with panitumumab vs. 11.9 months with bevacizumab (HR, 1.00; 95% CI, 0.83-1.20); in the overall population, progression-free survival was 12.2 months vs. 11.4 months (HR, 1.05; 95% confidence interval, 0.90-1.24). For left-sided tumors, response rates with panitumumab and bevacizumab were 80.2% and 68.6%, respectively (difference, 11.2%; 95% CI, 4.4%-17.9%); in the overall population, the response rate was 74.9 % versus 67.3% (difference, 7.7%; 95% CI, 1.5%-13.8%). The median duration of response was 13.1 months vs. 11.2 months in left-sided tumors (HR, 0.86; 95% CI, 0.70-1.10), in the overall population, duration of response was 11.9 months vs. 10.7 months (HR, 0.89; 95% CI, 0.74-1.06). For left-sided tumors, curative resection rates were 18.3% with panitumumab versus 11.6% with bevacizumab (difference, 6.6%; 95% CI, 1.0%-12.3%); in the overall population, curative resection rates were 16.5 % vs 10.9% (difference 5.6%; 95% CI, 1.0%-10.3%).
Common treatment-emergent adverse events were acneiform rash (panitumumab: 74.8%; bevacizumab: 3.2%), peripheral sensory neuropathy (panitumumab: 70.8%; bevacizumab: 73.7%) and stomatitis (panitumumab: 61.6%; bevacizumab: 40.5%).
Conclusions and Relevance: In patients with RAS wild-type metastatic colorectal cancer, the addition of panitumumab to standard first-line chemotherapy significantly improved overall survival compared with bevacizumab in patients with left-sided tumors and in the overall population.
参考文献 Reference
Watanabe J et al. JAMA Onc 2023; 329: 1271
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PectaSol-C modified citrus pectin治疗非转移性生化复发性前列腺癌 (9/23/2023)
PectaSol-C modified citrus pectin (P-MCP) in non-metastatic biochemically relapsed prostate cancer
背景：P-MCP是半乳糖凝集素 3 蛋白的抑制剂，该蛋白参与前列腺癌的发病机制。研究者报告了多中心 II 期研究(NCT01681823)的最终长期结果。
方法：非转移性生化复发性前列腺癌患者入组并接受 P-MCP 治疗，4.8 克 x 3/天，为期 6 个月（试验第一阶段）。 PSA 没有进展和/或 PSA 倍增时间改善且扫描结果呈阴性的患者接受额外 12 个月的治疗（试验的第二阶段）。
结果：最初招募了 59 名患者。 最初 6 个月的治疗后，46 名患者 (78%) 没有出现疾病进展，进入了额外 12 个月治疗的第二阶段。 其中，7名患者撤回同意并选择继续自费治疗。 其余 39 名患者中，又经过一年的治疗（总共 18 个月），85% (n =33) 获得了总体长期缓解，PSA 下降/稳定（62%，n =24），并且PSA 倍增时间有所改善（90%，n =35），并扫描阴性。 没有患者出现 3/4 级毒性。
结论：P-MCP 对非转移性生化复发性前列腺癌患者患者可能具有持久的长期疗效。
Background: P-MCP is an inhibitor of galectin-3 protein, which is involved in the pathogenesis of prostate cancer. Investigators reported final long-term results from a multicenter phase II study (NCT01681823).
Methods: Patients with non-metastatic biochemically recurrent prostate cancer were enrolled and treated with P-MCP, 4.8 g x 3/day, for 6 months (trial phase 1). Patients with no PSA progression and/or improvement in PSA doubling time and negative scans received an additional 12 months of treatment (phase 2 of the trial).
Results: Fifty-nine patients were initially recruited. After the initial 6 months of treatment, 46 patients (78%) showed no disease progression and entered a second phase of additional 12 months of treatment. Among them, 7 patients withdrew their consent and chose to continue treatment at their own expense. Of the remaining 39 patients, after an additional year of treatment (18 months total), 85% (n =33) achieved overall long-term remission, with a decreased/stable PSA (62%, n =24), and improved PSA doubling time (90%, n =35) and with negative scans. No patients experienced grade 3/4 toxicity.
Conclusions: P-MCP may have durable long-term efficacy in patients with non-metastatic biochemically recurrent prostate cancer.
参考文献 Reference
Keizman d et al. J Clin Onc 2023; 41: 6_suppl 162
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Mezigdomide联合地塞米松治疗复发性和难治性多发性骨髓瘤 (9/17/2023)
Mezigdomide in combination with dexamethasone in relapsed and refractory multiple myeloma
Mezigdomide 是一种新型 cereblon E3 泛素连接酶调节剂，在多发性骨髓瘤临床前模型中具有杀肿瘤活性。
方法: 这是一项I-II 期研究(NCT03374085)，招募复发/难治性骨髓瘤患者口服Mezigdomide联合地塞米松。 第一阶段（剂量递增队列）的主要目标是评估安全性和药代动力学，并确定第二阶段的剂量和时间表。第二阶段（剂量扩展队列）的目标包括评估总体响应（部分响应, 或更好）, 以及Mezigdomide联合地塞米松在第一阶段确定的剂量和时间表的安全性和有效性。
结果: 在第一阶段，共有 77 名患者参加了该研究。 最常见的剂量限制性毒性反应是中性粒细胞减少症和发热性中性粒细胞减少症。 根据第一阶段研究结果，研究人员确定第二阶段Mezigdomide的推荐剂量为 1.0 毫克，每日一次，与地塞米松联合用药，持续 21 天，然后停药 7 天，每个 28 天的周期。 在第 2 阶段，共有 101 名患者按照相同的时间表接受了第 1 阶段确定的剂量。 剂量扩展队列中的所有患者均患有三级难治性多发性骨髓瘤，30 名患者 (30%) 既往接受过抗 B 细胞成熟抗原 (抗 BCMA) 治疗，40 名患者 (40%) 患有浆细胞瘤。 最常见的不良事件几乎全部被证明是可逆的，包括中性粒细胞减少症（77% 的患者）和感染（65%）。 没有遇到意外的毒性作用。
共有41% 的患者出现总体响应（95% 置信区间 [CI]，31 至 51），中位响应持续时间为 7.6 个月（95% CI，5.4 至 9.5；数据不成熟），中位进展 无生存期为 4.4 个月（95% CI，3.0 至 5.5），中位随访时间为 7.5 个月（范围，0.5 至 21.9）。
结论: Mezigdomide加地塞米松的全口服组合对经过大量治疗的多发性骨髓瘤患者显示出良好的疗效，治疗相关的不良事件主要包括骨髓毒性作用。
Mezigdomide is a novel cereblon E3 ubiquitin ligase modulator with tumoricidal activity in preclinical models of multiple myeloma.
Methods: This is a phase I-II study (NCT03374085) enrolling patients with relapsed/refractory myeloma to receive oral mezigdomide in combination with dexamethasone. The primary objectives of phase I (dose-escalation cohort) are to assess safety and pharmacokinetics and to determine dose and schedule for phase 2. The objectives of phase 2 (dose expansion cohort) include assessment of overall response (partial response, or better), as well as the safety and efficacy of mezigdomide in combination with dexamethasone at the doses and schedule established in phase 1.
Results: In phase 1, a total of 77 patients were enrolled. The most common dose-limiting toxicities were neutropenia and febrile neutropenia. Based on the results of the phase 1 study, researchers determined that the recommended dose of mezigdomide in phase 2 is 1.0 mg once daily in combination with dexamethasone for 21 days followed by 7 days off in each 28-day cycle. In phase 2, a total of 101 patients received the doses determined in phase 1 on the same schedule. All patients in the dose expansion cohort had triple-class-refractory multiple myeloma, 30 patients (30%) had received prior anti-B cell maturation antigen (anti-BCMA) therapy, and 40 patients (40%) had plasmacytoma. The most common adverse events, nearly all of which proved reversible, included neutropenia (in 77% of the patients) and infection (65%). No unexpected toxic effects were encountered.
A total of 41% of patients experienced an overall response (95% confidence interval [CI], 31 to 51), the median duration of response was 7.6 months (95% CI, 5.4 to 9.5; data not mature), and the median progression-free survival was 4.4 months (95% CI, 3.0 to 5.5), and the median follow-up was 7.5 months (range, 0.5 to 21.9).
Conclusion: The all-oral combination of mezigdomide plus dexamethasone showed good efficacy in heavily treated patients with multiple myeloma. Treatment-related adverse events mainly included myelotoxic effects.
参考文献 Reference
Richardson P et al. N Engl J Med 2023; 389:1099
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针对有肺癌家族史和重度吸烟史检测早期肺癌: 来自台湾的报导 (9/16/2023)
Screening lung cancer in population with heavy-smoking or lung cancer family history: A report from Taiwan
台湾于 2022 年 7 月启动了全国肺癌筛查计划，针对两个符合条件的人群： 有肺癌家族史(父母, 子女或兄弟姐妹)的个人，特别是50至74岁的男性和45至74岁的女性; 50至74岁的人群且有30 包/年或以上吸烟史且愿意戒烟或在过去 15 年内戒烟的个人。 该计划利用美国放射学院的肺部 低剂量CT 筛查报告和数据系统作为结节管理指南，并确保对阳性筛查结果进行适当的随访。 收集的数据包括危险因素、图像判读结果和评估结果。
研究报告称，2022 年 7 月至 2023 年 6 月, 共有 49,508 人接受了筛查，其中 58% (n = 28,617) 有肺癌家族史，其中 38% (n = 18,970) 是重度吸烟者。 在参与筛查的人中，4,406人获得阳性筛查结果，531人最终诊断为肺癌。 阳性率为9.2%，肺癌检出率为1.1%。 重要的是，85% 的肺癌病例是在早期（0 期或 I 期）被诊断出来的。
美国现有的筛查标准仅限于重度吸烟者。 台湾的研究( TALENT 试验) 发现,肺癌家族史在台湾可能是患肺癌的一个重要危险因素。
Taiwan launched a national lung cancer screening program in July 2022, targeting two eligible populations: individuals with a family history of lung cancer (parents, children or siblings), especially men aged 50 to 74 and 45 to 74 years old women; individuals aged 50 to 74 years with a smoking history of 30 packs/year or more who are willing to quit smoking or have quit smoking within the past 15 years. The program utilizes the American College of Radiology’s low-dose CT Screening of lung cancer and reporting and data system as a guide for nodule management and to ensure appropriate follow-up of positive screening results. Data collected include risk factors, image interpretation results, and assessment.
The study reported that between July 2022 and June 2023, a total of 49,508 people were screened, 58% (n = 28,617) of whom had a family history of lung cancer, and 38% (n = 18,970) were heavy smokers. Among those who participated in the screening, 4,406 received positive screening results and 531 were ultimately diagnosed with lung cancer. The positive rate was 9.2%, and the lung cancer detection rate was 1.1%. Importantly, 85% of lung cancer cases were diagnosed in the early stages (stage 0 or I).
Current lung cancer screening in the United States is limited to heavy smokers. A study in Taiwan (TALENT trial) found that family history of lung cancer may be an important risk factor for lung cancer in Taiwan.
参考文献 Reference
Yang P et al. Int Asso for the Study of Lung Cancer, World Conf on lung cancer 2023
Yang P. J Thorac Onc 2021; 16 (issue 3; suppl_S58)
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NAPOLI-3: 第一线治疗转移性胰腺导管腺癌的III 期研究 (9/10/2023)
NAPOLI-3: a randomized phase III study in treatment-naïve metastatic pancreatic ductal cancer
方法：这是一项随机, 开放标签 III期临床试验（NALIRIFOX, NCT04083235），未经治疗的转移性胰腺导管腺癌患者被随机 (1:1) 接受 28 天周期的第 1 天和第 15 天的 NALIRIFOX (脂质体伊立替康 50 毫克/平方米 + 5-氟尿嘧啶 2400 毫克/平方米 + 亚叶酸 400 毫克/平方米 + 奥沙利铂 60 毫克/平方米)治疗或白蛋白结合型紫杉醇 125 毫克/平方米 + 吉西他滨 1000 毫克/平方米 在 28 天周期的第 1, 8 和 15 天。主要终点是总生存期； 次要终点是无进展生存期, 总响应率和安全性。
结果：总体而言，纳入了 770 名患者（NALIRIFOX，n = 383；紫杉醇 + 吉西他滨，n = 387）。 各组之间的基线特征非常平衡。 中位随访时间为 16.1 个月，共发生 544 起事件。 NALIFIROX 组的中位总生存期 为 11.1 个月，而紫杉醇 + 吉西他滨组为 9.2 个月（HR 0.84 [95% CI 0.71–0.99]；p = 0.04）； 无进展生存期也显著改善（7.4 个月相对于5.6 个月；HR 0.70 [0.59–0.84]；p = 0.0001）。
接受 NALIRIFOX 治疗的≥10%的3/4 级不良事件发生频率与紫杉醇 + 吉西他滨相比包括腹泻（20.3% 相对于4.5%）, 恶心（11.9% 相对于2.6%）, 低钾血症（15.1% 相对于4.0%）, 贫血（10.5% 相对于17.4%）和中性粒细胞减少症（14.1% 相对于24.5%）。
结论：与紫杉醇 + 吉西他滨相比，一线 NALIRIFOX 在未经治疗的转移性胰腺导管腺癌患者中显示出具有临床意义和统计学意义的总生存期和无进展生存期改善。 NALIRIFOX 的安全性是可控的。
Methods: This is a randomized, open-label phase III clinical trial (NALIRIFOX, NCT04083235) in which patients with untreated metastatic pancreatic ductal adenocarcinoma were randomized (1:1) to receive treatment of NALIRIFOX (liposomal irinotecan 50 mg/m2 + 5-fluorouracil 2400 mg/m2 + leucovorin 400 mg/m2 + oxaliplatin 60 mg/m2) on days 1 and 15 of a 28-day cycle, or nab-paclitaxel 125 mg/m2 + gemcitabine 1000 mg/m2 on days 1, 8 and 15 of a 28-day cycle. The primary endpoint was overall survival; secondary endpoints were progression-free survival, overall response rate and safety.
Results: Overall, 770 patients were included (NALIRIFOX, n = 383; paclitaxel + gemcitabine, n = 387). Baseline characteristics were well balanced between groups. Median follow-up was 16.1 months, with 544 events. Median overall survival was 11.1 months in the NALIFIROX arm compared with 9.2 months in the paclitaxel + gemcitabine arm (HR 0.84 [95% CI 0.71–0.99]; p = 0.04); progression-free survival was also significantly improved (7.4 months vs. 5.6 months; HR 0.70 [0.59–0.84]; p = 0.0001).
Grade 3/4 treatment-emergent adverse events with ≥10% frequency in patients treated with NALIRIFOX compared with paclitaxel + gemcitabine included diarrhea (20.3% vs. 4.5%), nausea (11.9% vs. 2.6%), hypokalemia (15.1% vs. 4.0%), anemia (10.5% vs. 17.4%) and neutropenia (14.1% vs. 24.5%).
Conclusions: First-line NALIRIFOX demonstrated clinically meaningful and statistically significant improvements in overall survival and progression-free survival compared with paclitaxel + gemcitabine in patients with untreated metastatic pancreatic ductal adenocarcinoma. The safety profile of NALIRIFOX was manageable.
参考文献 Reference
Wainberg ZA et al. J Clin Onc 2023; 41: (4 suppl _LBA661)
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PHERGain 试验评估HER2[+]早期乳腺癌化疗降阶梯治疗 (9/9/2023)
PHERGain trail evaluating chemotherapy de-escalation in HER2[+] early breast cancer
这是一项随机II期临床试验（PHERGain, NCT5732164），PHERGain 中的患者接受 HER2 阻断（曲妥珠单抗和帕妥珠单抗）联合化疗（多西他赛和卡铂）或单独 HER2 阻断治疗。在第一阶段的治疗中，患者按 1:4 的比例随机分配至以下组： A 组：HER2 阻断(曲妥珠单抗和帕妥珠单抗)加化疗 (多西他赛, 卡铂)：两个周期 (n = 71); B 组：单独 HER2 阻断两个周期 (n = 285)。 经过两个周期的指定治疗后，患者接受了全身 PET 扫描。 如果扫描显示乳腺病变较基线减少至少 40%，则患者被视为 PET 响应者。 此后，A组和B组遵循以下路线： 单独 HER2 阻断组（B 组）中的响应者继续接受双重 HER2 阻断 6 个周期以上（如果有需要，可添加内分泌治疗）。 单独 HER2 阻断组（B 组）中的无响应应者被转至HER2 阻断加化疗组组，再进行六个周期。 无论响 应如何，分配到 HER2 阻断加化疗组（A 组）的患者仍保留在该组。
在这项研究的早期分析中，B 组 285 名患者中共有 227 名 (79.7%) 为 PET 响应者，在这 227 名患者中有 86 名 (37.9%，95% CI，31.6 至 44.5；p < 0.0001）实现了病理完全响应，达到了第一个主要终点（Perez-Garcia JM，Lancet Oncol 2021）。研究者最近报告了 B 组中根据意向治疗接受手术患者的第二个主要终点，即 3 年无侵袭性疾病生存期(iDFS)的结果。
结果：2017年6月26日至2019年4月24日期间，随机分配356例患者（A组71例，B组285例），B 组包括I-IIIA 期, HER2[+]早期乳腺癌患者，最初接受曲妥珠单抗和帕妥珠单抗（± 内分泌治疗）治疗, 在两个治疗周期后没有 PET 响应和/或没有病理完全响应的患者中引入化疗。分别有63例（89.0%, A组）和267例（93.7%, B组）患者接受手术。 在 B 组中，根据意向治疗人群的 3 年 iDFS 率为 95.4%（95% CI，92.8 至 98），满足第二个主要终点（p <0.001）。 中位随访时间为 43.3 个月（范围为 2.4-63.0）后，总共报告了 12 起 iDFS 事件，包括 8 起远处复发 (3.0%)、3 起局部同侧复发 (1.1%) 和 1 起非相关死亡 （0.4%）。 在未接受化疗的一部分的B组PET 响应者并且病理完全响应患者中 (n = 86)，只有一名患者发生侵袭性病事件（同侧局部复发），3 年 iDFS 率为 98.8% (95 % CI，96.3 至 100.0）。
分配到 A 组患者中与治疗相关的不良事件和严重不良事件高于分配到 B 组的患者（≥3 级，61.8% 相对于 32.9% [p <0.001]；严重不良事件，27.9% 相对于13.8% [p =0.01]）。 B组中获得病理完全响应的PET 响应患者的治疗相关 3 级以上不良事件发生率最低 (1.2%), 且无任何严重不良事件。 没有报告与治疗相关的死亡。
结论：在 HER2[+] 早期乳腺癌患者中，基于 PET 响应并且病理完全响应的适应策略与 3 年 iDFS 相关。大约三分之一的 HER2[+] 早期乳腺癌患者可以安全地省略化疗，并降低毒性。
This is a randomized phase II clinical trial (PHERGain, NCT5732164) in which patients in PHERGain received HER2 blockade (trastuzumab and pertuzumab) plus chemotherapy (docetaxel and carboplatin) or HER2 blocking treatment alone. In the first phase of treatment, patients were randomly assigned in a 1:4 ratio to the following groups: Group A: HER2 blockade (trastuzumab and pertuzumab) plus chemotherapy (docetaxel, carboplatin): two cycles (n = 71); Group B: HER2 blockade alone for two cycles (n = 285). After two cycles of assigned treatment, patients underwent whole-body PET scans. Patients were considered PET responders if the scan showed at least a 40% reduction in breast lesions from baseline. Thereafter, Arms A and B followed the following path: responders in the HER2 blockade alone arm (Arm B) continued to receive dual HER2 blockade for 6 more cycles (with the addition of endocrine therapy if needed). Non-responders in the HER2 blockade alone arm (arm B) were transferred to the HER2 blockade plus chemotherapy arm for an additional six cycles. Patients assigned to the HER2 blockade plus chemotherapy arm (Arm A) remained in that arm regardless of response.
This is a randomized phase II clinical trial (PHERGain, NCT5732164). In the early analysis of this study, a total of 227 (79.7%) of 285 patients in arm B were PET responders, and 86 of these 227 patients achieved a pathological complete response (37.9%, 95% CI, 31.6 to 44.5; p < 0.0001), meeting the first primary endpoint (Perez-Garcia JM, Lancet Oncol 2021). Investigators recently reported results for the second primary endpoint, 3-year invasive disease-free survival (iDFS), in cohort B patients who underwent surgery on an intent-to-treat basis.
Results: Between June 26, 2017 and April 24, 2019, 356 patients (71 patients in group A and 285 patients in group B) were randomly assigned. Group B included patients with stage I-IIIA, HER2[+] early breast cancer, initially treated with trastuzumab and pertuzumab (± endocrine therapy), chemotherapy was given to patients who had no PET response and/or no pathological complete response after two cycles of treatment. A total of 63 (89.0%, group A) and 267 (93.7%, group B) patients underwent surgery, respectively. In Arm B, the 3-year iDFS rate in the intent-to-treat population was 95.4% (95% CI, 92.8 to 98), meeting the second primary endpoint (p <0.001). After a median follow-up of 43.3 months (range, 2.4-63.0), a total of 12 iDFS events were reported, including 8 distant recurrences (3.0%), 3 local ipsilateral recurrences (1.1%) and 1 unrelated death (0.4%). Among the group B PET responders who did not receive chemotherapy and had a pathological complete response (n = 86), only one patient had an invasive disease event (ipsilateral local recurrence), and the 3-year iDFS rate was 98.8% (95 % CI , 96.3 to 100.0). Patients assigned to Arm A had more treatment-related adverse events and serious adverse events than those assigned to Arm B (grade ≥3, 61.8% vs 32.9% [p < 0.001]; serious adverse events, 27.9% vs 13.8 % [p=0.01]). PET-responding patients who achieved a pathologic complete response in Arm B had the lowest rate of treatment-related grade 3+ adverse events (1.2%), without any serious adverse events. No treatment-related deaths were reported.
Conclusions: An adaptive strategy based on PET response and pathologic complete response was associated with 3-year iDFS in patients with HER2[+] early breast cancer. Approximately one-third of patients with HER2[+] early-stage breast cancer can safely omit chemotherapy with reduced toxicity.
参考文献 Reference
Cortes J et al. J Clin Onc 2023; LBA206 41: 17-suppl LBA506
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Zanidatamab 治疗 HER2 扩增, 局部晚期或转移性胆道癌 (9/3/2023)
Zanidatamab for HER2-amplified locally-advanced or metastatic biliary tract cancer
方法: HERIZON-BTC-01（NCT04466891）是一项全球性(北美, 南美, 亚洲和欧洲的九个国家), 多中心, 单臂 IIb 期试验，受试者为 HER2 扩增, 不可切除, 局部晚期或转移性胆道癌患者，且之前接受基于吉西他滨的治疗后疾病进展。根据 HER2 免疫组织化学 (IHC) 评分将患者分配至队列：队列 1（IHC 2+ 或 3+；HER2 阳性）和队列 2（IHC 0 或 1+）。 患者每两周静脉注射 zanidatamab (针对两个不同 HER2 表位的双特异性抗体)20 mg/kg。 主要终点是通过独立中央审查评估的队列 1 中确认的客观响应率。 对接受任何剂量的所有参与者的抗肿瘤活性和安全性进行了评估。
发现: 2020 年 9 月 15 日至 2022 年 3 月 16 日期间，共有 87 名患者入组 HERIZON-BTC-01：队列 1 中有 80 名患者（中位年龄为 64 岁 [IQR 58-70]），队列 2 中有 7 名（中位年龄为 62 岁[ IQR 58-77]）。 截至数据截止时（2022 年 10 月 10 日），18 名患者（21%）（队列 1 中 17 名，队列 2 中 1 名）正在继续接受zanidatamab治疗； 69 名 (79%) 患者停止治疗（64 名患者 [74%] 患者出现放射学进展）。 中位随访时间为 12.4 个月 (IQR 9.4–17.2)。 在队列 1 的 33 名患者中观察到经独立中央审查确认的客观反应（41.3% [95% CI 30.4–52.8]）。
16 名（18%）患者出现 3 级治疗相关不良事件； 最常见的是腹泻（4名[5%]患者）和射血分数降低（3名[3%]患者）。 没有发生 4 级治疗相关不良事件，也没有治疗相关死亡。
解释: Zanidatamab 在治疗难治性 HER2 阳性胆道癌患者中显示出有意义的临床益处和可控的安全性, 可考虑作为 HER2 阳性胆道癌未来治疗的选择。
Methods: HERIZON-BTC-01 (NCT04466891) is a global (nine countries in North America, South America, Asia, and Europe), multicenter, single-arm phase IIb trial in HER2-amplified, unresectable, localized patients with advanced or metastatic biliary tract cancer following disease progression on prior gemcitabine-based therapy. Patients were assigned to cohorts based on HER2 immunohistochemistry (IHC) score: cohort 1 (IHC 2+ or 3+; HER2 positive) and cohort 2 (IHC 0 or 1+). Patients received zanidatamab (a bispecific antibody targeting two different HER2 epitopes) 20 mg/kg intravenously every two weeks. The primary endpoint was confirmed objective response rate in cohort 1 assessed by independent central review. Antitumor activity and safety were assessed for all participants who received any dose.
Findings: Between September 15, 2020, and March 16, 2022, 87 patients were enrolled in HERIZON-BTC-01: 80 patients in cohort 1 (median age 64 years [IQR 58-70]) , seven in cohort 2 (median age 62 years [IQR 58-77]). As of data cutoff (October 10, 2022), 18 patients (21%) (17 in Cohort 1 and 1 in Cohort 2) were continuing treatment with zanidatamab; 69 (79%) patients discontinued treatment (64 patients [74%] developed radiographic progression). Median follow-up was 12.4 months (IQR 9.4–17.2). Objective responses confirmed by independent central review were observed in 33 patients in cohort 1 (41.3% [95% CI 30.4–52.8]).
Grade 3 treatment-related adverse events occurred in 16 (18%) patients; the most common were diarrhea (4 [5%] patients) and decreased ejection fraction (3 [3%] patients). There were no grade 4 treatment-related adverse events and no treatment-related deaths.
Interpretation: Zanidatamab demonstrated meaningful clinical benefit and a manageable safety profile in patients with refractory HER2-positive biliary tract cancer and may be considered as an option for future treatment of HER2-positive biliary tract cancer.
参考文献 Reference
Harding JJ et al. Lancet Onc 2023;24: 772
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奥拉帕尼新辅助治疗 BRCA 突变卵巢癌患者的初步研究 (9/1/2023)
Pilot study of neoadjuvant Olaparib in ovarian cancer patients with BRCA mutation
这是一项单组, 开放标签试点试验 (NOW), 评估了奥拉帕尼在新辅助治疗中的益处，研究对象为不适合进行原发性肿瘤减灭手术的晚期, 高级别上皮性卵巢癌, 腹膜癌或输卵管癌患者。 所有患者均存在 BRCA1, BRCA2, RAD51C, RAD51D 或PALB2 种系突变。 主要目标是奥拉帕尼在新辅助治疗中的可行性，其定义是不可接受的毒性（剂量中断 > 2周或两次剂量减少）或疾病进展。 如果 10 名患者能够立即进行肿瘤缩小手术，则该干预措施被认为是可行的。
该研究纳入了 51 名接受基因检测的患者，其中 20 人被发现有相关突变，15 人最终接受了奥拉帕尼治疗。 该研究中40% 患有 IV 期疾病，73% 患有 BRCA1 突变。患者接受两个为期 28 天的奥拉帕尼周期，然后通过影像学和 CA-125 测量进行疗效评估。 如果适合，患者立即进行手术。 如果患者有响应但不适合手术，或者疾病进展，则开始使用紫杉醇和卡铂进行化疗，然后如果可能的话进行手术。 手术后，患者接受紫杉醇/卡铂辅助治疗，然后根据患者情况接受奥拉帕尼维持治疗。
共有13 名患者 (86.6%) 在接受奥拉帕尼治疗后可以进行手术； 1例患者在化疗后接受手术，1例患者因体能状态恶化而无法手术。 共85% 的手术病例术后无肉眼残留病灶。 所有患者都接受了最佳的肿瘤缩小手术，其中一名患者实现了病理完全响应。 化疗周期的中位数为六个。在 13 名患有可测量疾病的患者中，部分响应率为 53.8%，并且这些患者均未出现疾病进展。奥拉帕利两个周期后，93% 的患者 CA-125 水平降低，75% 的患者降低了 75%。中位随访 11.7 个月时，未达到中位无进展生存期，12 个月无进展生存率为 81%。
PARP 抑制剂治疗的不良事件与预期一致，最常见的毒性是腹痛、便秘和贫血，但只有贫血是 3 级事件 (20%) 。只有一名患者需要减少剂量，另一名患者需要中断剂量。
This is a single-arm, open-label pilot trial (NOW) evaluating the benefit of olaparib in neoadjuvant therapy in patients with advanced, high-grade epithelial ovarian, peritoneal or fallopian tube carcinoma not eligible to primary debulking surgery. All patients had BRCA1, BRCA2, RAD51C, RAD51D, or PALB2 germline mutations. The primary objective was the feasibility of olaparib in neoadjuvant therapy, defined as unacceptable toxicity (dose interruption >2 weeks or two dose reductions) or disease progression. The intervention was considered feasible if 10 patients were able to undergo immediate tumor reduction surgery.
The study included 51 patients who underwent genetic testing, of whom 20 were found to have relevant mutations, and 15 were ultimately treated with olaparib. Forty percent of the study had stage IV disease, and 73% had BRCA1 mutations. Patients received two 28-day cycles of olaparib and were then evaluated for efficacy by imaging and CA-125 measurements. If appropriate, the patient was immediately operated on. If the patient responded but was not a candidate for surgery, or if the disease progressed, chemotherapy with paclitaxel and carboplatin was started, followed by surgery if possible. After surgery, patients received adjuvant paclitaxel/carboplatin, and then olaparib maintenance therapy as per the discretion of patients or providers.
Surgery after olaparib was possible in 13 patients (86.6%) ; 1 patient underwent surgery after chemotherapy and 1 patient was inoperable due to deteriorating performance status. A total of 85% of surgical cases had no gross residual disease after surgery. All patients underwent optimal tumor reduction, and one patient achieved a pathologic complete response. The median number of chemotherapy cycles was six. Among the 13 patients with measurable disease, the partial response rate was 53.8%, and none of these patients experienced disease progression. After two cycles of olaparib, CA-125 levels were reduced in 93% of patients and for 75% of patients the reduction was 75%. At a median follow-up of 11.7 months, the median progression-free survival was not reached, and the 12-month progression-free survival rate was 81%.
Adverse events with PARP inhibitor were as expected, with the most common toxicities being abdominal pain, constipation, and anemia, but only anemia was a grade 3 event (20%). One patient required a dose reduction and the one required a dose interruption.
参考文献 Reference
Westin SN et al. Soc Gyn Onc Ann Meeting on Women’s Cancer 2023; Abstr 138
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重复活检对三阴性乳腺癌患者的 HER2 低状态的影响 (8/27/2023)
HER2-low status on repeated biopsies in triple-negative breast cancer
方法：这项研究包括 2017 年至 2022 年间在单个大型学术中心接受治疗的所有诊断时患有三阴性乳腺癌患者。HER2 状态不知道的活检被排除在外。HER2-低被定义为免疫组织化学 1+，或 2+（原位杂交非扩增）。 根据活检获取的时间和方法，活检的类型分空心针活检, 手术活检或转移性活检。 对于早期转移匹配分析，空心针活检被认为是早期活检，除非空心针活检缺失，然后使用手术活检代替。 对于具有多个转移性活检的病例，使用第一个转移性活检。
结果：一共纳入了 529 名诊断时患有三阴性乳腺癌的连续患者。活检次数为（1（192 人）, 2（235 人）, 3（52 人）, 4（38 人）和 5-9（12 人）时, HER2 低结果分别为 60%, 74%, 83%, 87% 和 100% 。 在之前没有 HER2-低结果的女性中，大约三分之一在每次连续的额外活检中转化为 HER2-低。 不同类型活检之间的 HER2 状态分布没有显著差异（分别有 58%、63% 和 54% 的患者在其空心针, 手术或转移性活检中具有 HER2 低结果； p =0.2）。 在 246 名进行了匹配的空心针/ 手术活检的女性中，四分之一的人的 HER2 状态发生了变化（55% 从低到 0, 44% 从 0 到低，1% 从低到 3+）。 接受新辅助治疗且有残留病灶的女性与以手术作为主的女性之间，空心针/手术 HER2 状态转换率没有差异。 在具有匹配的早期/转移性（70 例）或两个匹配的转移性活检（39 例）的女性中，近一半 (44%) 的 HER2 状态发生转变。
结论：研究者认为，三阴性乳腺癌患者的 HER2 状态是动态的变化而非为特定实体。对于先前没有 HER2-低结果的三阴性乳腺癌患者，在进展时重复活检可以增加获得 HER2-低结果的机会以及随后的治疗意义。 不清楚的是动态 HER2 结果是否代表生物学或分析差异仍有待确定。
Methods: This study included all patients with triple-negative breast cancer at the time of diagnosis. They were treated in a single large academic center between 2017 and 2022. Biopsies with unknown HER2 status were excluded. HER2-low was defined, by immunohistochemistry, as 1+ or 2+ (non-amplified by in situ hybridization). Depending on when and how the biopsy was obtained, the types of biopsy are core biopsy, surgical biopsy, or metastatic biopsy. For early metastases matching analysis, core biopsies were considered early biopsies, unless the core biopsy was missing, then surgical biopsy was used instead. For cases with multiple metastatic biopsies, the first metastatic biopsy was used.
Results: A total of 529 consecutive patients with triple-negative breast cancer at diagnosis were included. HER2 low results were 60%, 74%, 83%, 87% and 100% when the number of biopsies was 1 (192 patients), 2 (235 patients), 3 (52 patients), 4 (38 patients) and 5-9 (12 patients) respectively. Among women with no previous HER2-low results, approximately one-third converted to HER2-low at each successive additional biopsy. There were no significant differences in the distribution of HER2 status between the different types of biopsies (58%, 63%, and 54% of patients had a HER2-low status on their core needle, surgical, or metastatic biopsies, respectively; p =0.2). Of the 246 women who had a matched core-surgical biopsies, one quarter had a change in HER2 status (55% from low to 0, 44% from 0 to low, and 1% from low to 3+). Core-surgical HER2 status conversion rates did not differ between women who had neoadjuvant therapy with residual disease and those who had surgery as their primary treatment modality. Among women with matched early-metastatic (70 cases) or two matched metastatic biopsies (39 cases) nearly half (44%) converted their HER2 status.
Conclusions: The investigators believe that HER2 status in patients with triple-negative breast cancer is dynamic rather than a specific entity. For triple-negative breast cancer patients with no previous HER2-low results, repeat biopsies at the time of progression can increase the chance of obtaining a HER2-low result and consequent treatment implication. Whether the dynamic HER2 results represent biological or analytical variations remains to be determined.
参考文献 Reference
Bar Y et al. J Clin Onc 2023; 41 (16 suppl 1005)
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Scintix 生物引导放射治疗癌症 (8/26/2023)
Scintix biology-guided cancer radiotherapy
根据最近报告, 首例癌症患者在加利福尼亚州的斯坦福医学癌症中心接受Scintix生物引导放射治疗。
Scintix 生物引导放疗利用癌症自身的生物学特性来指导放疗。 这是第一个将正电子发射断层扫描（PET）技术与用于受控辐射剂量管理的直线加速器（LINAC）相结合的平台。可潜在治疗多种肿瘤, 而不影响健康组织。
Scintix 利用计算机断层扫描 (CT) 的解剖数据和 PET 的功能成像数据为癌症治疗提供个性化放射治疗。 在接受治疗之前，患者会被注射氟脱氧葡萄糖 F18 (FDG)。 FDG 是一种放射性示踪剂，将氟 18 等诊断放射性同位素与葡萄糖结合在一起， 当癌细胞消耗 FDG 时，肿瘤就会产生排放物。 配备 Scintix 技术的 ReflexXion X1 机器可检测这些发射，并根据患者癌细胞的数据不断构建地图，以确定治疗中要传送的辐射位置和数量。 Scintix 技术可检测注射放射性示踪剂的发射，并在短短半秒内将辐射束返回肿瘤以摧毁它们。
Scintix 生物引导放射治疗的优点在于放射治疗过程中实时跟踪癌细胞的放射剂量，从而最大限度地减少向患者整个内部靶区提供大剂量放射的需要, 以保护周围的健康组织免受伤害。 它可以治疗寡转移和多转移疾病; 可以与化疗, 免疫疗法和靶向药物一起使用，以改善患者的治疗效果。
The first cancer patient received Scintix biology-guided radiation therapy at Stanford Medicine Cancer Center in California, according to a recent report. Scintix biology-guided radiation therapy uses the cancer’s own biology to guide radiation therapy. It is the first platform to combine positron emission tomography (PET) technology with a linear accelerator (LINAC) for controlled radiation dose management. It can potentially treat a variety of tumors without affecting healthy tissue.
Scintix uses anatomical data from computed tomography (CT) and functional imaging data from PET to deliver personalized radiation therapy for cancer treatment. Prior to treatment, patients are given an injection of fluorodeoxyglucose F18 (FDG). FDG is a radiotracer that combines a diagnostic radioisotope, such as fluorine-18, with glucose. When FDG is consumed by cancer cells, tumors produce emissions. The ReflexXion X1 machine, equipped with Scintix technology, detects these emissions and continuously constructs a map based on data from the patient’s cancer cells to determine where and how much radiation to be delivered during treatment. Scintix technology detects the emission of an injected radiotracer and returns beamlets of radiation to tumors to destroy them in as little as half a second.
The advantage of Scintix biology-guided radiation therapy is that the radiation dose to cancer cells is tracked in real time during radiation treatment, thereby minimizing the need to deliver large doses of radiation to the patient’s entire internal target volume to protect surrounding healthy tissue from harm. It can treat oligo-metastatic and multi-metastatic diseases; it can be used together with chemotherapy, immunotherapy and targeted drugs to improve patient outcomes.
参考文献 Reference
https://www.medicaldevice-network.com/projects/reflexion-scintix-radiotherapy
American Society for Therapeutic Radiology and Oncology: https://www.astro.org RefleXion_PressRel
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Ribociclib 和内分泌治疗作为 HR+/HER2- 早期乳腺癌的辅助治疗 (8/20/23)
Ribociclib plus endocrine therapy as adjuvant treatment in pHR+/HER2- early breast cancer
背景：III 期临床试验 (NATALEE, NCT03701334) 在具有复发风险的 II 期或 III 期 HR+/HER2− 早期乳腺癌患者中评估了辅助Ribociclib + 内分泌治疗， 包括没有淋巴结受累的患者 (N0)。选择 400 毫克剂量的 3 年Ribociclib 持续时间以提高耐受性，同时保持疗效。 以下是中期分析的结果。
方法：男性和绝经前或绝经后女性按 1:1 随机分配至 Ribociclib（400 毫克/天；3 周用药/1 周停药，持续 3 年）+ 内分泌治疗（来曲唑 2.5 毫克/天或阿那曲唑 1 毫克/天，≥ 5 年) 或单独进行内分泌治疗。 男性和绝经前女性也接受goserelin治疗。 符合条件的患者具有AJCC（第 8 版）的 IIA（T2N0 并具有其他危险因素或 1-3 个腋窝淋巴结 [N1]）, IIB (T2N1, T3N0) 期或 III (N2, T3N1)期。根据 STEEP 标准定义,预先指定的无侵袭性疾病生存期 (iDFS)中期分析是在约 425 个 iDFS 事件（约占计划总事件的 85%）之后计划的。通过 Kaplan-Meier 方法进行评估，并通过分层对数秩检验进行统计比较。
结果：从2019年1月10日至2021年4月20日，5,101名患者被随机分组（Ribociclib +内分泌治疗，n = 2,549；单独内分泌治疗，n = 2,552）。 截至数据截止（2023 年 1 月 11 日），中位随访时间为 34 个月（最少21 个月）。515名患者 (20.2%) 和 1449名患者 (56.8%)分别完成了3 年和 2 年 Ribociclib 治疗； 3810 名 (74.7%) 仍在研究治疗中（Ribociclib +内分泌治疗，n = 1,984；仅内分泌治疗，n = 1,826）。 iDFS 在 426 个事件后进行评估（Ribociclib + 内分泌治疗，n = 189；单独内分泌治疗，n = 237）。Ribociclib +内分泌治疗表现出比单独内分泌治疗显著的, 更长的 iDFS（HR，0.748；95% CI，0.618-0.906；P = .0014）； 3 年 iDFS 率分别为 90.4% 和 87.1%。 iDFS 获益在分层因素和其他亚组中总体上是一致的。 总生存期, 无复发生存期和远处无病生存期的次要终点始终有利于Ribociclib。 400 毫克的 Ribociclib 具有良好的安全性，没有出现新的信号。
结论：研究者认为, Ribociclib 添加到标准护理内分泌治疗中，iDFS 具有统计学上显著的, 有临床意义的改善，且安全性良好。 NATALEE 结果支持 ribociclib + 内分泌治疗作为广泛的 II 期或 III 期 HR+/HER2− 早期乳腺癌患者（包括 N0 疾病患者）的治疗选择。
Background: A phase III trial (NATALEE, NCT03701334) evaluated adjuvant ribociclib + endocrine therapy in patients with stage II or III HR+/HER2− early breast cancer at risk of recurrence, including patients without nodal involvement (N0). A 3-year duration of ribociclib at 400 mg dose was chosen to improve tolerability while maintaining efficacy. The results of the interim analysis were presented.
Methods: Men and premenopausal or postmenopausal women were randomized 1:1 to ribociclib (400 mg/day; 3 weeks on/1 week off for 3 years) + endocrine therapy (letrozole 2.5 mg/day or anastrozole 1 mg/day for ≥ 5 years) or endocrine therapy alone. Men and premenopausal women were also treated with goserelin. Eligible patients had AJCC (8th Edition) stage IIA (T2N0 with other risk factors or 1-3 axillary nodes [N1]), IIB (T2N1, T3N0) or III (N2, T3N1) stages. The prespecified interim analysis of invasive disease-free survival (iDFS) was planned after approximately 425 iDFS events (approximately 85% of the total planned events), as defined by STEEP criteria. Evaluations were performed by the Kaplan-Meier method and statistical comparisons were performed by the stratified log-rank test.
Results: From January 10, 2019, to April 20, 2021, 5,101 patients were randomized (Ribociclib + endocrine therapy, n = 2,549; endocrine therapy alone, n = 2,552). As of data cutoff (January 11, 2023), median follow-up was 34 months (minimum 21 months). 515 patients (20.2%) and 1449 patients (56.8%) completed 3 and 2 years of ribociclib treatment, respectively; 3810 (74.7%) remained on study treatment (ribociclib + endocrine therapy, n = 1,984; endocrine therapy only, n = 1,826). iDFS was assessed following 426 events (Ribociclib + endocrine therapy, n = 189; endocrine therapy alone, n = 237). Ribociclib + endocrine therapy demonstrated significantly longer iDFS than endocrine therapy alone (HR, 0.748; 95% CI, 0.618-0.906; P = .0014); 3-year iDFS rates were 90.4% vs 87.1%, respectively. iDFS benefit was generally consistent across stratification factors and other subgroups. The secondary endpoints of overall survival, relapse-free survival, and distant disease-free survival consistently favored ribociclib. Ribociclib 400 mg had a favorable safety profile with no new signals emerging.
Conclusions: The investigators concluded that the addition of ribociclib to standard-of-care endocrine therapy produced a statistically significant, clinically meaningful improvement in iDFS with a favorable safety profile. The NATALEE results support ribociclib + endocrine therapy as a treatment option for a broad range of patients with stage II or III HR+/HER2− early breast cancer, including those with N0 disease.
参考文献 Reference
Slamon DJ et al. J Clin Onc 2023; 41: 17_suppl LBA500
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固定疗程 venetoclax 加 obinutuzumab 治疗老年慢性淋巴细胞白血病(CLL)患者的长期结果 (8/19/2023)
Long-term results of fixed-duration venetoclax and obinutuzumab in elderly patients with CLL
这是一项前瞻性, 多中心, 开放标签, 随机 III 期临床试验(CLL14),旨在评估固定疗程venetoclax加 obinutuzumab 与苯丁酸氮芥(chlorambucil)加 obinutuzumab 相比, 对患者的疗效和安全性。 该试验纳入了 432 名患者，所有患者均先前未接受治疗，中位年龄为 72 岁，且风险状况各异。 患者接受了1年的治疗。 然后，无论可测量残留病灶（MRD）或响应如何，所有患者都停止治疗。
6 年随访结果: 与接受苯丁酸氮芥加 obinutuzumab (对照组)治疗的患者相比，接受固定疗程venetoclax加 obinutuzumab(试验组) 治疗的患者继续获得改善的无进展生存期（风险比 [HR] = 0.40）和更高的不可检测 MRD 发生率（53.1 % 相对于21.7%）。 中位无进展生存期为 76.2 个月。 数据还显示，与对照组 (37.1%) 相比，试验组的下次治疗时间显著改善，为 65.2% (HR = 0.44)。亚组分析显示，具有 TP53 畸变或未突变 IGHV 状态等高危因素的患者也受益于 Venetoclax 加 obinutuzumab 的治疗。但与没有这些高危因素的患者相比，他们的无进展生存期较短，治疗结束时 MRD 水平较高的患者的生存结果明显较短。 在安全性方面，该研究显示两个治疗组的治疗后毒性发生率均较低，并且没有新的安全信号。
试验组中最常发生的 3 级（≥ 2%）不良事件是中性粒细胞减少, 血小板减少, 输注相关反应, 贫血, 发热性中性粒细胞减少、肺炎和白细胞减少。 试验组中某些实体器官肿瘤和黑色素瘤的继发性恶性肿瘤发生率在数字上较高，但这些差异并不具有统计学意义。
这些结果证实了固定疗程的 Venetoclax 和 obinutuzumab 对于既往未接受治疗且患有共存疾病的 CLL患者具有治疗益处。
This is a prospective, multicenter, open-label, randomized phase III clinical trial (CLL14) designed to evaluate the efficacy and safety of fixed-duration venetoclax plus obinutuzumab compared with chlorambucil plus obinutuzumab in patients with CLL. The trial enrolled 432 patients, all treatment-naive, with a median age of 72 years and varying risk profiles. They received treatment for 1 year. All patients then discontinued treatment regardless of measurable residual disease (MRD) or response.
Six-year follow-up results: Patients treated with a fixed duration of venetoclax plus obinutuzumab (experimental arm) continued to have improved progression-free survival compared to patients treated with chlorambucil plus obinutuzumab (control arm) (hazard ratio [HR ] = 0.40) and a higher incidence of undetectable MRD (53.1 % vs 21.7%). Median progression-free survival was 76.2 months. The data also showed a significant improvement in time to next treatment in the experimental group of 65.2% (HR = 0.44) compared to the control group (37.1%). Subset analyzes showed that patients with high-risk factors such as TP53 mutations or unmutated IGHV status also benefited from venetoclax plus obinutuzumab. But they had shorter progression-free survival than patients without these high-risk factors. Patients with higher MRD levels at the end of treatment had significantly shorter survival outcomes.
In terms of safety, the study showed a low incidence of post-treatment toxicity in both treatment arms and no new safety signals. The most frequent grade 3 (≥ 2%) adverse events in the trial arm were neutropenia, thrombocytopenia, infusion-related reactions, anemia, febrile neutropenia, pneumonia, and leukopenia. Rates of secondary malignancies for certain solid organ tumors and melanoma were numerically higher in the trial group, but these differences were not statistically significant.
These results confirm the therapeutic benefit of a fixed-duration of venetoclax and obinutuzumab in previously untreated CLL patients with comorbidities.
参考文献 Reference
Al-Sawaf O et al. Eur Hematol Asso (EHA) 2023 Hybrid Congress Abstr S145
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第一线治疗无肿瘤 BRCA1/2 突变的晚期卵巢癌后给予维持 durvalumab, 贝伐单抗和奥拉帕尼 (8/13/2023)
Maintenance durvalumab, bevacizumab and olaparib following first-line treatment of BRCA1/2-free advanced ovarian cancer patients without tumor BRCA1/2 mutations
方法：这是一项III期安慰剂对照临床试验（DUO-O），患者为 III 期或IV 期, 高级别上皮细胞, 无肿瘤 BRCA1/2 突变的晚期卵巢癌，并已完成或计划接受减瘤手术和1 个周期紫杉醇/卡铂 ± 贝伐单抗。 在第 2 周期，患者按 1:1:1 随机分配至第 1 组(意向性测试人群)：紫杉醇/卡铂 + 贝伐单抗（15 毫克/公斤, IV 每3星期一次）+ 安慰剂Durvalumab（最多 6 个周期），然后是维持贝伐单抗（15 毫克/公斤, IV 每3星期一次；总共 15 个月) + 安慰剂Durvalumab (总计 24 个月) + 安慰剂奥拉帕尼 (总计 24 个月)； 第 2 组：紫杉醇/卡铂 + 贝伐单抗 + Durvalumab (1120 毫克 IV 每3星期一次)，然后是安慰剂贝伐单抗 + Durvalumab (1120 毫克IV 每3星期一次) + 安慰剂奥拉帕尼； 或第 3 组(试验组)：紫杉醇/卡铂 + 贝伐单抗 + Durvalumab，然后是维持贝伐单抗 + Durvalumab + 奥拉帕尼（300 毫克每天两次）。 主要终点，即比较第 3 组相对于第 1 组的无进展生存期，首先在无肿瘤 BRCA1/2 突变 HRD+ 人群（GIS [基因组不稳定性评分]≥ 42）中进行测试，然后是意向性测试人群。
结果：1,130 名患者被随机分组：第 1 组中 378 名患者、第 2 组中 374 名患者和第 3 组中 378 名患者。在预先指定的中期分析（2022 年 12 月 5 日）中，观察到第 3 组(试验组)与第 1 组（意向性测试人群）相比，无进展生存期具有统计显著性改善, 在HRD+ 和意向性测试人群中的 HR 分别为和0.49 (95% CI 0.34–0.69；P <0.0001), 和 0.63 (95% CI 0.52–0.76；P <0.0001)； 在 HRD 亚组中观察到一致的无进展生存期效果（HR 0.68，95% CI 0.54-0.86）。 与第 1 组，第 2 组的无进展生存期有所改善，但未达到统计学显著性。 在研究期间，第 1, 2 和 3 组中分别有 34%、43% 和 39% 的患者报告出现严重不良事件。
结论：在新诊断的无肿瘤 BRCA1/2 突变的晚期卵巢癌患者中，紫杉醇/卡铂 + 贝伐单抗 + Durvalumab后继维持贝伐单抗 + Durvalumab + 奥拉帕尼, 与紫杉醇/卡铂 + 贝伐单抗后继维持贝伐单抗相比，无进展生存期具有统计学意义和临床意义的改善。 安全性总体上与每种药物的已知情况一致。
Methods: This was a phase III placebo-controlled clinical trial (DUO-O) in patients with stage III or IV, high-grade epithelial, advanced ovarian cancer without tumor BRCA1/2 (non-tBRCA1/2) mutations. They had completed or planned to undergo tumor debulk surgery and 1 cycle of paclitaxel/carboplatin ± bevacizumab. In cycle 2, patients were randomized 1:1:1 to arm 1 (intention-to-treat population): paclitaxel/carboplatin + bevacizumab (15 mg/kg, IV every 3 weeks) + placebo durvalumab (up to 6 cycles) followed by maintenance bevacizumab (15 mg/kg IV every 3 weeks; total 15 months) + placebo durvalumab (total 24 months) + placebo olaparib (total 24 months); Arm 2: paclitaxel/carboplatin + bevacizumab + Durvalumab (1120 mg IV q3w), then placebo bevacizumab + durvalumab (1120 mg IV every 3 weeks) + placebo olaparib; or Arm 3 (experiment arm): paclitaxel/carboplatin + bevacizumab + durvalumab followed by maintenance bevacizumab + durvalumab + olaparib (300 mg twice daily). The primary endpoint was progression-free survival comparing Arm 3 (experiment arm) and Arm 1 (intention-to treat arm), in the non-tBRCA1/2-mutated HRD+ population (GIS [Genomic Instability Score] ≥ 42), followed by intention-to-treat population.
Results: 1,130 patients were randomized: 378 patients in arm 1, 374 patients in arm 2, and 378 patients in arm 3. At the prespecified interim analysis (December 5, 2022), a statistically significant improvement in progression-free survival was observed in Arm 3 compared to Arm 1, with HRs in the HRD+ and intention-to-test populations, being 0.49 (95% CI 0.34–0.69; P<0.0001), and 0.63 (95% CI 0.52–0.76; P<0.0001) respectively; a consistent progression-free survival effect was observed in the HRD subgroup (HR 0.68, 95% CI 0.54-0.86). Progression-free survival was improved in arm 2 compared with arm 1 (intention-to-treat population), but did not reach statistical significance. Serious adverse events were reported by 34%, 43% and 39% of patients in arms 1, 2 and 3, respectively, during the study period.
Conclusions: In patients with newly diagnosed advanced ovarian cancer without tumor BRCA1/2 mutations, paclitaxel/carboplatin + bevacizumab + Durvalumab followed by maintenance bevacizumab + Durvalumab + olaparib, compared with paclitaxel/carboplatin + Bevacizumab followed by maintenance bevacizumab resulted in a statistically significant and clinically meaningful improvement in progression-free survival. Safety profiles were generally consistent with what is known for each drug.
参考文献 Reference
Harter P et al. J Clin Onc 2023; 41; 17_suppl LBA5506
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第一线或第二线CDK4/6 抑制剂治疗 HR+/HER2- 晚期乳腺癌 (8/12/2023)
First- vs second-line CDK4/6 inhibitor in advanced ER+/HER2- breast cancer
方法： 这是一项III 期试验(SONIA, NCT03425838), 荷兰 74 家医院纳入了既往未接受晚期乳腺癌治疗的 HR+/HER2-, 疾病可测量或可评估绝经前和绝经后妇女 (N=1050)。患者以 1:1 的比例随机分配接受方案A（第一线治疗采用非甾体芳香酶抑制剂 + CDK4/6抑制剂，病情进展后采用氟维司群或方案 B（一线治疗采用非甾体芳香酶抑制剂，病情进展后采用氟维司群 + CDK4/6 抑制剂)。在可用的 CDK4/6抑制剂（abemaciclib, Palbociclib, ribociclib）之一之间进行选择是一个分层因素，由治疗医生自行决定。 主要终点是从随机分组到第二个客观疾病进展（由当地研究人员评估）或死亡。 次要终点包括总生存期, 安全性, 生活质量和成本效益。
结果：中位随访 37.3 个月后，方案 A 的中位死亡的时间为 31.0 个月，而方案 B 为 26.8 个月（风险比 0.87；95% 置信区间，0.74 至 1.03；P =0.10）。 治疗效果在预先定义的亚组水平上是一致的。 安全性是内分泌治疗 + CDK4/6抑制剂的特征。 方案 A 中 CDK4/6抑制剂的中位时间为 24.64 个月，方案B 中为 8.08 个月。 方案 A 的 3 级以上不良事件数为 2782 例, 方案 B 为 1620 例。
结论：与二线使用相比，一线使用 CDK4/6抑制剂 + 内分泌治疗HR+,HER2- 晚期乳腺癌并未提供统计学上显著的, 也没有临床意义的无进展生存期益处。 在一线使用会使 CDK4/6抑制剂的治疗时间延长 16.56 个月 ，并增加毒性和成本。 因此，二线使用可能是大多数患者的首选。
Methods: This is a phase III trial (SONIA, NCT03425838), involving 74 hospitals in the Netherlands enrolling HR+/HER2- women with measurable or evaluable disease in premenopausal or postmenopausal advanced breast cancer patients (N=1050 ). Patients were randomly assigned in a 1:1 ratio to receive plan A (first-line treatment with non-steroidal aromatase inhibitor + CDK4/6 inhibitor; fulvestrant after disease progression or plan B (first-line treatment with non-steroidal aromatase inhibitor; fulvestrant + CDK4/6 inhibitor after disease progression). Choosing between one of the available CDK4/6 inhibitors (abemaciclib, palbociclib, ribociclib) is a stratification factor, determined by treatment physicians’ discretion. Primary endpoint was time from randomization to second objective disease progression (assessed by local investigators) or death. Secondary endpoints included overall survival, safety, quality of life, and cost-effectiveness.
Results: After a median follow-up of 37.3 months, the median time to death was 31.0 months for regimen A and 26.8 months for regimen B (hazard ratio, 0.87; 95% confidence interval, 0.74 to 1.03; P = 0.10). Treatment effects were consistent across pre-defined subgroup levels. Safety is characteristic of endocrine therapy + CDK4/6 inhibitors. The median duration of CDK4/6 inhibitors was 24.64 months in regimen A and 8.08 months in regimen B. The number of grade 3 or higher adverse events was 2,782 cases in regimen A and 1,620 cases in regimen B.
Conclusions: First-line use of CDK4/6 inhibitors + endocrine therapy in HR+, HER2- advanced breast cancer did not provide a statistically significant, nor clinically meaningful, benefit in progression-free survival compared with second-line use. Use in the first line prolongs the duration of treatment with CDK4/6 inhibitors by 16.56 months and increases toxicity and cost. Therefore, second-line use may be the first choice for most patients.
参考文献 Reference
Sonke GS et al. J Clin Onc 2023; 41: 17_suppl LBA1000
在哌柏西利的治疗出现进展后继续维持哌柏西利+二线内分泌治疗并没有改善无进展生存期 (8/12/2023)
Continued maintenance of Palbociclib plus second-line endocrine therapy after progression on Palbociclib did not improve progression-free survival
一项研究旨在确定哌柏西利(Palbociclib) 维持疗法是否可以提高该患者群体二线治疗的抗肿瘤活性。 方法：共有 198 名 HR+/HER2- 晚期乳腺癌患者，接受过一线哌柏西利加内分泌治疗（芳香酶抑制剂或氟维司群）而疾病进展。 如果患者对一线治疗有响应或疾病稳定≥24周，或者在辅助治疗中采用基于哌柏西利的治疗完成后超过 12 个月而疾病进展，则符合资格。 患者被随机分配（2:1 比例）接受哌柏西利加二线内分泌治疗（来曲唑或氟维司群）或单独二线内分泌治疗。主要终点是无进展生存期。 次要终点包括总客观响应率, 临床受益率, 总体生存率和安全性。
结果：2019 年 4 月至 2022 年 10 月期间，分别有 136 名和 62 名患者随机接受哌柏西利加内分泌治疗 和内分泌治疗。 中位年龄为 59 岁（范围：33-85），61.1% 患有内脏疾病，89.9% 的患者接受芳香酶抑制剂 + 哌柏西利作为转移性疾病的一线治疗。 在 8.7 个月的中位随访和 155 个无进展生存期事件中，经研究者评估，哌柏西利加内分泌治疗组的中位无进展生存期为 4.2 个月（95% CI 3.5–5.8），而内分泌治疗组为 3.6 个月（95% CI 2.7–4.2） （风险比 0.8，95% CI 0.6–1.1，p=0.206）。在 138 名患有可测量疾病的患者中，哌柏西利加内分泌治疗和内分泌治疗组的总响应率（6.4% vs. 2.3%）或临床受益率（33.0% vs. 29.5%）没有观察到显著差异。 使用哌柏西利加内分泌治疗治疗的患者中 3-4 级不良事件较高（45.2% vs. 8.3%）。
结论：对于 HR+/HER2- 晚期乳腺癌患者，在先前基于哌柏西利的治疗出现进展后，与单独使用二线内分泌治疗治疗相比，使用维持哌柏西利+二线内分泌治疗并没有改善无进展生存期。
Maintenance of palbociclib plus second-line endocrine therapy after progression on palbociclib did not improve progression-free survival
A study aimed to determine whether maintenance therapy with palbociclib could improve the antitumor activity of second-line therapy in ER+/HER2- advanced breast patient population.
Methids: A total of 198 patients with HR+/HER2- advanced breast cancer had disease progression on first-line palbociclib plus endocrine therapy (aromatase inhibitor or fulvestrant). Patients were eligible if they responded to first-line therapy or had stable disease for ≥ 24 weeks, or if their disease progressed more than 12 months after completion of palbociclib-based adjuvant therapy. Patients were randomly assigned (2:1 ratio) to receive palbociclib plus second-line endocrine therapy (letrozole or fulvestrant) or second-line endocrine therapy alone. The primary endpoint was progression-free survival. Secondary endpoints included objective response rate, clinical benefit rate, overall survival and safety.
Results: Between April 2019 and October 2022, 136 and 62 patients were randomized to receive palbociclib plus endocrine therapy or endocrine therapy, respectively. The median age was 59 years (range: 33-85), 61.1% had visceral disease, and 89.9% of patients received an aromatase inhibitor + palbociclib as first-line therapy for metastatic disease. At a median follow-up of 8.7 months and 155 progression-free survival events, median progression-free survival was 4.2 months (95% CI 3.5–5.8) in the palbociclib plus endocrine therapy group by investigator assessment, In the endocrine therapy group it was 3.6 months (95% CI 2.7–4.2) (hazard ratio 0.8, 95% CI 0.6–1.1, p=0.206). Among 138 patients with measurable disease, no significant differences in overall response rates (6.4% vs. 2.3%) or clinical benefit rates (33.0% vs. difference. Grade 3-4 adverse events were higher in patients treated with palbociclib plus endocrine therapy (45.2% vs. 8.3%).
Conclusions: In HR+/HER2- advanced breast cancer patients after progression on prior palbociclib-based therapy, maintenance palbociclib + second-line endocrine therapy did not improve progression-free survival compared with second-line endocrine therapy alone.
参考文献 Reference
LLombart-Cussac A et al. J Clin Onc 2023; 41: 16-suppl 1001
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FDA 加速批准 epcoritab-bysp 治疗复发或难治性弥漫性大 B 细胞淋巴瘤(8/6/2023)
FDA granted accelerated approval to epcoritab-bysp for relapsed or refractory diffuse large B-cell lymphoma not otherwise specified
FDA加速批准 epcoritamab-bysp（Epkinly）用于治疗未另有说明的复发或难治性弥漫性大 B 细胞淋巴瘤（DLBCL），包括惰性淋巴瘤引起的 DLBCL 和经过两次或多次全身治疗后的高级别 B 细胞淋巴瘤。
Epcoritamab-bysp 是一种双特异性 CD20 导向的 CD3 T 细胞接合剂，在 EPCORE NHL-1 (NCT03625037) 中进行了评估，这是一项开放标签, 多队列, 多中心单臂试验。 有效人群包括 148 名患有复发性或难治性 DLBCL 的患者，以及经过两种或多种全身治疗（包括至少一种抗 CD20 单克隆抗体）后的高级别 B 细胞淋巴瘤。 主要疗效结果指标是总体响应率，并由独立审查委员会评估。体响应率为 61% (95% CI: 53, 69)，其中 38% 的患者达到完全响应。响应者的中位随访时间为 9.8 个月，中位响应持续时间为 15.6 个月（95% CI：9.7，未达到）。
在接受推荐剂量 epcoritab-bysp 的 157 名复发或难治性大 B 细胞淋巴瘤患者中，51% 的患者发生细胞因子释放综合征，6% 发生免疫效应细胞相关神经毒性综合征，15% 发生严重感染。 对于细胞因子释放综合征，37% 的患者发生 1 级，17% 发生 2 级，2.5% 发生 3 级。 对于免疫效应细胞相关神经毒性综合征，1 级发生率为 4.5%，2 级发生率为 1.3%，5 级发生率为 0.6%。
由于存在细胞因子释放综合征和免疫效应细胞相关神经毒性综合征风险，患者在第 1 周期第 15 天服用 48 毫克剂量后应住院 24 小时。 最常见（≥ 20%）的不良反应是慢性鼻窦炎、疲劳、肌肉骨骼疼痛、注射部位反应、发热、腹痛、恶心和腹泻。 最常见的3至4级实验室异常（≥10%）是淋巴细胞计数减少、中性粒细胞计数减少、白细胞计数减少、血红蛋白减少和血小板减少。
推荐的方案包括以 28 天为周期皮下注射 epcoritab-bysp，直至疾病进展或出现不可接受的毒性。 推荐剂量是在第 1 周期中逐步增加剂量（第 1 天 0.16 毫克，第 8 天 0.8 毫克，第 15 天和第 22 天 48 毫克），然后在第 2 至第 3 周期期间每周固定剂量 48 毫克。 第 4 周期到第 9 周期每隔一周进行一次，在后续周期每四周进行一次。
FDA granted accelerated approval to epcoritamab-bysp (Epkinly) for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified, including DLBCL caused by indolent lymphoma and after two or more systemic therapies of high-grade B-cell lymphoma. Epcoritamab-bysp, a bispecific CD20-directed CD3 T cell engager, was evaluated in EPCORE NHL-1 (NCT03625037), an open-label, multicohort, multicenter single-arm trial. The active population included 148 patients with relapsed or refractory DLBCL and high-grade B-cell lymphoma following two or more systemic therapies including at least one anti-CD20 monoclonal antibody. The primary efficacy outcome measure was the overall response rate and was assessed by an independent review committee.
The overall response rate was 61% (95% CI: 53, 69), with 38% of patients achieving a complete response. Responders were followed for a median of 9.8 months, and the median duration of response was 15.6 months (95% CI: 9.7, not reached).
Among 157 patients with relapsed or refractory large B-cell lymphoma who received the recommended dose of epcoritab-bysp, 51% developed cytokine release syndrome, 6% developed immune effector cell-associated neurotoxicity syndrome, and 15% developed severe Infection. For cytokine release syndrome, grade 1 occurred in 37% of patients, grade 2 in 17%, and grade 3 in 2.5%. For immune effector cell-associated neurotoxicity syndrome, grade 1 occurred in 4.5%, grade 2 in 1.3%, and grade 5 in 0.6%. Due to the risk of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, patients should be hospitalized for 24 hours following the 48 mg dose on day 15 of cycle 1. The most common (≥ 20%) adverse reactions were chronic sinusitis, fatigue, musculoskeletal pain, injection site reactions, pyrexia, abdominal pain, nausea, and diarrhea. The most common grade 3 to 4 laboratory abnormalities (≥10%) were decreased lymphocyte count, decreased neutrophil count, decreased white blood cell count, decreased hemoglobin, and decreased platelets.
The recommended regimen consists of subcutaneous injections of epcoritab-bysp in 28-day cycles until disease progression or unacceptable toxicity. The recommended dose is a dose escalation in cycle 1 (0.16 mg on day 1, 0.8 mg on day 8, 48 mg on days 15 and 22) followed by a weekly fixed dose of 48 mg during cycles 2 to 3, every other week during cycle 4 through 9, and then every four weeks on Day 1 of subsequent cycles.
参考文献 Reference
https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-epcoritamab-bysp-relapsed-or-refractory-diffuse-large-b-cell
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膀胱保留的根治性剂量放疗相对于膀胱切除术治疗非转移性膀胱癌 (8/5/2023)
Bladder-sparing treatment with radical dose radiation versus radical cystectomy in non-metastatic bladder cancer
方法: 这是一项英国肿瘤中心的回顾性分析。该研究纳入了 2012 年至 2021 年间在英国四个肿瘤中心提供的诊断为非转移性临床淋巴结阳性（cN+ M0）膀胱癌的 287 名患者的三模式治疗*和根治性膀胱切除术的数据。 主要结局指标是总体生存期和无进展生存期。
结果: 163 名患者接受了根治性治疗，124 名患者接受了姑息治疗。根治性治疗与更好的中位总生存期相关（2.4 相对于 0.89 年，风险比 [HR] = 0.32，95% 置信区间 [CI] = 0.23–0.44 ，P < .001），以及更好的中位无进展生存期（1.5 相对于 0.63 年，HR = 0.36，95% CI = 0.27–0.46，P < .001）。
在接受根治性治疗的患者中，87 例接受根治性剂量放疗，76 例接受根治性膀胱切除术，多变量分析表明根治性治疗的选择对生存结果没有显著影响。 根治性剂量放疗与根治性膀胱切除术的中位总生存期分别为 2.53 年和 2.09 年（HR = 0.94，95% CI = 0.63–1.41，P = 0.76），2 年生存率分别为 60% 相对于 51%，并且 中位无进展生存期为 1.93 年 相对于1.22 年（HR = 0.74，95% CI = 0.50–1.08，P = .12）。
结论: 无论是接受手术还是根治性放疗，非转移性临床淋巴结阳性患者队列的生存结果均相同。研究者认为，保留膀胱的三联疗法应该成为非转移性临床淋巴结阳性患者的一种选择。
*三联疗法包括经尿道膀胱肿瘤最大切除术，随后同步化疗和放疗。
Methods: This is a retrospective analysis of four oncology centers in UK. The study included data on trimodal therapy* and radical cystectomy for 287 patients diagnosed with non-metastatic clinically node-positive (cN+ M0) bladder cancer between 2012 and 2021. The primary outcome measured were overall survival and progression-free survival.
Results: 163 patients received curative treatment and 124 patients received palliative care. Definitive treatment was associated with better median overall survival (2.4 versus 0.89 years, hazard ratio [HR] = 0.32, 95% confidence interval [CI] = 0.23–0.44, P < .001), and better median progression-free survival (1.5 versus 0.63 years, HR = 0.36, 95% CI = 0.27–0.46, P < .001). Among patients who received curative therapy, 87 received curative-dose radiotherapy and 76 underwent radical cystectomy. Multivariate analysis showed that the choice of curative therapy had no significant effect on survival outcomes. The median overall survival was 2.53 and 2.09 years (HR = 0.94, 95% CI = 0.63–1.41, P = 0.76) for radical-dose radiotherapy vs. radical cystectomy, respectively, and the 2-year survival rate was 60% vs. 51%. The median progression-free survival was 1.93 vs. 1.22 years (HR = 0.74, 95% CI = 0.50–1.08, P = .12).
Conclusions: Survival outcomes were the same in the cohort of patients with nonmetastatic clinically node-positive patients whether they received surgery or definitive radiotherapy. The investigators believed that bladder-sparing trimodal therapy should be an option for patients with non-metastatic clinically node-positive disease.
*Trimodal therapy consists of transurethral maximal resection of the bladder tumor followed by concurrent chemotherapy and radiotherapy.
参考文献 Reference
Swinton M et al. J Clin Onc 2023; published July 21. DOI: 10.1200/JCO.23.00725
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野生型 TP53晚期子宫内膜癌患者selinexor 维持疗法的长期随访 (7/30/2023)
Long-term follow-up of Selinexor as maintenance therapy in wild-type TP53 advanced endometrial cancer
野生型 TP53 (TP53wt) 存在于约 75% 的新诊断子宫内膜癌和 50% 的晚期/复发肿瘤中。Selinexor 是一种口服 XPO1 抑制剂，可驱动野生型肿瘤抑制蛋白（包括 p53）的核保留和功能激活。
方法： SIENDO (NCT03555422) 是一项 III 期双盲研究，评估 selinexor 与安慰剂作为对既往全身治疗有响应后的晚期/复发性子宫内膜癌患者的维持治疗。 总共 220 名患者在完成至少 12 周的针对原发性 IV 期或复发性疾病的铂类联合化疗±免疫治疗后，获得部分缓解或完全缓解的患者按照 1:1 的比例随机分配，每周一次使用 selinexor 60 毫克或安慰剂，28 天为一个周期，直至疾病进展/出现毒性，如果完全缓解则持续 3 年。主要终点是无进展生存期，该终点曾于 2022 年在 ESMO 全体会议上提出。目前，通过对预先指定的 TP53wt子宫内膜癌患者亚组进行长期随访，进一步评估了 selinexor 作为维持治疗的安全性和有效性。
结果： 113 名 TP53wt子宫内膜癌患者被随机分配接受 selinexor 与安慰剂作为维持治疗（selinexor，n =77/安慰剂，n =36）。 截至2022年11月30日数据截止，中位随访时间为20.3个月，分别有26.3%和22.9%的患者仍在接受selinexor和安慰剂治疗。 Selinexor 组的 TP53wt 亚组中位无进展生存期为 20.8 个月，而安慰剂组为 5.2 个月（HR 0.46；95% CI (0.27, 0.79)，名义单侧 p =0.002）。无论 MSS/MSI 状态如何，均观察到疗效。
任何级别（selinexor/安慰剂）最常见的不良事件是恶心（90%/34%）、呕吐（61%/11%）和腹泻（38%/34%）； 最常见的 3+ 级 不良事件包括：中性粒细胞减少症 (18%/0%)、恶心 (12%/0%) 和血小板减少症 (9%/0%)。因不良事件导致停药的分别占 15%/0% 的患者。
结论：TP53wt子宫内膜癌中selinexor 维持疗法可获得持久的无进展生存期益处。数据表明 TP53 状态是子宫内膜癌的稳健预后生物标志物。
Wild-type TP53 (TP53wt) is present in approximately 75% of newly-diagnosed endometrial cancers and 50% of advanced/recurrent tumors. Selinexor is an oral XPO1 inhibitor that drives nuclear retention and functional activation of wild-type tumor suppressor proteins, including p53.
Methods: SIENDO (NCT03555422) was a phase III double-blind study evaluating selinexor versus placebo as maintenance therapy in patients with advanced/recurrent endometrial cancer. They achieved a partial or complete response after completing at least 12 weeks of platinum-based combination chemotherapy ± immunotherapy for primary stage IV or recurrent disease. A total of 220 patients were randomly assigned in a 1:1 ratio to once a week Selinexor 60 mg or placebo in 28-day cycles until disease progression/toxicity or 3 years in case of complete remission. The primary endpoint is progression-free survival. The results were initially presented at the ESMO plenary meeting in 2022. The safety and efficacy of selinexor as maintenance therapy are now further evaluated with long-term follow-up of a prespecified subgroup of patients with TP53wt endometrial cancer.
Results: 113 patients with TP53wt endometrial cancer were randomly assigned to receive selinexor versus placebo as maintenance therapy (selinexor, n = 77/placebo, n = 36). As of the data cutoff on November 30, 2022, the median follow-up time was 20.3 months, and 26.3% and 22.9% of patients were still receiving selinexor and placebo treatment, respectively. The median progression-free survival in the TP53wt subgroup was 20.8 months in the Selinexor group versus 5.2 months in the placebo group (HR 0.46; 95% CI (0.27, 0.79), nominal one-sided p=0.002). Efficacy was observed regardless of MSS/MSI status.
The most common adverse events of any grade (selinexor/placebo) were nausea (90%/34%), vomiting (61%/11%), and diarrhea (38%/34%). The most common grade 3+ adverse events included : neutropenia (18%/0%), nausea (12%/0%) and thrombocytopenia (9%/0%). Adverse events led to discontinuation in 15%/0% of patients, respectively.
Conclusions: Selinexor maintenance therapy in TP53wt endometrial cancer was associated with durable progression-free survival benefit. Data suggest that TP53 status is a robust prognostic biomarker in endometrial cancer.
参考文献 Reference
Vergote I et al. J Clin Onc 2023; 41 (16 suppl TP55627)
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双相雄激素治疗随后雄激素受体抑制序贯治疗前列腺癌 (7/29/2023)
Bipolar androgen therapy in sequence with androgen receptor blockade in prostate cancer
过去的研究表明，长期去势(castration)诱导的去势抵抗性前列腺癌细胞中的雄激素受体, 表现出在体外和小鼠异种移植物中对超生理雄激素的脆弱性，从而诱导细胞死亡和生长停滞。 基于这些结果，研究者开发了一种名为双极雄激素疗法, 治疗去势抵抗性前列腺癌，其中间歇性施用超生理雄激，导致血清睾酮从超生理的极端水平循环到接近去势水平。这种快速循环的目的是破坏与长期暴露于高或低水平睾酮相关的雄激素受体调节的适应性，同时针对异质性去势抵抗性前列腺癌肿瘤中存在的雄激素受体表达谱。 研究者已在超过 250 名去势抵抗性前列腺癌患者中测试了双极雄激素疗法。 这些研究共同证明双极雄激素疗法可以安全地给予患有去势抵抗性前列腺癌的男性，改善生活质量，并对约 30% 的患者产生治疗反应。
TRANSFORMER 研究 (NCT02286921) 是一项随机 II 期研究，旨在比较双相雄激素疗法与恩杂鲁胺(enzalutamide)对使用阿比特龙治疗进展后无症状去势抵抗性前列腺癌的疗效，该研究在 195 名接受 1:1 随机分组的患者中进行: 接受标准剂量恩杂鲁胺 (n = 101), 或双相雄激素疗法, 每 28 天肌注 400 毫克 环丙酸睾酮 (n = 94)。 主要终点是临床/放射学无进展生存期。 在疾病进展时，患者可以选择转向替代疗法。 该试验未达到相对于恩杂鲁胺改善临床/放射学无进展生存期的主要终点，双臂的临床/放射学无进展生存期均为 5.7 个月 (P = .2267)。双相雄激素疗法的响应率为 24.4%，恩杂鲁胺为 4.2% (P = .067) ）。 双相雄激素疗法的最佳 PSA50 反应为 28.4%，恩杂鲁胺为 25.5%（P = .697）。总体而言，与恩杂鲁胺相比，双相雄激素疗法对 1-2 级和 3-5 级疲劳的耐受性良好。 与恩杂鲁胺相比，接受双相雄激素疗法治疗的患者出现更广泛的肌肉骨骼疼痛和水肿，但全身症状（例如恶心、厌食、抑郁和失眠）较少。
在所有双相雄激素疗法研究中，对无症状、没有前列腺癌引起的骨痛且没有令人担忧的病变（即脊髓压迫和骨折）的患者进行资格限制，还排除了因前列腺癌继发前列腺肥大或良性前列腺肥大而需要导尿的尿路梗阻患者。迄今为止，对于无症状去势抵抗性前列腺癌男性非常安全。 这些结果支持进一步测试双相雄激素疗法作为一种新型前列腺癌疗法。
Previous studies have shown that long-term castration-induced androgen receptors in castration-resistant prostate cancer cells exhibit vulnerability to supraphysiological androgens in vitro and in mouse xenografts, and consequent cellular death and growth arrest. Based on these results, the researchers developed a treatment model called bipolar androgen therapy for castration-resistant prostate cancer, in which supraphysiological androgens are administered intermittently, resulting in cycling of serum testosterone from supraphysiological extremes to near-castrate levels . The purpose of this rapid cycling is to disrupt the fitness of androgen receptor regulation associated with chronic exposure to high or low levels of testosterone, while targeting the androgen receptor expression profile present in heterogeneous castration-resistant prostate cancer tumors. Researchers have tested bipolar androgen therapy in more than 250 castration-resistant prostate cancer patients. Together, these studies demonstrate that bipolar androgen therapy can be safely given to men with castration-resistant prostate cancer, improves quality of life, and achieves response to treatment in approximately 30% of patients.
The TRANSFORMER study (NCT02286921) is a randomized phase II study comparing bipolar androgen therapy with enzalutamide in asymptomatic castration-resistant prostate cancer after progression on abiraterone. It was conducted in 195 patients randomized 1:1 to either standard dose enzalutamide (n = 101), or bipolar androgen therapy with intramuscular injection of testosterone cypionate 400 mg every 28 days (n = 94) . The primary endpoint was clinical/radiological progression-free survival. As the disease progresses, patients may choose to switch to alternative therapies. The trial did not meet its primary endpoint of improved clinical/radiographic progression-free survival versus enzalutamide, which was 5.7 months in both arms (p = .2267). The response rate was 24.4% for bipolar androgen therapy and 4.2% for enzalutamide (p = .067). The best PSA50 response was 28.4% for bipolar androgen therapy and 25.5% for enzalutamide (p = .697). Overall, grades 1-2 and 3-5 fatigue were well tolerated with bipolar androgen therapy compared with enzalutamide. Patients treated with bipolar androgen therapy experienced more extensive musculoskeletal pain and edema but fewer systemic symptoms (eg, nausea, anorexia, depression, and insomnia) compared with enzalutamide.
In all bipolar androgen therapy studies, eligibility was restricted to asymptomatic patients without bone pain from prostate cancer and no worrisome lesions (such as spinal cord compression and fractures), Also excluded were patients with urinary tract obstruction requiring catheterization due to prostate cancer or BPH. So far, it has been very safe in men with asymptomatic castration-resistant prostate cancer. These results support further testing of bipolar androgen therapy as a novel prostate cancer therapy.
参考文献 Reference
Denmeade SR et al. the Oncologist 2023; 28; 465
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FOLFOX 在局部晚期直肠癌新辅助治疗并不劣于放化疗 (7/23/2023)
FOLFOX was non-inferior to chemoradiation in rectal cancer
方法: 这是一项随机III期临床试验（PROSPECT），符合条件的患者(临床分期为 T2 淋巴结阳性、T3 淋巴结阴性或 T3 淋巴结阳性且适合保留括约肌手术的直肠癌患者),以非盲方式随机分配至 6 个周期的改良 FOLFOX6（试验组）或放化疗（对照组），在 5.5 周内给予 5,040 cGy，同时口服卡培他滨或静脉注射 5-FU 进行化疗。 试验组的参与者在化疗后重新分期。 如果肿瘤消退 ≥ 20%，则绕过放射治疗而接受直肠手术，并进行全直肠系膜切除。 反应欠佳（肿瘤消退 < 20%）的患者在手术前接再受了放化疗。 主要终点是无病生存期。 局部复发时间, 总生存期, 完全（R0）切除率, 完全缓解和毒性是次要终点。
结果:从 2012 年 6 月到 2018 年 12 月，1,194 名参与者被随机分配,1,128 名患者开始接受治疗（试验组 585 名，对照组 543 名）。 两组患者的特征非常平衡。 平均年龄为 57 岁。 两组的肿瘤位置相似（试验组距肛门边缘分别为 8.6 厘米相对于对照组 8.5 厘米）。 两组中 84.4% 的参与者均进行了盆腔 MRI 基线分期。 分配时患有临床淋巴结阳性肿瘤的参与者比例在试验组中为 60.3%，在对照组中为 63.5%。 由于 FOLFOX 的反应 < 20% 或不耐受，试验组中有 53 名参与者 (9.1%) 接受了化放疗。 经过 227 次事件和中位随访 58 个月后，试验组的 5 年无病生存率为 80.8%，而放化疗组（对照组）的 5 年无病生存率为 78.6%（HR 0.92，90.2% CI [0.74，1.14]；分层非劣效性 P = 0.0051），满足非劣效性标准。5 年总生存率分别为 89.5% 相对于 90.2% (HR 1.04, 0.74, 1.44) 。 另外, 完全切除率分别为98.9% 相对于97.1%; 病理性完全响应率分别为21.9% 相对于24.3%;手术径向切缘阳性率分别为1.2% 相对于1.5%。
试验组术前 ≥ 3 级不良事件发生的频率更高（41.0%相对于 22.8%），而对照组术后发生 ≥ 3 级不良事件的数量较多（39.0% 相对于试验组的 25.6%）。 两个治疗组均没有新毒性的证据。
根据试验作者, 试验的一些局限性包括参与中心主要位于北美，参与者并不能充分代表北美人口的多样性。 并未对所有参与者进行微卫星不稳定状态和 MRI 分期。此外，该研究结果并不适用于所有直肠癌患者。患有接触骨盆壁的高危肿瘤的患者需要放射治疗(没有将这一群体纳入研究中)。
Methods: This was a randomized phase III trial (PROSPECT) in which eligible patients (clinical stage T2 node-positive, T3 node-negative, or T3 node-positive rectal cancer candidates for sphincter-sparing surgery) were randomized in an open-label manner to 6 cycles of modified FOLFOX6 (experimental group) or chemoradiotherapy (control group), given 5,040 cGy over 5.5 weeks, concurrently with oral capecitabine or intravenous 5 -FU for chemotherapy. Participants in the experimental group were restaged after chemotherapy. If tumor regression was ≥ 20%, rectal surgery (total mesorectal excision) was performed, bypassing radiation therapy. Patients with poor response (tumor regression < 20%) received additional chemoradiotherapy before surgery. The primary endpoint was disease-free survival. Time to local recurrence, overall survival, complete (R0) resection rate, complete response and toxicity were secondary endpoints.
Results: From June 2012 to December 2018, 1,194 participants were randomized and 1,128 patients started treatment (585 in the experimental group and 543 in the control group). The patients’ characteristics of the two groups were well balanced. The average age was 57 years old. Tumor location was similar in the two groups (8.6 cm from the anal verge in the experimental group versus 8.5 cm in the control group, respectively). Baseline staging with pelvic MRI was performed in 84.4% of participants in both groups. The proportion of participants with clinically node-positive tumors at the time of assignment was 60.3% in the experimental group and 63.5% in the control group. Fifty-three participants (9.1%) in the trial arm received chemoradiation due to < 20% response or intolerance to FOLFOX. After 227 events and a median follow-up of 58 months, the 5-year disease-free survival rate was 80.8% in the experimental arm compared with 78.6% in the chemoradiation arm (control group) (HR 0.92, 90.2% CI [0.74 to 1.14]; stratified noninferiority P = 0.0051), meeting the noninferiority criteria. The 5-year overall survival rate was 89.5% vs 90.2% (HR 1.04, 0.74, 1.44), respectively. In addition, the complete resection rate was 98.9% vs. 97.1%; the pathological complete response rate was 21.9% vs. 24.3%; the positive radial surgical margin rate was 1.2% vs. 1.5%.
Preoperative ≥ 3 grade adverse events occurred more frequently in the experimental group (41.0% vs. 22.8%), whereas postoperative ≥3 grade adverse events occurred in a higher number in the control group (39.0% vs. 25.6% in the experimental group). There was no evidence of new toxicities in either treatment group.
According to the trial author, some limitations of the trial included that the participating centers were primarily located in North America and that the participants were not adequately representative of the diversity of the North American population. Microsatellite instability and MRI staging were not performed on all participants. In addition, the findings do not apply to all patients with rectal cancer. Patients with high-risk tumors involving the pelvic wall required radiation therapy (this group was not included in the study).
参考文献 Reference
Scgrag D et al. N Engl J Med 2023; DOI: 10.1056/NEJMoa2303269
根据直肠癌风险确定新辅助放化疗 (7/23/2023)
Risk-adapted neoadjuvant chemoradiation in rectal cancer
方法: 在一项前瞻性多中心,研究性的临床试验中 (OCUM)，根据肿瘤, 可疑淋巴结或肿瘤沉积物与直肠系膜(mesorectal fascia)之间的最小距离（mrMRF）对直肠癌患者（cT2-4、任何cN, cM0）进行分类。 距离 > 1毫米(低风险组)的患者接受一线全直肠系膜切除术（TME），而距离≤1毫米和/或直肠下三分之一的cT4和cT3肿瘤的患者（高风险组）接受新辅助放化疗，然后进行TME手术。 主要终点是 5 年局部复发率。
结果: 在纳入的 1,099 名患者中，884 名（80.4%）根据方案接受了治疗。 共有 530 名患者 (60%) 接受了一线手术，354 名患者 (40%) 接受了 nCRT 随后进行手术。 Kaplan-Meier 分析显示，按方案治疗的患者的 5 年局部复发率为 4.1%（95% CI，2.7 至 5.5），一线手术后为 2.9%（95% CI，1.3 至 4.5），新辅助放化疗后再手术后为 5.7%（95% CI，3.2 至 8.2）。 5年远处转移率分别为15.9%（95% CI，12.6至19.2）和30.5%（95% CI，25.4至35.6）。 在对 570 名直肠下三分之一和中三分之一 的cII 和 cIII 肿瘤患者进行的亚组分析中，257 例 (45.1%) 处于低风险。 一线手术后，该组的 5 年局部复发率为 3.8%（95% CI，1.4 至 6.2）。 在 271 名高危患者（涉及 mrMRF 和/或 cT4）中，5 年局部复发率为 5.9%（95% CI，3.0 至 8.8），转移率为 34.5%（95% CI，28.6 至 40.4）； 无病生存率和总生存率最差。
结论: 研究结果支持低风险患者应避免接受新辅助放化疗，高危患者应加强新辅助治疗以改善预后。
Methods: In a prospective multicenter, investigational study (OCUM), patients with rectal cancer (cT2-4, any cN, cM0) were classified according to the minimum distance (mrMRF) between the tumor, suspicious lymph nodes or tumor deposits and the mesorectal fascia. Patients with a distance >1 mm (low risk group) received upfront total mesorectal excision (TME), whereas patients with cT4 and cT3 tumors with a distance ≤1 mm and/or lower third of the rectum (high risk group) received neoadjuvant chemoradiotherapy followed by TME surgery. The primary endpoint was the 5-year local recurrence rate.
Results: Of the 1,099 patients included, 884 (80.4%) were treated according to the protocol. A total of 530 patients (60%) underwent upfront surgery and 354 patients (40%) underwent neoadjuvant chemoradiotherapy followed by surgery. Kaplan-Meier analyzes showed a 5-year local recurrence rate of 4.1% (95% CI, 2.7 to 5.5) for patients treated as per protocol, 2.9% (95% CI, 1.3 to 4.5) after upfront surgery, and 5.7% (95% CI, 3.2 to 8.2) after neoadjuvant chemoradiation followed by surgery. The 5-year rate of distant metastasis was 15.9% (95% CI, 12.6 to 19.2) and 30.5% (95% CI, 25.4 to 35.6), respectively. In a subgroup analysis of 570 patients with cII and cIII tumors in the lower and middle third of the rectum, 257 (45.1%) were at low risk. After upfront surgery, the 5-year local recurrence rate in this group was 3.8% (95% CI, 1.4 to 6.2). Among 271 high-risk patients (involving mrMRF and/or cT4), the 5-year local recurrence rate was 5.9% (95% CI, 3.0 to 8.8) and the metastatic rate was 34.5% (95% CI, 28.6 to 40.4); disease-free survival and overall survival were the worst.
Conclusion: The findings support that low-risk patients should avoid neoadjuvant chemoradiotherapy, and high-risk patients should intensify neoadjuvant therapy to improve prognosis.
参考文献 Reference
Ruppert R et al. J Clin Onc 2023; June 19. DOI: 10.1200/JCO.22.02166
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CGX1321 联合或不联合 Pembrolizumab 对胃肠道癌症的I期试验 (7/22/2023)
CGX1321 with or without pembrolizumab in GI cancers
许多胃肠道肿瘤（包括结直肠癌）是由 WNT 信号传导驱动的，临床前研究发现CGX1321 可破坏 WNT 信号传导的化合物，它阻断 WNT 配体的分泌，是一种有效的选择性 O-酰基转移酶 Porcupine 抑制剂。另外, CGX1321 减少了带有失活 RNF43 突变或 RSPO 融合的肿瘤的生长。
一项在美国 (NCT02675946) 和在中国（NCT03507998）进行的I/Ib 期首次人体试验。CGX1321联合或不联合派姆单抗（pembrolizumab）治疗晚期胃肠道肿瘤。 该试验包括I期剂量递增部分和剂量扩展部分。该试验的共同主要终点包括安全性, 耐受性, 推荐 2 期剂量以及给药方案。
推荐的CGX1321 2 期剂量确定为每天 18 mg，连续 3 周，停药 1 周。 此外，在研究的剂量扩展部分期间，该药物作为单一疗法以及与派姆单抗联合治疗，在患有 RSPO 或 RNF43 改变的胃肠道癌症患者中进行了评估。 总共对 77 名患者进行了评估，其中包括单药 CGX1321 剂量递增队列中的 38 名实体瘤患者，以及 CGX1321/pembrolizumab 剂量递增队列中的 19 名微卫星稳定 (MSS) 结直肠癌患者。 此外，18 名患有 RSPO 或 RNF43 改变的结直肠癌或小肠癌的患者属于单药扩展队列，10 名患有 MSS 胃肠道肿瘤的患者属于联合扩展队列。
CGX1321 具有良好的耐受性，并且对 WNT 突变肿瘤具有显著的抑制活性。接受 CGX1321 单药治疗的患者疾病持续稳定，ctDNA 显著减少，疾病控制率为 77%。 这在具有 RSPO 融合的胃肠道肿瘤患者中可见。在没有这些改变的肿瘤中，疾病控制率为 0%。 在联合治疗组中，MSS 肿瘤患者的疾病控制率为 83%。在 RSPO 融合患者中观察到的疾病控制率为 33%。需要在更大的 WNT 激活突变患者中进一步评估该药物。
Many gastrointestinal tumors, including colorectal cancer, are driven by WNT signaling, and preclinical studies have found that CGX1321, a compound that disrupts WNT signaling, blocks the secretion of WNT ligands and is a potent and selective O-acyltransferase porcupine inhibitor. Additionally, CGX1321 reduced the growth of tumors bearing inactivating RNF43 mutations or RSPO fusions.
This is a phase I/Ib first-in-human trial in the US (NCT02675946) and China (NCT03507998). GX1321 with or without pembrolizumab in the treatment of advanced gastrointestinal tumors. The trial included a phase I dose-escalation portion and a dose-expansion portion. Co-primary endpoints of the trial included safety, tolerability, recommended phase 2 dose (RP2D), and dosing regimen.
The recommended phase 2 dose of CGX1321 was determined to be 18 mg per day for 3 weeks with a 1-week rest period. Additionally, the drug was evaluated as monotherapy and in combination with pembrolizumab in patients with gastrointestinal cancers with RSPO or RNF43 alterations during the dose-expansion portion of the study. A total of 77 patients were evaluated, including 38 patients with solid tumors in the single-agent CGX1321 dose-escalation cohort and 19 patients with microsatellite stable (MSS) colorectal cancer in the CGX1321/pembrolizumab dose-escalation cohort. In addition, 18 patients with RSPO or RNF43-altered colorectal or small bowel cancer were in the single-agent expansion cohort, and 10 patients with MSS gastrointestinal tumors were in the combined expansion cohort.
CGX1321 was well tolerated and showed significant inhibitory activity against WNT mutant tumors. Patients receiving CGX1321 monotherapy had sustained stable disease, a significant reduction in ctDNA, and a disease control rate of 77%. This was seen in patients with gastrointestinal tumors with RSPO fusions. In tumors without these alterations, the disease control rate was 0%. In the combination therapy group, the disease control rate was 83% for patients with MSS tumors. The disease control rate observed in patients with RSPO fusions was 33%. The drug needs to be further evaluated in patients with larger studies.
参考文献 Reference
Giannakis M et al. 2023 ASCO; Abstr 3514
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植入式超声装置打开血脑屏障输送白蛋白结合紫杉醇治疗复发性胶质母细胞瘤 (7/16/2023)
Opening blood-brain barrier with an implantable ultrasound device for delivery of albumin-bound paclitaxel in recurrent glioblastoma
背景：低强度脉冲超声联合静脉微泡（LIPU-MB）可用于打开血脑屏障。 试验目的是评估在白蛋白结合紫杉醇向复发性胶质母细胞瘤患者瘤周脑的输送LIPU-MB 的安全性和药代动力学。
方法：这是一项剂量递增I期临床试验 。复发性胶质母细胞瘤患者, 在肿瘤(直径 < 70 毫米)切除后植入颅骨窗, 每 3 周进行一次 LIPU-MB 静脉输注白蛋白结合紫杉醇，最多 6 个周期。 评估了白蛋白结合紫杉醇的六种剂量水平（40, 80, 135, 175, 215和 260 毫克/平方米）。 主要终点是在超声处理和白蛋白结合紫杉醇化疗的第一个周期中发生的剂量限制性毒性。 对所有接受治疗的患者进行安全性评估。 分析是在符合方案的人群中进行的。 在超声处理之前和之后通过 MRI 研究血脑屏障的开放情况。还在当前研究的一个患者亚组和作为类似试验 (NCT03744026) 一部分接受卡铂的患者亚组中进行了 LIPU-MB 的药代动力学分析。
结果：2020 年 10 月 29 日至 2022 年 2 月 21 日期间入组了 17 名患者（9 名男性和 8 名女性）。截至 2022 年 9 月 6 日数据截止，中位随访时间为 11.89 个月（IQR 11.12 – 12.78）。 一名患者接受白蛋白结合紫杉醇剂量水平 1 至 5 (40-215 毫克/平方米) 的治疗，12 名患者接受剂量水平 6 (260 毫克/平方米) 的治疗。 总共进行了 68 个基于 LIPU-MB 的血脑屏障开放周期（每位患者平均 3 个周期 [范围 2-6]）。 在剂量为 260 毫克/平方米 时，第一个周期期间 12 名患者中的一名 (8%) 发生脑病（3 级）（被认为是剂量限制性毒性），第二周期期间另一名患者发生脑病（2 级） 。 在这两种情况下，毒性均得到缓解，并以较低剂量的白蛋白结合紫杉醇继续治疗，3 级脑病的剂量为 175 毫克/平方米，2 级脑病的剂量为 215 毫克/平方米。 在 260 毫克/平方米 白蛋白结合紫杉醇的第三个周期中，一名患者观察到 2 级周围神经病变。 没有观察到由 LIPU-MB 引起的进行性神经功能缺损。 基于 LIPU-MB 的血脑屏障开放最常与立即但短暂的 1-2 级头痛相关（17 名患者中的 12 名 [71%]）。 最常见的 3-4 级治疗引起的不良事件是中性粒细胞减少症（8 例 [47%]）、白细胞减少症（5 例 [29%]）和高血压（5 例 [29%]）。 研究期间没有发生与治疗相关的死亡。
成像分析显示 LIPU-MB 靶向的大脑区域血脑屏障在超声处理后的第 1 小时内减少。药代动力学分析表明，LIPU-MB 导致白蛋白结合紫杉醇的平均脑实质浓度增加（从非超声处理脑中的 0.037 μM [95% CI 0.022-0.063] 增加到 0.139 μM [ 0.083-0.232] 在超声处理的大脑中 [3.7 倍增加]，p < 0.0001）和卡铂（从非超声处理的大脑中的 0.991 μM [0.562-1.747] 到 在超声处理的大脑中的5.878 μM [3.462-9.980] [5.9 倍增加]，p = 0.0001)。
解释：LIPU-MB 使用植入式超声设备短暂打开血脑屏障，使细胞毒性药物能够安全重复地渗透到大脑中。 这项试验促使后续的 2 期研究LIPU-MB 与白蛋白结合紫杉醇加卡铂 (NCT04528680) 相结合。
Background: Low-intensity pulsed ultrasound combined with concomitant intravenous microbubbles (LIPU-MB) can be used to open the blood-brain barrier. The aim of the trial was to evaluate the safety and pharmacokinetics of LIPU-MB delivered with nab-paclitaxel to the peritumoral brain in patients with recurrent glioblastoma.
Methods: This is a phase I dose-escalation trial. Patients with recurrent glioblastoma were implanted with a cranial window after tumor resection (<70 mm in diameter), and received LIPU-MB IV nab-paclitaxel every 3 weeks for a maximum of 6 cycles. Six dose levels (40, 80, 135, 175, 215 and 260 mg/m2) of nab-paclitaxel were evaluated. The primary endpoint was dose-limiting toxicities during the first cycle of sonication and nab-paclitaxel chemotherapy. Safety assessments were performed on all treated patients. Analyzes were performed in a per-protocol population. Blood-brain barrier patency was studied by MRI before and after sonication. Pharmacokinetic analysis of LIPU-MB was also performed in a subgroup of patients in the current study and in a subgroup of patients who received carboplatin as part of a similar trial (NCT03744026).
Results: Seventeen patients (9 males and 8 females) were enrolled between October 29, 2020, and February 21, 2022. As of data cut-off September 6, 2022, median follow-up was 11.89 months (IQR 11.12 – 12.78). One patient received nab-paclitaxel dose levels 1 to 5 (40-215 mg/m2) and 12 patients received dose level 6 (260 mg/m2). A total of 68 cycles of LIPU-MB-based blood-brain barrier opening (average of 3 cycles per patient [range 2-6]) were performed. At 260 mg/m2, one of 12 patients (8%) developed encephalopathy (grade 3) during the first cycle (considered a dose-limiting toxicity) and another patient during the second cycle (grade 2). In both cases, toxicity resolved and treatment was continued at lower doses of nab-paclitaxel, with175 mg/m2 in the case of grade 3 encephalopathy and 215 mg/m2 in the case of grade 2 encephalopathy. Grade 2 peripheral neuropathy was observed in one patient during the third cycle of nab-paclitaxel at 260 mg/m2. No progressive neurologic deficits were observed due to LIPU-MB. Blood-brain barrier opening based on LIPU-MB was most commonly associated with immediate but transient grade 1-2 headache (12 of 17 patients [71%]). The most common grade 3-4 treatment-associated adverse events were neutropenia (8 [47%]), leukopenia (5 [29%]), and hypertension (5 [29%]) . No treatment-related deaths occurred during the study. Pharmacokinetic analysis showed that LIPU-MB resulted in an increase in mean brain parenchymal concentrations of nab-paclitaxel (from 0.037 μM [95% CI 0.022-0 063] ] in non-sonicated brain to 0.139 μM [0.083-0.232 in sonicated brains [3.7-fold increase], p < 0.0001) and carboplatin (from 0.991 μM [0.562-1.747] in non-sonicated brains to 5.878 μM [3.462-9.980] in sonicated brains [5.9-fold increase], p = 0.0001).
Interpretation: LIPU-MB uses an implantable ultrasound device to briefly open the blood-brain barrier, allowing cytotoxic drugs to penetrate the brain safely and reproducibly. This trial prompted a follow-up phase 2 study of LIPU-MB in combination with nab-paclitaxel plus carboplatin (NCT04528680).
参考文献 Reference
Sonabond AM et al. Lancet Onc 2023; 24;509
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Erdafitinib 相对于化疗治疗患有选择性成纤维细胞生长因子受体改变的晚期尿路上皮癌 (7/9/2023)
Erdafitinib vs. chemotherapy in advanced urothelial cell cancer with selective fibroblast growth factor receptor alterations
这是一项随机 III 期研究(THOR, NCT03390504)，评估了对于经过 1 或 2 次既往治疗（包括抗 PD-(L)1 药物）后病情进展的晚期或转移性尿路上皮癌, 并有选择选择性成纤维细胞生长因子受体改变（突变/融合）的患者。患者以1:1 的比例随机接受erdafitinib（每天8 毫克，第 14 天药效学指导上调至 9 毫克）或研究者选择的化疗（多西紫杉醇或长春氟宁）每3星期，直至疾病进展 或无法忍受的毒性。 主要终点是总生存期。 次要终点包括无进展生存期, 客观响应率和安全性。
结果： 266 名患者被随机分配：136 名患者分配至erdafitinib，130 名患者分配至化疗。 所有患者的中位年龄为 67 岁； 30% 的人之前接受过一线治疗，70% 的人之前接受过2线治疗； 74%有内脏转移； 90% 的 PD-L1 水平较低（CPS <10）。 中位随访时间为 15.9 个月。 该研究的主要终点得到满足，erdafitinib显著提高了总生存期，并将死亡风险降低了 36%； 中位总生存期为 1 年。 这些数据符合预先确定的优越性停止标准。 与化疗相比，erdafitinib 还显著改善了中位无进展生存期（5.6 个月相对于2.7 个月）和客观响应率（46% 相对于12%）。
没有看到新的安全信号。 在接受 erdafitinib和化疗的患者中，分别有 13% 和 24% 的患者观察到严重的治疗相关不良事件，在接受erdafitinib和化疗的患者中，分别有 46% 和 46% 的患者观察到 3/4 级治疗相关不良事件。Erdafitinib和化疗分别有 1 例和 6 例患者报告了导致死亡的治疗相关不良事件。Erdafitinib (66%) 与化疗 (21%) 相比，观察到更多导致剂量减少的治疗相关不良事件； 导致终止erdafitinib和化疗的分别有8% 和 13% 的患者。 有23 名 erdafitinib患者（17%）发生中心性浆液性视网膜病变。
结论： 在先前接受 PD-(L)1 治疗后患有有选择性成纤维细胞生长因子受体改变晚期或转移性的尿路上皮癌患者中，与研究者选择的化疗相比，erdafitinib显著改善了总生存期, 无进展生存期和客观响应率。Erdafitinib毒性与已知的安全性一致。
This is a randomized phase III study (THOR, NCT03390504) evaluating patients with advanced or metastatic urothelial carcinoma who had progressed after 1 or 2 lines of prior therapy, including anti-PD-(L)1 agents. The had elective fibroblast growth factor receptor alterations (mutation/fusion). Patients were randomized 1:1 to receive erdafitinib (8 mg daily, with pharmacodynamic guidance up to 9 mg on day 14) or investigator’s choice of chemotherapy (docetaxel or vinflunine) every 3 weeks until disease progression or intolerable toxicity. The primary endpoint was overall survival. Secondary endpoints included progression-free survival, objective response rate, and safety.
Results: 266 patients were randomized: 136 to erdafitinib and 130 to chemotherapy. The median age of all patients was 67 years; 30% had previously received first-line therapy and 70% had previously received 2-lines of therapy; 74% had visceral metastases; 90% had low PD-L1 levels (CPS <10 ). Median follow-up was 15.9 months. The primary endpoint of the study was met: erdafitinib significantly improved overall survival and reduced the risk of death by 36%; median overall survival was 1 year. These data met pre-determined superiority stopping criteria. Erdafitinib also significantly improved median progression-free survival (5.6 months vs. 2.7 months) and objective response rate (46% vs. 12%) compared with chemotherapy.
No new safety signals were seen. Serious treatment-related adverse events were observed in 13% and 24% of patients receiving erdafitinib and chemotherapy, respectively; in 46% and 46% of patients receiving erdafitinib and chemotherapy had 3/4 grade treatment-related adverse events. Treatment-related adverse events leading to death were reported in 1 patient with erdafitinib and 6 patients with chemotherapy. More treatment-related adverse events leading to dose reductions were observed with erdafitinib (66%) than with chemotherapy (21%); discontinuation of erdafitinib and chemotherapy were in 8% and 13% of patients, respectively. Central serous retinopathy occurred in 23 patients (17%) taking erdafitinib.
Conclusions: In patients with advanced or metastatic urothelial carcinoma with selective fibroblast growth factor receptor alterations following prior PD-(L)1 therapy, erdafitinib significantly improved the outcome compared with investigator’s choice of chemotherapy, including overall survival, progression-free survival and objective response rate. Erdafitinib toxicity was consistent with known safety profile.
参考文献 Reference
Loriot Y et al. J Clin Oncol 2023; 41: (suppl 17; abstr LBA4619)
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微创切除早期胰腺癌不亚于开腹远端切除胰腺 (7/9/2023)
Minimally invasive distal pancreatectomy noninferior to open surgery for early-stage pancreatic cancer
方法： 一项国际随机非劣效性(noninferior)试验，纳入了来自 12 个国家 35 个中心的可切除胰腺癌患者。 患者被随机分配接受微创切除（腹腔镜或机器人）或开腹远端胰腺切除术。 患者和病理学家都对指定的方法不知情。 主要终点是最终接受切除患者的根治性切除率（R0，与周围组织距离至少 1 毫米）。 主要终点分析采用改良意向治疗，排除未接受切除的患者。预先定义的非劣效性界限设定为 -7%。
结果： 2018年5月8日至2021年5月7日期间，258名患者被随机分配至微创切除（131名患者）或开腹远端胰腺切除（127名患者）。 修改后的意向治疗人群包括微创切除组的 117 名患者和开腹远端胰腺切除组的 114 名患者。 微创切除组有 83 例 (73%) 患者发生 R0 切除，开腹远端胰腺切除组有 76 例 (69%) 患者发生 R0 切除（差异 4%，90% CI -6 至 14%；p = 0.039）。 中位淋巴结产量相当（22.0 [16.0-30.0] 与 23.0 [14.0-32.0] 个淋巴结，p = 0.86），腹膜内复发率也相当（41% 与 38%，p = 0.45）。 其他术后结果具有可比性。
结论： 在这项试验中，微创切除后的根治性切除率并不比开腹远端胰腺切除低。 这显示了微创手术在可切除胰腺癌患者中的有效性。
Methods: An international randomized noninferior trial recruited patients with resectable pancreatic cancer from 35 centers in 12 countries. Patients were randomly assigned to undergo minimally invasive resection (laparoscopic or robotic) or open distal pancreatectomy. Both patients and pathologists were blinded to the assigned methods. The primary endpoint was the rate of curative resection (R0, at least 1 mm from surrounding tissue) in patients who eventually underwent resection. The primary end point was analyzed with modified intention-to-treat, excluding patients who did not undergo resection. The pre-defined non-inferiority margin was set at -7%.
Results: Between May 8, 2018, and May 7, 2021, 258 patients were randomly assigned to minimally invasive resection (131 patients) or open distal pancreatectomy (127 patients). The modified intention-to-treat population included 117 patients in the minimally invasive resection group and 114 patients in the open distal pancreatectomy group. R0 resection occurred in 83 (73%) patients in the minimally invasive resection group and in 76 (69%) patients in the open distal pancreatectomy group (difference 4%, 90% CI -6 to 14%; p = 0.039). Median lymph node yield was comparable (22.0 [16.0-30.0] vs 23.0 [14.0-32.0] nodes, p = 0.86), as were intraperitoneal recurrence rates (41% vs 38%, p = 0.45). Other postoperative results were comparable.
Conclusions: In this trial, the rate of radical resection after minimally invasive resection was non-inferior compared with that of open distal pancreatectomy. This shows the effectiveness of minimally invasive surgery in patients with resectable pancreatic cancer.
参考文献 Reference
Hilal MA et al. J Clin Oncol 41, 2023; 41: suppl 16, abstr 4163
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晚期子宫内膜癌化疗添加放疗并没有改善生存率 (7/8/2023)
Adding radiation to chemotherapy not improving survival in advanced endometrial cancer
NRG Oncology GOG-258临床试验评估了III/IVA 期子宫内膜癌患者放化疗与单纯化疗的疗效。 经过近 10 年的中位随访后，总体生存率或无复发生存率没有差异。 接受单纯化疗患者局部复发较多，但接受放化疗患者远处复发较多。
在 813 名患者中，每组大约 75% 的患者患有 IIIC1 或 IIIC2 期疾病。 患者被随机分配接受放化疗或单独化疗。 实验组包括第 1 天和第 29 天的顺铂 50 毫克/平方米加上 45 Gy 的体积定向放射（有或没有近距离放射治疗），随后每 21 天接受卡铂曲线下面积 (AUC) 5 加紫杉醇 175 毫克/平方米四个周期。 单纯化疗组包括 AUC 6 的卡铂加紫杉醇 175 毫克/平方米，每 21 天一次，共六个周期。
先前报道的主要分析是在中位随访 47 个月时进行的。在 60 个月时，存活且未复发的患者百分比基本相同：接受放化疗的患者为 59%，接受单纯化疗的患者为 58%（风险比 HR = 0.90；90% 置信区间 [CI] = 0.74–1.10；P = .20）。 与单独化疗相比，放化疗的 5 年阴道复发率更低（2% 相对于 7%；HR = 0.36）以及更低的盆腔和主动脉旁淋巴结复发率（11% 相对于 20%；HR = 0.43；）较低，但 接受放化疗的女性中远处复发更为常见（27% 相对于 21%；HR = 1.36）。 最新分析显示，中位随访时间为 112 个月，放化疗组有 134 例死亡，单纯化疗组有 125 例死亡（HR = 1.05；95% CI = 0.82-1.34）。 与化疗相比，在任何亚组中，放化疗都没有改善总体生存率，包括分期, 组织学, 体重指数, 残留疾病的存在和年龄。
The NRG Oncology GOG-258 clinical trial evaluated chemoradiotherapy versus chemotherapy alone in patients with stage III/IVA endometrial cancer. After a median follow-up of nearly 10 years, there was no difference in overall survival or recurrence-free survival. Patients who received chemotherapy alone had more local recurrences, while patients who received chemotherapy and radiotherapy had more distant recurrences.
Of the 813 patients, approximately 75 percent in each group had stage IIIC1 or IIIC2 disease. Patients were randomly assigned to receive chemoradiotherapy or chemotherapy alone. The experimental arm consisted of cisplatin 50 mg/m2 on days 1 and 29, plus volume-directed radiation of 45 Gy with or without brachytherapy followed by carboplatin every 21 days (AUC=5) plus paclitaxel 175 mg/m2 for four cycles. The chemotherapy-alone arm consisted of carboplatin at AUC 6 plus paclitaxel 175 mg/m2 every 21 days for six cycles.
The previously reported primary analysis was performed at a median follow-up of 47 months. At 60 months, the percentages of patients alive and free of recurrence were essentially the same: 59% for those who received chemoradiation and 58% for those who received chemotherapy alone (hazard ratio, HR = 0.90; 90% confidence interval [CI] = 0.74– 1.10; P = .20). Chemoradiation was associated with lower 5-year vaginal recurrence rates (2% vs. 7%; HR = 0.36) and lower rates of pelvic and para-aortic nodal recurrence (11% vs. 20%; HR = 0.36) compared with chemotherapy alone. 0.43), while distant recurrence was more common in women who received chemoradiation (27% vs. 21%; HR = 1.36). The latest analysis showed that at a median follow-up of 112 months, there were 134 deaths in the chemoradiotherapy group and 125 deaths in the chemotherapy-alone group (HR = 1.05; 95% CI = 0.82-1.34). Chemoradiation did not improve overall survival compared with chemotherapy in any subgroup, including stage, histology, body mass index, presence of residual disease, and age.
参考文献 Reference
Matei DE et al. 2023 SGO Annual Meeting on Women’s Cancer. March 25, 2023.
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化疗加 pembrolizumab (派姆单抗) 提高晚期宫颈癌的生存率 (7/2/2023)
Pembrolizumab added to chemotherapy improves survival in advanced cervical cancer
方法： KEYNOTE-826是一项III期临床试验（NCT03635567），患有复发或转移性宫颈癌且既往未接受过全身化疗（允许之前进行放射增敏化疗）且不适合根治性治疗（手术或放疗）的成人, 按 1:1 随机分配至派姆单抗 200 毫克或安慰剂, 每3星期一次，最多 35 周期, , 加上化疗（紫杉醇 175 毫克/平方米 + 顺铂 50 毫克/平方米 或卡铂 AUC 5），± 贝伐珠单抗15 毫克/公斤。 根据诊断时的转移状态（是/否）, 计划使用贝伐珠单抗（是/否）和 PD-L1 CPS（<1、1 至 <10 或≥10）对患者进行分层。 双重主要终点是总生存期和中位无进展生存期。
结果： 从2018年11月到2020年1月，617名患者被随机分配（派姆单抗 + 化疗，n = 308 [63.6% + 贝伐珠单抗]；安慰剂 + 化疗，n = 309 [62.5% + 贝伐珠单抗]）； 548 名 (88.8%) 患者的 PD-L1 CPS ≥1，317 名 (51.4%) 患者的 CPS ≥10。 截至 2022 年 10 月 3 日数据截止，中位随访时间为 39.1 个月。派姆单抗 + 化疗显著改善了 CPS ≥1, CPS ≥10 人群和所有人群的总生存期和中位无进展生存期。24个月的总生存率为个53.3% 相对于39.4%（HR 0.6, CPS ≥1）, 54.43% 相对于42.5%（HR 0.58, CPS ≥10）, 52.1% 相对于38.7%（HR 0.63, 所有人群）。无论是否使用贝伐珠单抗，都可以看到派姆单抗 + 化疗的益处。
治疗相关的副作用(≥3级)发生率在派姆单抗 + 化疗组中为 82.4%，在安慰剂 + 化疗组中为 75.4%。 最常见的≥3级治疗相关的副作用为贫血（30.3% 相对于 27.8%）、中性粒细胞减少症（12.4% 相对于 9.7%）和高血压（10.4% 相对于 11.7%）。
结论： 在化疗±贝伐珠单抗中添加派姆单抗可显著降低PD-L1 CPS ≥1人群的死亡风险40%，将所有人群的死亡风险降低37%，将CPS ≥10人群的死亡风险降低42%，可作为复发或转移性宫颈癌一线治疗。
Methods: KEYNOTE-826 is a phase III clinical trial (NCT03635567) in patients with recurrent or metastatic cervical cancer who had not received prior systemic chemotherapy (previous radiosensitizing chemotherapy was allowed) and were not eligible for curative treatment (surgery or radiotherapy). They were randomized 1:1 to pembrolizumab 200 mg or placebo every 3 weeks for up to 35 cycles, plus chemotherapy (paclitaxel 175 mg/m2 + cisplatin 50 mg/m2 or carboplatin AUC 5), ± bevacizumab 15 mg/kg. Patients were stratified by bevacizumab (yes/no) and PD-L1 CPS (<1, 1 to <10, or ≥10) based on metastatic status at diagnosis (yes/no). The dual primary endpoints were overall survival and median progression-free survival.
Results: From November 2018 to January 2020, 617 patients were randomly assigned (pembrolizumab + chemotherapy, n = 308 [63.6% with bevacizumab]; placebo + chemotherapy, n = 309 [ 62.5% with bevacizumab]); 548 (88.8%) patients had PD-L1 CPS ≥1 and 317 (51.4%) patients had CPS ≥10. As of data cutoff on October 3, 2022, median follow-up was 39.1 months. Pembrolizumab + chemotherapy significantly improved overall survival and median progression-free survival in the CPS ≥1, CPS ≥10, and all populations. The overall survival rate at 24 months was 53.3% vs 39.4% (HR 0.6, CPS ≥1), 54.43% vs 42.5% (HR 0.58, CPS ≥10), 52.1% vs 38.7% (HR 0.63, all crowd). The benefit of pembrolizumab plus chemotherapy was seen with or without bevacizumab.
Treatment-related side effects (grade ≥3) occurred in 82.4% of the pembrolizumab + chemotherapy arm and 75.4% of the placebo + chemotherapy arm. The most common grade ≥3 treatment-related side effects were anemia (30.3% vs 27.8%), neutropenia (12.4% vs 9.7%), and hypertension (10.4% vs 11.7%).
Conclusions: The addition of pembrolizumab to chemotherapy ± bevacizumab significantly reduced the risk of death in those with PD-L1 CPS ≥ 1 by 40%, in those with CPS ≥ 10 by 42%, and in all groups by 37%, The combination regime can be considered as first-line treatment for recurrent or metastatic cervical cancer.
参考文献 Reference
Monk BJ et al. 2023 ASCO; abstr 5500
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Regorafenib, Ipilimumab 和 Nivolumab 用于治疗微卫星稳定结直肠癌 (7/1/2023)
Regorafenib, Ipilimumab and Nivolumab in treating microsatellite stable colorectal cancer
该试验评估Regorafenib, Ipilimumab 和 Nivolumab(RIN)免疫治疗组合在微卫星稳定转移性结直肠癌患者中的活性。参与这项非随机临床试验是一项单中心 3 + 3 剂量降阶梯研究，在确定II 期剂量后，进行了一项研究修正，以探索Regorafenib剂量优化策略，以减轻与皮肤相关的毒性作用。总共纳入了 39 名微卫星稳定转移性结直肠癌患者，这些患者在标准化疗后疾病进展，并且之前未接受过Regorafenib或抗程序性细胞死亡蛋白 1 治疗。 患者每 4 周每天接受一次Regorafenib治疗，持续 21 天； 固定剂量 ipilimumab，1 毫克/公斤，每 6 周静脉注射一次； 固定剂量纳武单抗，每 2 周静脉注射 240 毫克。 患者接受治疗直至疾病进展, 出现不可接受的毒性作用或完成 2 年的治疗。主要终点是选择2 期剂量。 次要终点是安全性和推荐II期剂量下的总响应率。
结果: 共纳入39例患者，其中女性23例（59.0%），中位年龄54岁（范围25-75岁），黑人3例（7.7%），白人26例（66.7%）。 前 9 名患者在 RIN 起始剂量（Regorafenib每日 80 mg 剂量）下未发现剂量限制性毒性作用。 无需降低剂量。 该剂量被宣布为推荐的II期剂量。 另有二十名患者入组于此级别。 II期剂量队列中的总响应率, 中位无进展生存期和总生存期分别为 27.6%, 4 个月（IQR，2-9 个月）和 20 个月（IQR，7 个月至不可估计）。 对于 22 例无肝转移的患者，总响应率, 中位无进展生存期和总生存期分别为 36.4%, 5 个月（IQR，2-11）和大于 22 个月。 Regorafenib剂量优化队列在第 1 个周期为 40 毫克/天，在第 2 个周期及之后为 80 毫克/天，与较低的皮肤和免疫毒性作用相关，但对于 10 名患者中的 5 名患者来说，活性有限，疾病稳定作为最佳反应。
这项非随机临床试验的结论和相关性结果表明，II期剂量的 RIN 在无肝转移的晚期微卫星稳定结直肠癌患者中表现出临床活性。
The trial evaluated the activity of a combination of Regorafenib, Ipilimumab and Nivolumab (RIN) in patients with microsatellite stable metastatic colorectal cancer. Participation in this non-randomized clinical trial was a single-center 3 + 3 dose-escalation study, and after starting recommended phase II dose, a study amendment was made to explore regorafenib dose optimization strategies to mitigate skin-related toxic effects. A total of 39 patients with microsatellite-stable metastatic colorectal cancer whose disease had progressed after standard chemotherapy and who were not previously treated with regorafenib or ant-PD-1 were included. Patients received daily regorafenib every 4 weeks for 21 days; fixed-dose ipilimumab, 1 mg/kg, intravenously every 6 weeks; fixed-dose nivolumab, 240 mg intravenously every 2 weeks. Patients were treated until disease progression, unacceptable toxic effects, or completion of 2 years of treatment. The primary endpoint was to establish phase 2 dose. Secondary endpoints were safety and overall response rate at the recommended phase II dose.
Results: A total of 39 patients were included, including 23 females (59.0%), with a median age of 54 years (range, 25-75 years), 3 blacks (7.7%), and 26 whites (66.7%). No dose-limiting toxic effects were noted in the first 9 patients at the RIN starting dose (regorafenib 80 mg daily). No dose reduction is required. This dose was determined the recommended phase II dose. Another twenty patients were enrolled in this class. The overall response rate, median progression-free survival and overall survival at the phase II dose cohort were 27.6%, 4 months (IQR, 2-9 months) and 20 months (IQR, 7 months to not estimable). For the 22 patients without liver metastases, the overall response rate, median progression-free survival and overall survival were 36.4%, 5 months (IQR, 2-11) and >22 months, respectively. The regorafenib dose-optimized cohort at 40 mg/day in cycle 1 and 80 mg/day in cycle 2 and beyond was associated with lower skin and immune toxic effects, but had limited activity with stable disease for 5 of 10 patients as the best response.
Conclusions and relevance: This nonrandomized clinical trial demonstrated that phase II dose of RIN exhibits clinical activity in patients with advanced microsatellite stable colorectal cancer without liver metastases.
参考文献 Reference
Fakih M et al. JAMA Oncol 2023; 9:627
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Cemiplimab持久改善非小细胞肺癌生存率 (6/25/2023)
Durable improvement in overall survival with Cemiplimab in non-small cell lung cancer (NSCLC)
2023 年欧洲肺癌大会上更新了两项III 期试验(EMPOWER-Lung 1, 3)的扩展分析数据, 表明 cemiplimab (抗 PD-1) 在疾病晚期且无靶向驱动因素的情况下对NSCLC 具有持久活性。对于晚期 NSCLC 且 PD-L1 表达≥50% 的患者，使用 cemiplimab 单药一线治疗，在临床稳定脑转移患者中，中位随访时间为 33.3 个月（范围 24.0-50.3）。与化疗（n =35）相比, cemiplimab (n =34) 延长了中位总生存期 （ 不可估计与 20.7个月；风险比 [HR] 0.42；95% 置信区间 [CI] 0.20–0.87；p =0.0168）和中位无进展生存期（12.5个月相对于5.3 个月；HR 0.34；95% CI 0.18–0.63；p = 0.0004）。
与化疗相比，Cemiplimab 还带来了更高的客观响应率（55.9% 对比 11.4%）（比值比 9.27；95% CI 2.62-32.74；p=0.0002）, 更长的中位响应持续时间（31.7 个月对比 12.5 个月）以及较低的脑特异性疾病进展率（14.7% 相对于 20.0%）。 此外，cemiplimab 治疗引起的 ≥3 级不良事件较少（35.3% 相对于60.0%）。
针对任何 PD-L1 表达水平的NSCLC患者进行的额外 12 个月随访的积极数据(中位随访时间为 28.4个月)，与单独化疗相比，cemiplimab 加化疗可持久改善生存，中位总生存期时间分别为 21.1 个月相对于12.9 个月（HR 0.65；95% CI 0.51–0.82；p =0.0003）。 Cemiplimab联合化疗的中位无进展生存期为 8.2 个月相对于 5.5 个月（HR 0.55；95% CI 0.44–0.68；p <0.0001）。 客观响应率（43.6% 相对于 22.1%）和中位响应持续时间16.4 个月相对于 7.3 个月）。 接受 cemiplimab 加化疗的患者中有 48.7% 报告了≥3 级副作用，而化疗患者为 32.7%。
研究者认为, Cemiplimab 与其他一些检查点抑制剂不同，它的标签包括无法用确定性放化疗治疗的局部晚期疾病。虽然 EMPOWER-Lung试验中脑转移患者数量很少，但疗效数据与帕博利珠单抗在类似患者群体中的汇总分析结果一致。稳定的脑转移也可以接受免疫治疗。
Extended analyzes of data from two phase III trials (EMPOWER-Lung 1, 3) updated at European Lung Cancer Congress 2023, showed that cemiplimab (anti-PD-1) has durable efficacy in NSCLC in advanced stage and with no targetable driver. For patients with advanced NSCLC and clinically stable brain metastases, with PD-L1 expression ≥ 50%, the first-line therapy was cemiplimab monotherapy and the median follow-up time was 33.3 months (range 24.0-50.3).
Compared with chemotherapy (n = 35) cemiplimab (n =34) prolonged median overall survival (not estimable vs. 20.7 months; hazard ratio [HR] 0.42; 95% confidence interval [CI] 0.20–0.87; p = 0.0168) ; median progression-free survival (12.5 versus 5.3 months; HR 0.34; 95% CI 0.18–0.63; p = 0.0004). Cemiplimab also resulted in a higher objective response rate (55.9% vs. 11.4%) (odds ratio 9.27; 95% CI 2.62-32.74; p=0.0002) and a longer median duration of response (31.7 months vs. 12.5 months) and a lower rate of brain-specific disease progression (14.7% vs. 20.0%). In addition, fewer grade ≥3 treatment-related adverse events were associated with cemiplimab (35.3% vs. 60.0%).
Positive data from an additional 12 months of follow-up (median follow-up, 28.4 months) in NSCLC patients with any level of PD-L1 expression showed that cemiplimab plus chemotherapy resulted in a durable improvement in survival compared to chemotherapy alone: median overall survival was 21.1 versus 12.9 months (HR 0.65; 95% CI 0.51–0.82; p =0.0003); median progression-free survival with cemiplimab plus chemotherapy was 8.2 months vs. 5.5 months (HR 0.55; 95% CI 0.44–0.68; p < 0.0001).; objective response rate (43.6% vs. 22.1%) and median duration of response (16.4 months vs. 7.3 months). Grade ≥3 treatment-associated side-effects were reported in 48.7% of patients receiving cemiplimab plus chemotherapy compared with 32.7% of chemotherapy alone. According to the investigators, cemiplimab differs from some other checkpoint inhibitors in that its label includes locally advanced disease that cannot be treated with definitive chemoradiotherapy.
Although the number of patients with brain metastases in the EMPOWER-Lung trial was small, the efficacy data are consistent with pooled analyzes of pembrolizumab in similar patient populations. Stable brain metastases should not excluded from immunotherapy.
参考文献 Reference
Kilickap S et al. European Lung Cancer Congress 2023, Abstr 10MO
Makharadze T, et al. European Lung Cancer Congress 2023, Abstr 5O
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Tarlatamab, 一种首创的靶向双特异性 T 细胞接合剂，治疗复发性小细胞肺癌(6/24/2023)
Tarlatamab, a first-in-class bispecific T-cell engager, in treating recurrent small-cell lung cancer (SCLC)
Tarlatamab是一种双特异性 T 细胞接合分子，可结合 DLL样配体 3(DLL3 ,在大多数 SCLC 中异常表达)和 CD3，从而导致 T 细胞介导的肿瘤溶解。一项期临床试验评估了 tarlatamab 对复发/难治性 SCLC 患者的疗效。 主要终点是安全性。 次要终点包括抗肿瘤活性, 总生存期和药代动力学。
结果: 截至 2022 年 7 月 19 日，107 名患者在剂量探索（0.003 至 100 mg；n = 73）和扩展（100 mg；n = 34）队列中接受了 tarlatamab。 既往抗癌治疗中位数为 2（范围，1-6）； 49.5% 接受了抗程序性死亡 1/程序性死亡配体 1 治疗。 97 名患者 (90.7%) 发生任何级别的治疗相关不良事件, 一名患者 (1%) 患有 5 级肺炎。 细胞因子释放综合征是最常见的治疗相关不良事件，发生在 56 名患者 (52%) 中，其中 1 名患者 (1%) 发生 3 级不良事件。 未达到最大耐受剂量。 客观响应率为 23.4%（95% CI，15.7 至 32.5），包括 2 例完全响应和 23 例部分响应。 中位响应持续时间为 12.3 个月（95% CI，6.6 至 14.9）。 疾病控制率为51.4%（95% CI，41.5至61.2）。 中位无进展生存期和总生存期分别为 3.7 个月（95% CI，2.1 至 5.4）和 13.2 个月（95% CI，10.5 至未达到）。
结论: 在以往经过大量治疗的 SCLC 患者中，tarlatamab 表现出可控的安全性和持久的治疗响应。
Tarlatamab is a bispecific T cell engager molecule that binds DLL-like ligand 3 (DLL3, aberrantly expressed in most SCLCs) and CD3, resulting in T cell-mediated tumor lysis. A phase 1 trial evaluated tarlatamab in patients with relapsed/refractory SCLC. The primary endpoint was safety. Secondary endpoints included antitumor activity, overall survival, and pharmacokinetics.
Results: As of July 19, 2022, 107 patients received tarlatamab in the dose-finding (0.003 to 100 mg; n = 73) and expansion (100 mg; n = 34) cohorts. The median number of prior anticancer treatments was 2 (range, 1-6); 49.5% received anti-PD-1/PD-L1 therapy. Treatment-related adverse events of any grade occurred in 97 patients (90.7%), and one patient (1%) had grade 5 pneumonitis. Cytokine release syndrome was the most common treatment-related adverse event, occurring in 56 patients (52%), including a grade 3 adverse event in 1 patient (1%). The maximum tolerated dose was not reached. The objective response rate was 23.4% (95% CI, 15.7 to 32.5), including 2 complete responses and 23 partial responses. The median duration of response was 12.3 months (95% CI, 6.6 to 14.9). The disease control rate was 51.4% (95% CI, 41.5 to 61.2). Median progression-free survival and overall survival were 3.7 months (95% CI, 2.1 to 5.4) and 13.2 months (95% CI, 10.5 to not reached), respectively.
Conclusions: Tarlatamab demonstrated a manageable safety profile and durable response in previously heavily treated SCLC patients.
参考文献 Reference
Paz-Ares L et al. J Clin Onc 2023; 41:2893
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紫外线辐射诱导皮肤中的树突状细胞白血病转化 (6/18/2023)
Ultraviolet radiation and dendritic cell leukemic cell transformation in the skin
在骨髓中，克隆祖细胞可以恶性转化为急性白血病，或分化为导致外周组织疾病的免疫细胞。 在骨髓外，这些克隆可能会暴露于各种组织特异性突变过程。研究者以母细胞浆细胞样树突状细胞肿瘤(BPDCN) 作为模型, 它是一种不寻常的侵袭性白血病，起源于骨髓中的克隆前体细胞，通常表现为孤立的皮肤肿瘤，没有临床明显的血液或骨髓受累。
使用肿瘤系统基因组学和单细胞转录组学与基因分型，研究者发现 BPDCN 起源于骨髓中的克隆（癌前）造血前体。BPDCN 皮肤肿瘤首先在暴露于阳光下的解剖部位发展，并通过紫外线辐射诱导的克隆扩增突变。紫外线损伤可能先于获得与恶性转化相关的改变。 在功能上 Tet2 中的功能缺失突变是 BPDCN 中最常见的癌前改变，它赋予浆细胞样细胞而非传统树突状细胞对紫外线诱导的细胞死亡的抵抗力，这表明 TET2具有肿瘤抑制作用。 这些发现证明了远距离解剖部位的组织特异性环境暴露如何影响癌前克隆向播散性癌症的进化。
组织特异性突变过程在形成跨解剖部位的克隆性疾病进化中的作用值得进一步研究。
In the bone marrow, clonal progenitors can undergo malignantly transformation to acute leukemia or differentiate into immune cells that cause peripheral tissue disease. Outside the bone marrow, these clones may be exposed to various tissue-specific mutational processes. The researchers used as a model of blastic plasmacytoid dendritic cell neoplasm (BPDCN), an unusual and aggressive leukemia that arises from clonal precursor cells in the bone marrow and often presents as a solitary skin tumor without clinically significant blood or bone marrow involvement.
Using tumor phylogenomics and single-cell transcriptomics with genotyping, it was found that BPDCN originates from clonal (precancerous) hematopoietic precursors in the bone marrow. BPDCN skin tumors first develop at sun-exposed anatomical sites and are mutated by UV radiation-induced clonal expansion. UV damage may precede acquisition of changes associated with malignant transformation. Functionally, loss-of-function mutations in Tet2, the most common premalignant alteration in BPDCN, confer resistance to UV-induced cell death in plasmacytoid cells but not conventional dendritic cells, suggesting a tumor suppressor role for TET2. These findings demonstrate how tissue-specific environmental exposures at distant anatomical sites influence the evolution of precancerous clones to disseminated cancers.
The role of tissue-specific mutational processes in shaping the evolution of clonal disorders across anatomical sites warrants further investigation.
参考文献 Reference
Griffin GK et a. Nature 2023; June 7. https://doi.org/10.1038/s41586-023-06156-8
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FDA 批准 Glofitamab 用于复发/难治性弥漫性大 B 细胞淋巴瘤 (DLBCL) (6/16/2023)
FDA granted accelerated approval of Glofitamab for recurrent/refractory DLBCL
这是第一个被批准用于治疗复发/难治性 DLBCL 的 CD20xCD3 T 细胞结合双特异性抗体。该批准基于临床 1/2 期多中心, 开放标签, 剂量递增和剂量扩展试验研究（NP30179, NCT03075696）的结果。共有 132 名复发/难治性 DLBCL 患者进行了为期 8.5 个月的固定疗程 glofitamab。其中30% 的患者之前接受过嵌合抗原受体 T 细胞治疗，83% 的患者对最近的治疗无效。Glofitamab 治疗最多 12 个周期，包括递增剂量，直到疾病进展或不耐受。 第 1 周期后，glofitamab 每 3 周给药一次。该试验的主要终点是独立审查委员会的完全响应率，次要终点包括总体响应率,响应持续时间,无进展生存期,安全性和耐受性。
Glofitamab 产生了 56% 的总响应率和 43% 的完全响应，其中 68.5% 获得响应的患者持续响应至少 9 个月（95% CI， 56.7-80.3）。 此外，中位响应持续时间为 18.4 个月（95% CI，11.4-不可估计）。
最常见的145 例不良事件包括细胞因子释放综合征（70%）,肌肉骨骼疼痛（21%）,疲劳（20%）和皮疹（20%）。 细胞因子释放综合征通常为 1 级 (52%) 和 2 级 (14%) 的低级别。
This is the first CD20xCD3 T cell-binding bispecific antibody approved for the treatment of relapsed/refractory DLBCL. The approval is based on the results of a phase 1/2 multicenter, open-label, dose-escalation and dose-expansion study (NP30179, NCT03075696). A total of 132 patients with relapsed/refractory DLBCL received a fixed course of glofitamab for 8.5 months. Thirty percent of these patients had previously received chimeric antigen receptor T-cell therapy, and 83% were refractory to recent therapy. Glofitamab was treated for up to 12 cycles, including dose escalation, until disease progression or intolerance. After cycle 1, glofitamab was given every 3 weeks. The primary endpoint of the trial was complete response rate by independent review committee, and secondary endpoints included overall response rate, duration of response, progression-free survival, safety, and tolerability.
Glofitamab produced an overall response rate of 56% and a complete response rate of 43%, with 68.5% of patients who achieved a response continuing to respond for at least 9 months (95% CI, 56.7-80.3). In addition, the median duration of response was 18.4 months (95% CI, 11.4-not estimable). The most common adverse events in 145 patients included cytokine release syndrome (70%), musculoskeletal pain (21%), fatigue (20%) and rash (20%). Cytokine release syndrome was usually of low-grade grade 1 (52%) and grade 2 (14%).
参考文献 Reference
News release. Genentech. June 15, 2023. Accessed June 16, 2023. https://tinyurl.com/3hwsvvrb
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他莫昔芬对三阴性乳腺癌的治疗作用 (6/11/2023)
Tamoxifen in triple-negative breast cancer
虽然三阴性乳腺癌不表达 ERα，但有 25%-30% 的三阴性乳腺癌表达雌激素受体 β (ERβ) , 为靶向抗肿瘤发生治疗提供了机会。它另一个重要特征是 p53的高突变率 (~80%) 。临床前研究表明，ERβ 能够对抗突变 p53的某些促肿瘤发生功能 , ERβ 直接结合并拮抗 p53。
研究者报导了一个病例研究, 检查了选择性雌激素受体调节剂他莫昔芬在 p53 突变三阴性乳腺癌并脑转移的疗效。 在他莫昔芬治疗停止后观察到 ERβ 蛋白表达显着增加以及突变体 p53 和 ERβ 之间的抗增殖相互作用，脑转移显著消退。 该病例研究为在 p53 突变体 ERβ阳性的三阴性乳腺癌中使用他莫昔芬提供了支持证据，尤其是在脑转移的情况下。鉴于目前可用于三阴性乳腺癌的治疗选择有限，新发现可能会影响该乳腺癌人群的治疗。 研究者希望这些结果将促进对他莫昔芬在 p53 突变、雌激素受体 β 阳性三阴性乳腺癌中使用的进一步临床研究。
Although triple-negative breast cancer (TNBC) does not express ERα, estrogen receptor beta (ERβ) is expressed in 25%-30% of TNBC, presenting an opportunity for targeted anti-tumorigenic therapy. Another important feature of TNBC is the high mutation rate (~80%) of p53. Preclinical studies have shown that ERβ can antagonize some of the tumor-promoting functions of mutant p53, and ERβ directly binds to and antagonizes p53.
The investigators report a case study examining the efficacy of the selective estrogen receptor modulator tamoxifen in p53-mutated triple-negative breast cancer with brain metastases. Significant increases in ERβ protein expression and an antiproliferative interaction between mutant p53 and ERβ were observed after tamoxifen treatment cessation, and brain metastases regressed significantly. This case study provides supporting evidence for the use of tamoxifen in p53 mutant, ERβ-positive triple-negative breast cancer, especially in the setting of brain metastases. Given the limited treatment options currently available for TNBC, the new findings may impact the treatment of this breast cancer population. The investigators hope that these results will prompt further clinical investigation of the use of tamoxifen in p53-mutant, estrogen receptor beta-positive triple-negative breast cancer.
参考文献 Reference
Scarpetti L et al. Oncologists 2023; 28:358
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奥希替尼辅助治疗肿瘤切除后 IB–IIIA 期非小细胞肺癌 (6/10/2023)
Osimertinib as adjuvant therapy in stage IB–IIIA EGFR mutation positive NSCLC
ADAURA (NCT02511106) 是一项 III 期、双盲、随机研究，评估奥希替尼与安慰剂相比在肿瘤完全切除和辅助化疗后的 IB–IIIA 期EGFR 突变阳性的非小细胞肺癌患者中的疗效和安全性。
方法：符合条件的患者：≥18 岁（日本/台湾：≥20），原发性非鳞状 IB/II/IIIA 期完全切除非小细胞肺癌，确诊为EGFR 突变阳性（ex19del/L858R）, 允许术后化疗。 患者以 1:1 的比例随机分配至每日一次口服奥希替尼 80 mg 或安慰剂接受长达 3 年的治疗，并按分期 (IB/II/IIIA)、突变类型 (ex19del/L858R) 和种族（亚裔/非亚裔）分层。 主要终点：II-IIIA 期患者的无病生存期。 次要终点：总生存期和安全性。 数据截止：2020 年 1 月 17 日。
结果：在全球范围内，682 名患者被随机分配接受治疗：奥希替尼组 n = 339，安慰剂组 n = 343。 各组的基线特征是平衡的 (奥希替尼/安慰剂)：IB 期 31/31%，II/IIIA 期 69/69%，女性 68/72%，ex19del 55/56%，L858R 45/44%。 在 II–IIIA 期患者中，无病生存期风险比 (HR) 为 0.17 (95% CI 0.12, 0.23)； p < 0.0001（156/470 事件）； 奥希替尼组的 2 年无病生存率为 90%，安慰剂组为 44%。 在总体人群中，无病生存率 HR 为 0.21（0.16，0.28）； p < 0.0001（196/682 事件）；2 年无病生存率分别为 89% (奥希替尼)和 53% (安慰剂)。 总生存期未成熟（4% 成熟），在数据截止时有 29/682 例死亡（分别为9和20例）。 安全性与已知的奥希替尼安全性一致。
结论：辅助奥希替尼是全球试验中第一个在完全肿瘤切除和辅助化疗后显示具有统计学意义和临床意义的无病生存期改善的靶向药物。
ADAURA (NCT02511106) is a phase III, double-blind, randomized study evaluating the efficacy and safety of osimertinib compared with placebo in patients with stage IB–IIIA EGFR mutation-positive non-small cell lung cancer after complete tumor resection and adjuvant chemotherapy.
Methods: Eligible patients: ≥18 years old (Japan/Taiwan: ≥20), primary non-squamous stage IB/II/IIIA, completely resected non-small cell lung cancer, with EGFR mutation (ex19del/L858R), and postoperative chemotherapy allowed. Patients were randomized 1:1 to osimertinib 80 mg orally once daily or placebo for up to 3 years. They were stratified by stage (IB/II/IIIA), mutation type (ex19del/L858R) and race (Asian/non-Asian). Primary endpoint: disease-free survival in patients with stage II-IIIA. Secondary endpoints: overall survival and safety. Data cutoff: January 17, 2020.
Results: Globally, 682 patients were randomized to receive treatment: osimertinib, n = 339 and placebo , n = 343. Baseline characteristics were balanced across groups (osimertinib/placebo): stage IB 31/31%, stage II/IIIA 69/69%, female 68/72%, ex19del 55/56%, L858R 45/44 %. In stage II–IIIA patients, hazard ratio (HR) for disease-free survival was 0.17 (95% CI 0.12, 0.23); p < 0.0001 (156/470 events); 2-year disease-free survival in the osimertinib arm was 90% compared to 44% in the placebo group. In the overall population, disease-free survival HR was 0.21 (0.16, 0.28); p < 0.0001 (196/682 events); 2-year disease-free survival rates were 89% (osimertinib) and 53% (placebo). Overall survival was immature (4% mature), with 29/682 deaths at data cutoff (9 vs. 20, respectively). The safety was consistent with the known safety of osimertinib.
Conclusions: Adjuvant osimertinib was the first targeted agent in a global trial to show a statistically significant and clinically meaningful improvement in disease-free survival after complete tumor resection and adjuvant chemotherapy.
参考文献 Reference
Herbst RS et al. J Clin Onc 2023; 41: 1830
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Pembrolizumab 联合化疗治疗晚期子宫内膜癌 (6/4/2023)
Pembrolizumab in combination for advanced endometrial cancer
方法 在这项双盲, 安慰剂对照, 随机III 期试验中(NCT03914612)，研究者以 1:1 的比例分配了 816 名患有可测量疾病（III 期或 IVA 期）或 IVB 期或复发性子宫内膜癌的患者接受派姆单抗或安慰剂以及联合使用 紫杉醇联合卡铂治疗。 帕博利珠单抗或安慰剂的给药计划为每 3 周共 6 个周期，随后每 6 周最多 14 个维持周期。 根据患者是否患有错配修复缺陷 (dMMR) 或错配修复良好 (pMMR) 疾病，将患者分为两个队列。 如果无治疗间隔至少为 12 个月，则允许先前的辅助化疗。 主要结局是两个队列的无进展生存期。 计划在 dMMR 队列中发生至少 84 起死亡或进展事件以及 pMMR 队列中至少 196 起事件后触发中期分析。
结果 在 12 个月的分析中，Kaplan-Meier 估计 dMMR 队列的无进展生存期在派姆单抗组为 74%，在安慰剂组为 38%（进展或死亡的风险比，0.30；95% 置信区间 [CI ], 0.19 至 0.48；P <0.001)，相对风险有 70% 的差异。 在 pMMR 队列中，帕博利珠单抗组的中位无进展生存期为 13.1 个月，安慰剂组为 8.7 个月（风险比，0.54；95% CI，0.41 至 0.71；P <0.001）。 不良事件与帕博利珠单抗和联合化疗的预期一致。
结论 在患有晚期或复发性子宫内膜癌的患者中，和单独化疗相比, 将帕博利珠单抗加入标准化疗可显著延长无进展生存期。
方法 在这项双盲, 安慰剂对照, 随机III 期试验中(NCT03914612)，研究者以 1:1 的比例分配了 816 名患有可测量疾病（III 期或 IVA 期）或 IVB 期或复发性子宫内膜癌的患者接受派姆单抗或安慰剂以及联合使用 紫杉醇联合卡铂治疗。 帕博利珠单抗或安慰剂的给药计划为每 3 周共 6 个周期，随后每 6 周最多 14 个维持周期。 根据患者是否患有错配修复缺陷 (dMMR) 或错配修复良好 (pMMR) 疾病，将患者分为两个队列。 如果无治疗间隔至少为 12 个月，则允许先前的辅助化疗。 主要结局是两个队列的无进展生存期。 计划在 dMMR 队列中发生至少 84 起死亡或进展事件以及 pMMR 队列中至少 196 起事件后触发中期分析。
结果 在 12 个月的分析中，Kaplan-Meier 估计 dMMR 队列的无进展生存期在派姆单抗组为 74%，在安慰剂组为 38%（进展或死亡的风险比，0.30；95% 置信区间 [CI ], 0.19 至 0.48；P <0.001)，相对风险有 70% 的差异。 在 pMMR 队列中，帕博利珠单抗组的中位无进展生存期为 13.1 个月，安慰剂组为 8.7 个月（风险比，0.54；95% CI，0.41 至 0.71；P <0.001）。 不良事件与帕博利珠单抗和联合化疗的预期一致。
结论 在患有晚期或复发性子宫内膜癌的患者中，和单独化疗相比, 将帕博利珠单抗加入标准化疗可显著延长无进展生存期。
Methods: In this double-blind, placebo-controlled, randomized phase III trial (NCT03914612), investigators assigned 816 patients with measurable disease (stage III or IVA) or stage IVB or recurrent patients with endometrial cancer to pembrolizumab or placebo plus paclitaxel plus carboplatin. Dosing of pembrolizumab or placebo was scheduled for 6 cycles every 3 weeks, followed by up to 14 maintenance cycles every 6 weeks. Patients were divided into two cohorts based on whether they had mismatch repair deficient (dMMR) or mismatch repair proficient (pMMR) disease. Prior adjuvant chemotherapy was allowed if the treatment-free interval was at least 12 months. The primary outcome was progression-free survival in both cohorts. The interim analysis was planned to be triggered after at least 84 events of death or progression in the dMMR cohort and at least 196 events in the pMMR cohort.
Results: In a 12-month analysis, Kaplan-Meier estimates of progression-free survival in the dMMR cohort were 74% in the pembrolizumab group and 38% in the placebo group (hazard ratio for progression or death, 0.30; 95% confidence interval [CI ], 0.19 to 0.48; P <0.001), there was a 70% difference in relative risk. In the pMMR cohort, median progression-free survival was 13.1 months in the pembrolizumab group and 8.7 months in the placebo group (hazard ratio, 0.54; 95% CI, 0.41 to 0.71; P<0.001). Adverse events were as expected with pembrolizumab and combination chemotherapy.
Conclusions In patients with advanced or recurrent endometrial cancer, the addition of pembrolizumab to standard chemotherapy significantly prolonged progression-free survival compared with chemotherapy alone.
参考文献 Reference
Eskander RN et al. N Engl J Med 2023: DOI: 10.1056/NEJMoa2302312
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2023 年NCCN 肿瘤学临床指南更新: 结直肠癌/尿路上皮癌 (6/3/2023)
NCCN practice guideline updates for 2023: colorectal and uroepithelial cancers
临床T4b原发结直肠癌患者，伴有 dMMR/MSI-H, 可考虑使用检查点抑制剂进行新辅助(术前)治疗（首选）； 这些检查点抑制剂包括单药 dostarlimab-gxly, 单药 pembrolizumab 或nivolumab, 联合或不联合 ipilimumab。FOLOX（氟尿嘧啶、亚叶酸、奥沙利铂）和 CAPEOX（卡培他滨/奥沙利铂）仍然是替代选择。 MMR 正常/MSS 肿瘤患者的新辅助治疗是使用 FOLFOX 或 CAPEOX。
对可切除的单个转移灶疾病, 也可用同样的新辅助方法。 Dostarlimab (添加为2A类推荐) 用于 dMMR/MSI-H 可切除的同时性转移肝脏灶和/或肺转移灶直肠癌的新辅助治疗。 作为 dMMR/MSI-H 可切除的异时性结直肠癌转移患者的主要治疗方法，既往未接受过免疫治疗，dostarlimab、pembrolizumab 和 nivolumab 联合或不联合 ipilimumab 被添加为 2A 类推荐。
其他结直肠癌更新包括：
- 对于 HER2 扩增, RAS/BRAF野生型 MMR-proficient肿瘤患者，在接受奥沙利铂或伊立替康治疗后出现疾病进展，可考虑使用曲妥珠单抗加 tucatinib 和曲妥珠单抗加 fam-trastuzumab deruxtecan-nxki。
- 对于难治性转移性疾病，曲氟尿苷/替吡嘧啶联合贝伐珠单抗。
- 对于少数携带罕见基因改变的转移性肿瘤患者，selpercatinib用于 RET融合，larotrectinib和 entrectinib 用于 NTRK融合。
对转移性尿路上皮癌的治疗。 NCCN 指南仍然推荐以铂类为基础的化疗作为一线标准。对于不能耐受铂类一线治疗的患者，单药派姆单抗是一种选择, atezolizumab 作为另一种选择。 对于一线铂类化疗后取得响应或疾病稳定的患者，现在可以考虑使用 avelumab 进行维持治疗。
较新的靶向药物用于转移性尿路上皮癌治疗包括： Erdafitinib为第一个获得批准的生物标志物导向疗法; Enfortumab vedotin为第一个获得批准的抗体-药物偶联物; 最近与 pembrolizumab 联合获得加速批准的高度特异性抗体-药物偶联物 sacituzumab govitecan-hziy。
For clinical T4b primary colorectal cancer patients and dMMR/MSI-H, neoadjuvant treatment with checkpoint inhibitors may be considered (preferred); these checkpoint inhibitors include single agent dostarlimab-gxly, single agent pembrolizumab or nivolumab, with or without ipilimumab. FOLOX (fluorouracil, leucovorin, oxaliplatin) and CAPEOX (capecitabine/oxaliplatin) remain alternatives. Neoadjuvant therapy for patients with normal MMR/MSS tumors is FOLFOX or CAPEOX.
The same neoadjuvant approach can also be used for resectable oligo-metastatic disease. Dostarlimab (added as category 2A recommendation) for neoadjuvant treatment of rectal cancer with resectable synchronous liver and/or lung metastases with dMMR/MSI-H. Dostarlimab, pembrolizumab, and nivolumab with or without ipilimumab were added as a category 2A recommendation as primary treatment for patients with dMMR/MSI-H resectable metachronous colorectal metastases who have not received prior immunotherapy.
Other colorectal cancer updates include: 1) For patients with HER2-amplified, RAS/BRAF wild-type MMR-proficient tumors who have disease progression on oxaliplatin or irinotecan, trastuzumab plus tucatinib and trastuzumab plus fam-trastuzumab deruxtecan-nxki. 2) For refractory metastatic disease, trifluridine/tipiracil combined with bevacizumab. 3) For the small percentage of patients with metastatic tumors harboring rare genetic alterations: selpercatinib for RET fusions and larotrectinib and entrectinib for NTRK fusions.
Treatment of metastatic urothelial carcinoma. The NCCN guidelines still recommend platinum-based chemotherapy as the first-line standard. For patients who cannot tolerate platinum-based first-line therapy, single-agent pembrolizumab is one option and atezolizumab another. Maintenance therapy with avelumab can now be considered in patients who respond or have stable disease after first-line platinum-based chemotherapy.
Newer targeted agents for the treatment of metastatic urothelial carcinoma include: Erdafitinib, the first approved biomarker-directed therapy; Enfortumab vedotin, the first approved antibody-drug conjugate; pembrolizumab combined with the highly specific antibody-drug conjugate sacituzumab govitecan-hziy, which recently received approval.
参考文献 Reference
Helwick C ASCO Post 5/19/2023
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地中海饮食与晚期黑色素瘤免疫治疗结果的关联 (5/28/2023)
Association of Mediterran diet with outcome of immune check-point blockade in advanced melanoma
目的: 探讨饮食习惯与免疫检查点阻断治疗反应之间的关系。 这项多中心队列研究（PRIMM）在荷兰和英国的癌症中心进行，包括 91 名免疫检查点阻断初治晚期黑色素瘤患者，他们在 2018 年至 2021 年期间接受了免疫检查点阻断。患者接受抗程序性细胞死亡 1 和抗细胞毒性 T 淋巴细胞相关抗原 4 单一疗法或联合疗法治疗。 治疗前通过食物频率问卷评估膳食摄入量。 临床终点定义为总响应率,12 个月无进展生存期以及 2 级或更高级别的免疫相关不良事件。
结果: 共有 44 名荷兰参与者（平均年龄，59.43岁；22 名女性）和 47 名英国参与者（平均年龄，66.21岁；15 名女性). 前瞻性地收集了 2018 年至 2021 年间在英国和荷兰接受免疫检查点阻断治疗晚期黑色素瘤的 91 名患者的饮食和临床数据。 Logistic 广义相加模型显示富含全谷物、鱼类、坚果、水果和蔬菜的地中海饮食模式与总响应率和12 个月无进展生存期的概率之间存在正线性关联（总响应率概率为 0.77；P = .02；错误发现率，0.032；有效自由度，0.83；12 个月无进展生存期的概率为 0.74；P = .01；错误发现率，0.021；有效自由度，1.54）。
结论和相关性: 这项队列研究发现地中海饮食与对免疫检查点阻断治疗的响应之间存在正相关关系。 需要来自不同地区的大型前瞻性研究来证实这些发现。
Objective: To explore the relationship between dietary habits and response to immune checkpoint blockade therapy. The multicentre cohort study (PRIMM), conducted at cancer centers in the Netherlands and the UK, included 91 advance melanoma patients who were immune checkpoint blockade-naïve. They received immune checkpoint blockade between 2018 and 2021. The treatment included anti-programmed cell death 1 and anti-cytotoxic T-lymphocyte-associated antigen 4 monotherapy or combination therapy. Dietary intake was assessed by food frequency questionnaires before treatment. Clinical endpoints were defined as overall response rate, 12-month progression-free survival, and grade 2 or higher immune-related adverse events.
Results: A total of 44 Dutch participants (mean age, 59.43 years; 22 women) and 47 UK participants (mean age, 66.21 years; 15 women). Dietary and clinical data were prospectively collected from 91 patients receiving immune checkpoint blockade between 2018 and 2021 for advanced melanoma in the UK and the Netherlands. Logistic generalized additive models showed a positive linear association between a Mediterranean dietary pattern that was high in whole grains, fish, nuts, fruits, and vegetables and the overall response rate and the probability of 12-month progression-free survival (0.77 for the overall response rate ; P = .02; false discovery rate, 0.032; effective degrees of freedom, 0.83; probability of 12-month progression-free survival, 0.74; P = .01; false discovery rate, 0.021; effective degrees of freedom, 1.54).
Conclusions and relevance: This cohort study found a positive association between a Mediterranean diet and response to immune checkpoint blockade therapy. Large prospective studies from different regions are needed to confirm these findings.
参考文献 Reference
Bolte LA. JAMA Oncol 2023; 9: 705
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个体化mRNA癌症疫苗联合帕博利珠单抗用于切除的高危黑色素瘤 (5/26/2023)
Personalized mRNA vaccine in combination with pembrolizumab in resected high-risk melanoma
背景：T 细胞靶向突变衍生的表位（新抗原）已被证明可以驱动抗肿瘤免疫反应。 mRNA-4157 是一种基于 mRNA 的新型个体化癌症疫苗，可编码多达 34 种患者特异性肿瘤新抗原。
方法：这是一项随机, 开放标签II期临床试验（mRNA-4157-P201/Keynote-942），用以评价疗效和安全性。完全切除的高危皮肤黑色素瘤患者被随机分配为 2:1接受 mRNA-4157 联合 pembrolizumab 或 pembrolizumab 单独治疗。 mRNA-4157 (1毫克) 每 3 周肌肉注射一次，共 9 个剂量，pembrolizumab (200毫克) 每 3 周静脉注射一次，最多 18 个周期。 安全性作为次要终点进行评估。 总体意向治疗人群中的无进展生存期是主要终点。 当总共观察到 40 个无进展生存期事件时，该研究设计有 80% 的功效来检测 0.5 的风险比 (HR) 和 0.1 的总体单侧 I 型错误。无进展生存期的主要分析指定在所有患者完成至少 12 个月的研究并观察到至少 40 个无进展生存期事件后进行。
结果：107 名患者接受了 mRNA-4157 与 pembrolizumab 的联合治疗，50 名患者接受了 pembrolizumab 单药治疗。 联合治疗组 107 名患者中有 24 名 (22.4%) 和单药治疗组 50 名患者中有 20 名 (40%) 报告复发或死亡，中位随访时间分别为 101 周和 105 周。 联合治疗组和单药治疗组的 18 个月无进展生存率 (95% CI) 分别为 78.6% (69.0%, 85.6%) 和 62.2% (46.9%, 74.3%)。 与 pembrolizumab 相比，联合治疗组合显示了统计显著性和临床意义的无进展生存期改善，复发或死亡风险降低了 44%（HR = 0.561；95% CI：（0.309，1.017）。
大多数与治疗相关的不良事件为 1/2 级。与治疗相关的 ≥ 3 级不良事件的患者数量在两组之间大致相似（分别为 25% 和 18%） . 最常见的 mRNA-4157 相关 3 级事件是疲劳。没有报告与 mRNA-4157 相关的 4 级或 5 级事件。在 pembrolizumab 中添加 mRNA-4157 没有观察到免疫介导的不良事件的增强。
结论：与 pembrolizumab 相比，mRNA-4157 联合 pembrolizumab 作为辅助治疗切除的高危黑色素瘤显着延长了无进展生存期，而没有增加具有临床意义的不良事件。 这些结果提供了第一个随机证据表明个体化新抗原方法对切除的高危黑色素瘤有益, 将在患者中启动 3 期研究。
Background: T cell targeting of mutation-derived epitopes (neoantigens) has been shown to drive antitumor immune responses. The mRNA-4157 is a novel mRNA-based personalized cancer vaccine that encodes up to 34 patient-specific tumor neoantigens.
Methods: This is a randomized, open-label phase II clinical trial (mRNA-4157-P201/Keynote-942) to evaluate efficacy and safety. Patients with completely resected high-risk cutaneous melanoma were randomly assigned 2:1 to receive mRNA-4157 in combination with pembrolizumab or pembrolizumab alone. One mg of mRNA-4157 was given intramuscularly every 3 weeks for a total of 9 doses, and pembrolizumab (200 mg) was given intravenously every 3 weeks for a maximum of 18 cycles. Safety was assessed as a secondary endpoint. Progression-free survival in the overall intention-to-treat population was the primary endpoint. When a total of 40 progression-free survival events were observed, the study design had 80% power to detect a hazard ratio (HR) of 0.5 and an overall one-sided type I error of 0.1. The primary analysis of progression-free survival was specified after all patients had completed at least 12 months of the study and observed at least 40 progression-free survival events.
Results: 107 patients received mRNA-4157 in combination with pembrolizumab, and 50 patients received pembrolizumab alone. Relapse or death was reported in 24 (22.4%) of 107 patients in the combination arm and 20 (40%) of 50 patients in the monotherapy arm, with a median follow-up of 101 and 105 weeks, respectively. The 18-month progression-free survival rates (95% CI) were 78.6% (69.0%, 85.6%) in the combination therapy group and 62.2% (46.9%, 74.3%) in the monotherapy group, respectively. The combination therapy showed a statistically significant and clinically meaningful improvement in progression-free survival with a 44% reduction in the risk of relapse or death compared to pembrolizumab (HR = 0.561; 95% CI: (0.309, 1.017).
Most treatment-related adverse events were grade 1/2. The number of patients with treatment-related grade ≥ 3 adverse events was roughly similar between the two groups (25% vs 18%, respectively). The most common mRNA-4157-related grade 3 event was fatigue. No Grade 4 or 5 events related to mRNA-4157 were reported. No enhancement of immune-mediated adverse events was observed with the addition of mRNA-4157 to pembrolizumab.
Conclusions: Compared with pembrolizumab, mRNA-4157 plus pembrolizumab as adjuvant treatment of resected high-risk melanoma significantly prolonged progression-free survival without an increase in clinically meaningful adverse events. These results provide the first randomized evidence that an individualized neoantigen approach is beneficial in resected high-risk melanoma and will initiate a phase 3 study.
参考文献 Reference
Khattak A et al. 2023 AACR Meeting abstr CT001
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贝伐珠单抗联合化疗作为第一线治疗晚期胆道癌 (5/21/2023)
Bevacizumab in combination with chemotherapy as first line for advanced biliary tract cancer
背景： 血管内皮细胞生长因子阻断与细胞毒性化疗相结合可以促进免疫允许的肿瘤微环境，从而增强对 PD-L1 抑制的反应。 IMbrave151 (NCT04677504) 是一项随机, 双盲,全球 II 期研究，评估 atezolizumab,贝伐珠单抗以及顺铂和吉西他滨作为晚期胆道癌患者一线治疗的疗效。
方法： 既往未接受过治疗的晚期胆道癌患者按 1:1 随机分配接受atezolizumab（每 3 周 1200 毫克）+ 贝伐珠单抗（每 3 周15 毫克/公斤）或安慰剂 + 每 3 周的第1, 8天顺铂 25 毫克/平方米 和吉西他滨 1000 毫克/平方米，最多 8 个周期，然后是 atezolizumab（每 3 周 1200 毫克）+ 贝伐珠单抗（每 3 周15 毫克/公斤）或安慰剂，直到疾病进展或不可接受的毒性。 患者按疾病状态、地理区域和原发肿瘤位置分层。 主要终点是无进展生存期。 次要终点包括总生存期, 客观响应率, 响应持续时间, 疾病控制率和安全性。 没有进行正式的假设检验。
结果：总共有 162 名患者被随机分配接受 atezolizumab + 贝伐珠单抗 + 化疗 (n = 79) 或 atezolizumab + 安慰剂 + 化疗 (n = 83)。 中位年龄 63 岁，肝内/肝外胆管癌和胆囊 (54/19/27%)，以及转移/局部晚期 (82/18%)。无进展生存期的风险比为 0.76（95% CI：0.51，1.14）。Atezolizumab + 贝伐珠单抗 + 化疗组的中位无进展生存期 为 8.4 个月，相对于atezolizumab + 安慰剂 + 化疗组的 7.9 个月； 6 个月的无进展生存率分别为 78% 相对于 63%。总响应率分别为 24% 相对于 为 25%。≥ 6 个月的响应持续时间为 89% 相对于 47%。 未达到中位总生存期。
两组的 3 级或 4 级不良事件发生率相当似, 分别为 73% 和 74%。
结论： IMbrave151 的两种组合都显示出可控的安全性。 数据汇总表明，将 atezolizumab 与贝伐珠单抗和化疗相结合可能会给一部分晚期胆道癌患者带来临床益处。总生存期的后续行动正在进行中。
Background: Vascular endothelial growth factor blockade combined with cytotoxic chemotherapy promotes an immune-permissive tumor microenvironment that enhances the response to PD-L1 inhibition. IMbrave151 (NCT04677504) is a randomized, double-blind, global phase II study evaluating atezolizumab, bevacizumab, and cisplatin and gemcitabine as first-line treatment for patients with advanced biliary tract cancer.
Methods: Patients with previously untreated advanced biliary tract cancer were randomized 1:1 to receive atezolizumab (1200 mg every 3 weeks) + bevacizumab (15 mg/kg every 3 weeks) or placebo + Cisplatin 25 mg/m2 and gemcitabine 1000 mg/m2 on days 1, 8 every 3 weeks for up to 8 cycles, then atezolizumab (1200 mg every 3 weeks) + bevacizumab (15 mg/kg every 3 weeks) or placebo until disease progression or unacceptable toxicity. Patients were stratified by disease status, geographic region, and primary tumor location. The primary endpoint was progression-free survival. Secondary endpoints included overall survival, objective response rate, duration of response, disease control rate, and safety. No formal hypothesis testing was performed.
Results: A total of 162 patients were randomly assigned to receive atezolizumab + bevacizumab + chemotherapy (n = 79) or atezolizumab + placebo + chemotherapy (n = 83). Median age was 63 years, intrahepatic/extrahepatic cholangiocarcinoma and gallbladder (54/19/27%), and metastatic/locally advanced (82/18%). The hazard ratio for progression-free survival was 0.76 (95% CI: 0.51, 1.14). Median progression-free survival was 8.4 months in the atezolizumab + bevacizumab + chemotherapy arm vs. 7.9 months in the atezolizumab + placebo + chemotherapy arm; the 6-month progression-free survival rates were 78% vs. 63%. The overall response rates were 24% vs. 25%. Duration of response ≥ 6 months was 89% vs 47%. Median overall survival was not reached.
The incidence of grade 3 or 4 adverse events was similar in the two groups, 73% and 74%, respectively.
Conclusions: Both combinations of IMbrave151 showed manageable safety. Pooled data suggest that combining atezolizumab with bevacizumab and chemotherapy may confer clinical benefit in a subset of patients with advanced biliary tract cancer. Follow-up for overall survival is ongoing.
参考文献 Reference
El-Khoueiry AB al. J Clin Oncol 2023; 41 suppl 4, abstr 491
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新辅助 enoblituzumab用于局限性前列腺癌的 (5/20/2023)
Neoadjuvant enoblituzumab in locally advanced prostate cancer
B7 同系物 3 (B7-H3; CD276) 是一种肿瘤相关抗原和可能的免疫检查点，在前列腺癌中高表达，并且与早期复发和转移有关。 Enoblituzumab 是一种人源工程化B7-H3 的靶向抗体，可介导抗体依赖性细胞毒性。 在这项新辅助试验（NCT02923180）的第 2 阶段，共有32 名可手术的中度至高风险局限性前列腺癌患者参加，以评估在前列腺切除术前给予 enoblituzumab 的安全性,抗肿瘤活性和免疫原性。 主要结局是安全性和前列腺切除术后 1 年的不可检测的PSA水平 (PSA0)，目的是获得具有合理精度的 PSA0 估计值。
主要安全终点没有出现明显的意外手术或医疗并发症，也没有手术延误。 总体而言，12% 的患者经历了 3 级不良事件，没有发生 4 级事件。 前列腺切除术后 1 年 PSA0 率的共同主要终点为 66%（95% 置信区间 47-81%）。
研究者认为在前列腺癌中使用 B7-H3 靶向免疫疗法是可行和安全的，初步数据表明具有潜在的临床活性。
B7 homolog 3 (B7-H3; CD276), a tumor-associated antigen and possible immune checkpoint, is highly expressed in prostate cancer and is associated with early recurrence and metastasis. Enoblituzumab is a humanized, Fc-engineered B7-H3 targeting antibody that mediates antibody-dependent cellular cytotoxicity.
A total of 32 patients with operable intermediate-to-high-risk localized prostate cancer were enrolled in this phase 2 neoadjuvant trial (NCT02923180) to evaluate the safety, antitumor activity and immunogenicity of enoblituzumab administered before prostatectomy. The coprimary outcomes were safety and undetectable PSA levels (PSA0) at 1 year after prostatectomy, with the aim of obtaining estimates of PSA0 with reasonable precision.
The primary safety endpoint was met with no significant unexpected surgical or medical complications, or surgical delays. Overall, 12% of patients experienced grade 3 adverse events and no grade 4 events occurred. The co-primary endpoint of the 1-year PSA0 rate after prostatectomy was 66% (95% CI 47-81%).
The investigators concluded that the use of B7-H3-targeted immunotherapy in prostate cancer is feasible and safe, with preliminary data suggesting potential clinical activity.
参考文献 Reference
Shenderov E et al. Nature Medicine 2023: 29:888
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乳腺癌前哨淋巴结阳性后的腋窝放疗或手术：AMAROS 试验的 10 年结果 (5/17/2023)
Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer: 10-year Results of the AMAROS trial
欧洲癌症研究与治疗组织 (EORTC) 10981-22023 AMAROS 试验评估了 临床T1-2(< 5 cm), 淋巴结阴性和一个前哨淋巴结活检阳性患者的腋窝淋巴结清扫术与腋窝放疗。
方法：在这项开放标签多中心 III 期非劣效性试验中，4,806 名患者(2001-2020)接受了前哨淋巴结活检活检； 1,425 人为淋巴结阳性并随机分配至腋窝淋巴结清扫术（n = 744, 至少 I 级和 II 级，并且 >10 个淋巴结）或腋窝放疗（n = 681, 对腋窝的所有 3 个水平以及锁骨上窝的内侧部分进行 25 次 2 Gy 或生物学等效剂量）。
结果：根据意向治疗分析，腋窝淋巴结清扫术后 10 年腋窝复发率累积发生率为 0.93%（95% CI，0.18 至 1.68；7 起事件），腋窝放疗后为 1.82%（95% CI，0.74 至 2.94；11 起事件） （风险比 [HR]，1.71；95% CI，0.67 至 4.39）。 总生存率HR，1.17；95% CI，0.89 至 1.52）或无病生存率（HR，1.19；95% CI，0.97 至 1.46）没有差异。 在更新的 5 年分析中，腋窝淋巴结清扫术与较高的淋巴水肿率相关（24.5% 对 11.9%；P < .001）。 生活质量在 5 年内没有因治疗而不同。 探索性分析显示，腋窝放疗后第二原发癌的 10 年累积发生率为 12.1%（95% CI，9.6 至 14.9），腋窝淋巴结清扫术后为 8.3%（95% CI，6.3 至 10.7）。
结论：这项为期 10 年的分析, 证实了腋窝放疗和腋窝淋巴结清扫术后的低腋窝复发率，并且在总生存率, 无病生存率和局部区域控制方面没有差异。 考虑到较低的手臂发病率，对于前哨淋巴结阳性临床 T1-2 乳腺癌患者，腋窝放疗优于腋窝淋巴结清扫术。
The European Organization for Research and Treatment of Cancer (EORTC) 10981-22023 AMAROS trial evaluated axillary lymph node dissection and axillary radiotherapy in patients with clinical T1-2 (< 5 cm), negative nodes and one positive sentinel lymph node biopsy.
Methods: In this open-label, multicenter phase III non-inferiority trial, 4,806 patients (2001-2020) underwent sentinel lymph node biopsy; 1,425 were node positive and were randomly assigned to axillary lymph node dissection (n = 744, at least level I and II, and >10 lymph nodes) or axillary radiotherapy (n = 681, 25 fractions of 2 Gy or biologically equivalent dose to all 3 levels of the axilla and the medial portion of the supraclavicular fossa).
Results: According to the intention-to-treat analysis, the 10-year cumulative incidence of axillary recurrence was 0.93% (95% CI, 0.18 to 1.68; 7 events) after axillary lymph node dissection and 1.82% (95% CI, 0.74 -2.94, 11 events) after axillary radiotherapy (hazard ratio [HR], 1.71; 95% CI, 0.67 to 4.39). There was no difference in overall survival (HR, 1.17; 95% CI, 0.89 to 1.52) or disease-free survival (HR, 1.19; 95% CI, 0.97 to 1.46). In the updated 5-year analysis, axillary lymph node dissection was associated with a higher rate of lymphedema (24.5% vs 11.9%; P < .001). Quality of life did not differ by treatment over 5 years. In an exploratory analysis, the 10-year cumulative incidence of second primary cancer was 12.1% (95% CI, 9.6 to 14.9) after axillary radiotherapy and 8.3% (95% CI, 6.3 to 10.7) after axillary lymph node dissection.
Conclusions: This 10-year analysis demonstrated low axillary recurrence rates after axillary radiotherapy and axillary lymph node dissection, with no differences in overall survival, disease-free survival, and locoregional control. Given the lower arm morbidity, axillary radiotherapy is preferred over axillary lymph node dissection in patients with sentinel node-positive clinical T1-2 breast cancer.
参考文献 Reference
Bartels, SRL et al. J Clin Onc 2023;41:2159
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个体化 RNA 新抗原疫苗可刺激胰腺癌中的 T 细胞 (5/13/2023)
Personalized RNA neoantigen vaccine can stimulate T-cells in pancreatic cancer
美国纽约Sloane-Kettering 癌症中心在一项临床试验 I 期试验中，从手术切除的胰腺导管腺癌中实时合成了 mRNA 新抗原疫苗(autogene cevumeran)。手术后，患者依次接受 atezolizumab（抗 PD-L1 免疫疗法）, 自体 cevumeran（每位患者最多 20 种新抗原）和四药化疗方案（mFOLFIRINOX，包括亚叶酸、氟尿嘧啶、伊立替康和 奥沙利铂）。 试验终点包括通过高阈值测定的疫苗诱导的新抗原特异性 T细胞、18 个月无复发生存期和肿瘤学可行性。
16 名患者接受了 atezolizumab 和autogene cevumeran 治疗， 15 名患者接受了mFOLFIRINOX 。 Autogene cevumeran 在基准时间的 3 天内给药，在 16 名患者中的 8 名患者中是可耐受的并诱导了新的高强度新抗原特异性 T 细胞，其中一半针对一种以上的疫苗新抗原。 研究者使用一种新的数学策略来跟踪 T细胞克隆 (CloneTrack) 和功能测定，发现疫苗扩增的 T 细胞占所有血液 T 细胞的 10%，用疫苗加强剂重新扩增并包含长寿命的多功能新抗原 -特异性效应 CD8+ T 细胞。
在可评估安全性的队列中，接受autogene cevumeran 治疗的 16 名患者中有 1 名(6%) 出现 3 级治疗相关的副作用为发烧和高血压。 接受autogene cevumeran 治疗的所有 16 名患者 (100%) 均出现 1-2 级治疗相关的副作用。19名患者中只有 1 名 (5%) 的新抗原不足导致无法生产疫苗。 16 名患者中有 3 名 (19%) 没有接受所有 9 剂疫苗，这是由于疾病进展, 死亡或 mFOLFIRINOX 毒性。 因此，即使在复杂的肿瘤手术后，也可以快速施用autogene cevumeran。
在超过预定次要终点的 18 个月中位随访中，在可评估安全性队列中患者的中位总生存期和中位无进展生存期未达到。 对于生物标志物可评估队列中的患者，8 名autogene cevumeran 响应者的中位无进展生存期未达到，而 8 名无响应者的中位无进展生存期为 13.4 个月（P = 0.003，风险比 (HR) = 0.08（ 95% 置信区间 (CI 0.01–0.4)。
患者 29 对autogene cevumeran 的响应而扩增T 细胞的百分比在所有患者中第二高，其中包括疫苗新抗原特异性多功能 CD8 + T 细胞。 他的血清 CA19-9 水平升高，并伴有新的 7 毫米肝脏病变，提示疫苗启动后发生了转移。 活检样本未显示恶性细胞，但有致密的淋巴样浸润，其中包括所有 15 个autogene cevumeran 扩增的 CD8+ T 细胞克隆，具有裂解和效应潜能的表型证据, 数字微滴 PCR 显示，这种淋巴样浸润含有携带 TP53R175H 突变的稀有细胞，与该患者原发性肿瘤中的 R175H 驱动突变相同。 这种肝脏病变在随后的成像中消失了，这表明autogene cevumeran 扩增的 T 细胞可能具有根除微转移的能力。
An mRNA neoantigen vaccine (autogene cevumeran) was synthesized in real time from surgically resected pancreatic ductal adenocarcinoma in a phase I clinical trial conducted at the Sloane-Kettering Cancer Center in New York, USA. After surgery, patients sequentially received atezolizumab (anti-PD-L1 immunotherapy), autologous cevumeran (up to 20 neoantigens per patient), and a four-drug chemotherapy regimen (mFOLFIRINOX, including leucovorin, fluorouracil, irinotecan, and oxaliplatin). The endpoints of the trial included vaccine-induced neoantigen-specific T cells measured by a high threshold, 18-month relapse-free survival, and oncologic viability.
Sixteen patients received atezolizumab and the autogene cevumeran, and 15 patients received mFOLFIRINOX. Autogene cevumeran, administered within 3 days of benchmarked time, was tolerable and induced new high levels of neoantigen-specific T cells in 8 of 16 patients, with half targeting more than one vaccine neoantigen. Using a novel mathematical strategy to track T cell clones (CloneTrack) and functional assays, the researchers found that vaccine-expanded T cells accounted for 10% of all blood T cells, re-expanded with a vaccine booster and contained long-lived polyfunctional, neoantigen-specific effector CD8+ T cells.
In the safety-evaluable cohort of those who received autogene cevumeran, grade 3 treatment-related side effects were fever and hypertension in 1 of 16 patients (6%). All 16 patients (100%) treated with autogene cevumeran experienced grade 1-2 treatment-related side effects. Only 1 of 19 patients (5%) had insufficient neoantigens to allow vaccine production. Three of 16 patients (19%) did not receive all 9 doses of the vaccine due to disease progression, death or mFOLFIRINOX toxicity. Therefore, autogene cevumeran can be administered rapidly even after complex tumor surgery.
At a median follow-up of 18 months beyond the prespecified secondary endpoints, median overall survival and median progression-free survival were not reached for patients in the safety-evaluable cohort. For patients in the biomarker-evaluable cohort, the median progression-free survival was not reached for the 8 autogene cevumeran responders and 13.4 months for the 8 non-responders (P = 0.003, hazard ratio (HR) = 0.08 (95% confidence interval (CI 0.01–0.4).
Patient 29 had the second highest percentage of expanded T cells in response to autogene cevumeran, including vaccine neoantigen-specific multifunctional CD8+ T cells. His serum CA19-9 level was elevated, along with a new 7-mm liver lesion, suggestive of a metastasis after the vaccine priming. The biopsy sample showed no malignant cells but a dense lymphoid infiltrate that included all 15 autogene cevumeran-expanded CD8+ T cell clones with phenotypic evidence of lytic and effector potential. The digital droplet PCR showed the lymphoid infiltrate contained rare cells harboring the TP53R175H mutation, the same R175H driver mutation in this patient’s primary tumor. This liver lesion disappeared on subsequent imaging, suggesting that autogene cevumeran-expanded T cells may have the ability to eradicate micrometastases.
参考文献 Reference
Rojas LR et al. Nature 2023; 618:144
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TLR9 激活剂 pixatimod 与 nivolumab 联合治疗微卫星稳定的转移性实体瘤 (5/7/2023)
TLR9 activator in combination with nivolumab in microsatellite stable metastatic solid tumors
背景: Pixatimod 是 Toll 样受体 9 通路的独特激活剂。 一项 Ib 期开放标签, 多中心研究试验评估了 pixatimod 和 PD-1 抑制剂 nivolumab 在免疫性”冷”癌中的安全性, 有效性和药效学。
方法: 3+3 剂量递增用于58 名微卫星稳定转移性结直肠癌和转移性胰腺导管腺癌扩展队列。 参与者每周接受一次 pixatimod，每次 1 小时静脉输注，加上每 2 周一次的纳武单抗。 目标包括评估安全性, 抗肿瘤活性, 药效学和药代动力学特征。
结果: Pixatimod 的最大耐受剂量为 25 毫克 与 240 毫克 nivolumab 联合使用，后者用于研究的扩展阶段。 12 名参与者 (21%) 报告了 21 项 3-5 级治疗相关不良事件； 一名接受 50 毫克 pixatimod/nivolumab 的参与者出现了与治疗相关的 5 级副作用。 转移性结直肠癌队列 (n=33) 的 3/4 级发生率为 12%。转移性胰腺导管腺癌队列中没有响应者 (n = 18)。在转移性结直肠癌队列中，25 名参与者是可评估的（初始基线后评估扫描 > 6 周）； 其中，三名参与者已确认部分响应，八名参与者病情稳定至少 9 周。 临床获益 (部分响应和病情稳定) 与较低的泛免疫炎症值和血浆 IL-6 有关，但与 IP (interferon γ-induced protein)-10 和 IP-10/IL-8 比率增加有关。 在以部分响应为最佳反应的转移性结直肠癌参与者中，T 细胞, 树突状细胞和较小程度的 NK 细胞浸润增加，在治疗后 5 周明显增加。
结论: 25 毫克的 Pixatimod 与 nivolumab 联合使用耐受性良好。转移性结直肠癌的疗效信号和药效学变化值得进一步研究。
Background: Pixatimod is a unique activator of the Toll-like receptor 9 pathway. A phase Ib open-label, multicenter research trial evaluated the safety, efficacy, and pharmacodynamics of pixatimod and the PD-1 inhibitor nivolumab in immunological “cold” cancers.
Methods: 3+3 dose escalation was used in an expansion cohort of 58 microsatellite stable metastatic colorectal cancer and metastatic pancreatic ductal adenocarcinoma. Participants received pixatimod once a week as a 1-hour intravenous infusion, plus nivolumab every 2 weeks. Objectives included safety, antitumor activity, pharmacodynamics, and pharmacokinetic profiles.
Results: Pixatimod was administered at a maximum tolerated dose of 25 mg in combination with 240 mg of nivolumab, which was used in the extension phase of the study. Twelve participants (21%) reported 21 grade 3-5 treatment-related adverse events; one participant who received 50 mg pixatimod/nivolumab experienced a treatment-related grade 5 adverse event. The incidence of grade 3/4 in the metastatic colorectal cancer cohort (n=33) was 12%. There were no responders in the metastatic pancreatic ductal adenocarcinoma cohort (n = 18). In the metastatic colorectal cancer cohort, 25 participants were evaluable (initial post-baseline evaluation scan > 6 weeks); of these, three participants had confirmed partial responses and eight participants had stable disease for at least 9 weeks. Clinical benefit (partial response and stable disease) was associated with lower pan-immune inflammation values and plasma IL-6, but increased IP (interferon γ-induced protein)-10 and IP-10/IL-8 ratio. Among participants with metastatic colorectal cancer who responded best with a partial response, T cell, dendritic cell and, to a lesser extent, NK cell infiltration increased, significantly increasing at 5 weeks after treatment.
Conclusions: Pixatimod 25 mg in combination with nivolumab was well tolerated. Efficacy signaling and pharmacodynamic changes in metastatic colorectal cancer warrant further investigation.
参考文献 Reference
Liu ML et al. Cytokine Growth Factor Rev 2023; 22: 121.
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早期可手术乳腺癌的含蒽环类药物和含紫杉类药物的化疗：来自 86 项随机试验的 100,000 名的荟萃分析 (5/6/2023)
Anthracycline-containing and taxane-containing chemotherapy for early-stage operable breast cancer: a meta-analysis of 100,000 women from 86 randomized trials
背景: 与不化疗相比，用于早期乳腺癌的蒽环类紫杉烷化疗提高了生存率。 然而，由于对蒽环类药物副作用的担忧，导致越来越多地使用不含蒽环类药物的紫杉烷化疗，这可能会影响疗效。
方法: 研究者对随机试验进行了个体患者水平的荟萃分析，比较了紫杉类药物加上与不加蒽环类药物的疗效，并更新了之前对蒽环类药物加上与不加紫杉类药物的荟萃分析，并分析了44 项试验中相关的6 项比较。 研究者搜索了包括 MEDLINE、Embase、Cochrane 图书馆和会议摘要在内的数据库，以评估蒽环类和紫杉类化疗的试验。 如果辅助或新辅助试验在 2012 年 1 月 1 日之前开始，则符合条件。主要结果是乳腺癌复发和特定原因死亡率。 对数秩分析产生了首次事件发生率比 (RR) 和 CI。
发现: 确定了 28 项含或不含蒽环类药物的紫杉烷方案试验，其中 23 项被认为符合条件，15 项提供了 18,103 名女性的数据。 在提供个体数据的所有 15 项试验中，与不含蒽环类药物的紫杉类药物方案相比，复发率平均降低 14%（RR 0.86，95% CI 0.79–0.93；p = 0.0004）。 非乳腺癌死亡人数没有增加，但每 700 名接受治疗的女性就会增加 1 例急性髓性白血病病例。 与相同剂量的多西他赛加环磷酰胺相比，在多西他赛加环磷酰胺的同时加入蒽环类药物可最明显地减少复发（10 年复发风险 12.3% 对比 21.0%；风险差异 8.7%，95% 可信区间 4.5–12.9；RR 0.58、0.47–0.73；p < 0.0001）。 该组的 10 年乳腺癌死亡率降低了 4.2% (0.4–8.1; p = 0.0034)。 与多西他赛加环磷酰胺相比，紫杉烷加蒽环类药物的顺序方案没有显著降低复发风险（RR 0.94、0.83–1.06；p = 0.30）。 为了分析含紫杉烷类和不含紫杉烷类的蒽环类药物方案，35 项试验 (n = 52,976) 提供了个体患者数据。 当每组蒽环类药物的累 积剂量相同时（RR 0.87、0.82–0.93；p < 0.0001；n =11,167），相比于 对照组非紫杉烷类药物（主要是蒽环类药物）累积剂量是紫杉烷类药物组两倍的试验（RR 0.96、0.90–1.03；p =0.27；n =14,620） . 蒽环类和紫杉类方案之间的直接比较表明，更高的累积剂量和更高剂量强度的方案更有效。 在雌激素受体阳性和雌激素受体阴性疾病中，紫杉烷加蒽环类药物的复发比例降低相似，年龄、淋巴结状态或肿瘤大小或分级方面并没有产生差异。
解释: 蒽环类药物加紫杉类药物方案在减少乳腺癌复发和死亡方面最有效。 蒽环类药物加紫杉类药物累积剂量较高的方案提供了最大的益处，挑战了当前临床实践和指南中非蒽环类药物化疗的趋势，尤其是较短的方案，例如四个周期的多西紫杉醇-环磷酰胺。 通过汇集几乎所有相关试验的数据，该荟萃分析提供了可靠的证据基础，为个体治疗决策、临床指南和未来临床试验的设计提供信息。
Background: Anthracycline-taxane chemotherapy for early breast cancer substantially improves survival compared with no chemotherapy. However, concerns about side effects of anthracyclines have led to the increased use of taxane chemotherapy without anthracycline, which could compromise efficacy.
Methods: The investigators performed an individual patient-level meta-analysis of randomized trials comparing taxane regimes with versus without anthracyclines, and updated previous meta-analyses of anthracycline regimes with versus without taxanes, and analyzed 44 trials in 6 related comparisons. Researchers searched databases including MEDLINE, Embase, the Cochrane Library, and conference abstracts to evaluate trials of anthracycline and taxane chemotherapy. Adjuvant or neoadjuvant trials were eligible if started before January 1, 2012. Primary outcomes were breast cancer recurrence and cause-specific mortality. Log-rank analysis yielded first-event rate ratios (RR) and CIs.
Findings: Twenty-eight trials of taxane regimens with or without anthracyclines were identified, of which 23 were considered eligible and 15 provided data on 18,103 women. Across all 15 trials for which individual data were available, there was an average 14% reduction in relapse with taxane regimens including anthracycline than those without (RR 0.86, 95% CI 0.79–0.93; p = 0.0004). There was no increase in non-breast cancer deaths, but there was 1 additional case of acute myeloid leukemia for every 700 women treated. The clearest reductions in recurrence were found when anthracycline was added concurrently to docetaxel plus cyclophosphamide versus the same dose of docetaxel plus cyclophosphamide (10-year relapse risk 12.3% vs. 21.0%; risk difference 8.7%, 95% CI 4.5–12.9; RR 0.58, 0.47–0.73; p < 0.0001). Ten-year breast cancer mortality in this group was reduced by 4·2% (0.4–8.1; p = 0.0034). No significant reduction in recurrence risk was found for sequential schedules of taxane plus anthracycline when compared with docetaxel plus cyclophosphamide (RR 0.94, 0.83–1.06; p = 0.30). For the analysis of anthracycline regimens with versus without taxane, 35 trials (n = 52,976) provided individual patient data. Larger recurrence reductions were seen from adding taxane to anthracycline regimens when the cumulative dose of anthracycline was the same in each group (RR 0·87, 0·82–0·93; p<0·0001; n=11 167) than in trials with two-fold higher cumulative doses of non-taxane (mostly anthracycline) in the control group than in the taxane group (RR 0·96, 0·90–1·03; p=0·27; n=14 620). A direct comparison between anthracycline and taxane regimens showed higher cumulative doses and more dose-intense regimens were more efficacious. The proportional reductions in recurrence for taxane plus anthracycline were similar in estrogen receptor-positive and estrogen receptor-negative disease, and did not differ by age, nodal status, or tumor size or grade.
Interpretation: Anthracycline plus taxane regimens are most efficacious in reducing breast cancer recurrence and death. Regimen with higher cumulative doses of anthracycline plus taxane provided the greatest benefit. The results challenge the current trend in clinical practice and guidelines, towards non-anthracycline chemotherapy especially with shorter regimens such as four cycles of Docetaxel-cyclophosphamide. This meta-analysis provides a reliable evidence base to inform individual treatment decisions, clinical guidelines, and the design of future clinical trials.
参考文献 Reference
Warly Breast Cancer Trialists’ Collaborative Group Lancet 2023;401;1277
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CAR-T治疗晚期或转移性透明细胞肾细胞癌的I期临床试验 (4/30/2023)
CAR-T cell therapy in a phase I trial for advanced/metastatic renal cell carcinoma
背景：由于原发性和转移性肾细胞癌中 CD70 抗原表达的高发生率 (80%)，但在正常组织中表达有限，它被是用来验证 CD70 定向同种异体 CAR T 治疗原发性和转移性透明细胞肾细胞癌(ccRCC)。TRAVERSE (NCT04696731)，第一个这样的人体试验，旨在确定在 ccRCC 患者中使用含/不含 ALLO-647 的氟达拉滨/环磷酰胺预处理(conditioning)后 ALLO-316 的最大耐受剂量。 ALLO-316 是一种抗 CD70 同种异体 CAR T 细胞产品，它利用基因编辑敲除 TCRα (T细胞受体)恒定基因以降低移植物抗宿主病的风险, 并敲除 CD52 基因以允许使用 ALLO- 647（一种人源化抗 CD52）选择性地耗尽宿主 T 细胞而不影响同种异体 CAR T 细胞。
方法: 这项多中心, 单臂, 开放标签、3+3 剂量递增试验招募了转移性ccRCC患者, 既往必须接受过免疫检查点抑制剂和血管内皮生长因子靶向治疗，而且在治疗期间/之后疾病进展或因毒性而停药。 ALLO-316 在预处理后第 0 天以递增剂量（40 – 240 X 106个同种异体 CAR+ 细胞）给药。 主要终点是在输注 ALLO-316 后的前 28 天内，剂量限制性毒性的目标发生率 <33%。
结果：到 2022 年 12 月 3 日，18 名转移性 ccRCC 患者（中位年龄：63 岁；82% 为男性）入组； 所有患者之前接受过 3 线（中位数）治疗。 这些患者中有 11 名 (65%) 发现生了细胞因子释放综合征，除 1 名 (6%) 为3级外，其他均低于3级。未观察到免疫效应细胞相关神经毒性综合征或植物抗宿主病。 观察到一个 (6%) 肝功能升高且需要剂量扩展。 尚未达到最大耐受剂量。 三名患者在所有时间点都获得了部分响应的最佳总体响应，其中两名患者在随后的就诊中得到确认；总体响应率 = 12%，疾病控制率 = 71%。 在确认为 CD70+ 肿瘤的患者 (n = 9) 中，确认的总体响应率 = 22%（未确认的总体响应率 = 33%）和疾病控制率 = 100%。 在外周血中观察到高 CAR T 细胞扩增。
结论：ALLO-316 是一种针对晚期转移性肾细胞癌中 CD70 的同种异体 CAR T 细胞产品，显示抗肿瘤活性和可控的安全性。 TRAVERSE 试验中 ALLO-316 的最大耐受剂量将支持第 2 阶段试验设计。
Background: Due to the high incidence (80%) of CD70 antigen expression in primary and metastatic renal cell carcinoma, but limited expression in normal tissues, this feature was used to validate the CD70-directed allogeneic CAR T for the treatment of primary and metastatic clear cell renal cell carcinoma (ccRCC). TRAVERSE (NCT04696731) is the first-in-human trial, to determine the maximum tolerated dose (MTD) of ALLO-316 following fludarabine/cyclophosphamide conditioning with and without ALLO-647 in ccRCC patients. ALLO-316 is an anti-CD70 allogeneic CAR T cell product that uses gene editing to knock out the TCRα (T cell receptor) constant gene to reduce the risk of graft-versus-host disease, and knock out the CD52 gene to allow the use of ALLO -647 (a humanized anti-CD52 monoclonal antibody) selectively depletes host T cells without affecting allogeneic CAR T cells.
Methods: This multicenter, single-arm, open-label, 3+3 dose-escalation trial enrolled patients with metastatic ccRCC who had previously received immune checkpoint inhibitors and vascular endothelial growth factor-targeted therapy and had disease progression or discontinuation due to toxicity. ALLO-316 was administered in increasing doses (40 – 240 X 106 allogeneic CAR+ cells) on Day 0 after conditioning. The primary endpoint was a target incidence of dose-limiting toxicities of <33% within the first 28 days following infusion of ALLO-316.
Results: By December 3, 2022, 18 patients with metastatic ccRCC (median age: 63 years; 82% male) were enrolled; all patients had previously received 3 lines of (median) therapy. Cytokine release syndrome was found in 11 of these patients (65%), all but 1 (6%) were grade 3 and the rest were less than grade 3. No immune effector cell-associated neurotoxicity syndrome or GVHD was observed. Elevated hepatic function was observed in one (6%) patient and required dose expansion. The maximum tolerated dose has not been reached. Three patients achieved a best overall response of partial response at all time points, two of whom were confirmed at subsequent visits; overall response rate = 12%, disease control rate = 71%. Among patients with confirmed CD70+ tumors (n = 9), confirmed overall response rate = 22% (unconfirmed overall response rate = 33%) and disease control rate = 100%. High CAR T cell expansion was observed in peripheral blood.
Conclusions: ALLO-316, an allogeneic CAR T cell product targeting CD70 in advanced/metastatic renal cell carcinoma, showed antitumor activity and a manageable safety profile. The maximum tolerated dose of ALLO-316 in the TRAVERSE trial will support phase 2 trial design.
参考文献 Reference
Srour S et al. AACR Ann Meeting 2023; abstr CT011
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FDA 批准 polatuzumab vedotin-piiq 用于先前未治疗的弥漫性大 B 细胞/高级别 B 细胞淋巴瘤（4/29/2023）
FDA has approved polatuzumab vedotin-piiq in untreated diffuse large B-cell lymphoma and high-grade B-cell lymphpma
2023 年 4 月 19 日 FDA批准 polatuzumab vedotin-piiq与利妥昔单抗产品, 环磷酰胺, 多柔比星和泼尼松 (R-CHP) 一起用于先前未经治疗的弥漫性大 B细胞淋巴瘤 (DLBCL), 或高级别 B 细胞淋巴瘤 (HGBL) 且国际预后指数 (IPI) 评分为 2 或更高。
批准基于 POLARIX (NCT03274492) 随机, 双盲, 安慰剂对照试验，在 879 名先前未治疗的患者中进行，IPI 评分为 2-5。 该试验评估了在 R-CHOP（利妥昔单抗, 环磷酰胺, 多柔比星, 长春新碱和泼尼松）方案中用 polatuzumab vedotin 替代长春新碱的优越性。 患者被随机分配 (1:1) 接受 polatuzumab vedotin 加 R-CHP（试验组）或 R-CHOP 治疗六个 21 天周期，随后在双臂中分别接受两个单独的利妥昔单抗治疗周期。 患者为新诊断的 DLBCL, NOS (84%) 和 HGBL (11%)。 疗效基于研究者评估的无进展生存期。 试验组的无进展生存期在统计学上显著延长，风险比 (HR) 为 0.73（95% CI：0.57、0.95；p = 0.0177）。 该组在无事件生存率方面也有统计学意义的显著改善（HR 0.75；95% CI：0.58、0.96；p =0.0244）。 未观察到完全缓解率或总生存率有显著差异（HR 0.94；95% CI：0.67，最终分析为 1.33）。
试验组最常见的不良反应（≥20%）(不包括实验室异常)，是周围神经病变, 恶心, 疲劳, 腹泻, 便秘, 脱发和粘膜炎。 3 至 4 级实验室异常 (≥10%) 是淋巴细胞减少, 中性粒细胞减少, 高尿酸血症和贫血。 53% 的患者出现周围神经病变或恶化，58% 的患者在中位 4 个月后消退。 34%的患者出现严重不良反应，包括发热性中性粒细胞减少症和肺炎。
Polatuzumab vedotin 的推荐剂量为 1.8 mg/kg，每 21 天静脉输注一次，与 R-CHP 联合使用 6 个周期。 患者应预先服用抗组胺药和退热药，并接受预防性粒细胞集落刺激因子。该申请被授予孤儿药称号。
编者按: Polatuzumab vedotin 是一种 CD79b 导向的抗体-药物偶联物，可将monomethyl auristatin E (MMAE)（一种抗有丝分裂剂）递送至癌细胞并抑制其分裂。
April 19, 2023 FDA approved polatuzumab vedotin-piiq in combination with rituximab product, cyclophosphamide, doxorubicin and prednisone (R-CHP) for previously untreated diffuse large B cell lymphoma (DLBCL), or high-grade B-cell lymphoma (HGBL) with an International Prognostic Index (IPI) score of 2 or higher.
Approval was based on the randomized, double-blind, placebo-controlled trial of POLARIX (NCT03274492) in 879 previously untreated patients with an IPI score of 2-5. This trial evaluated the superiority of polatuzumab vedotin as a substitute for vincristine in the R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen. Patients were randomly assigned (1:1) to receive six 21-day cycles of polatuzumab vedotin plus R-CHP (experiment arm) or R-CHOP, followed by two additional cycles of rituximab in each arm. Patients were newly diagnosed with DLBCL, NOS (84%) or HGBL (11%). Efficacy was based on investigator-assessed progression-free survival (PFS). PFS was statistically significantly longer in the experiment arm with a hazard ratio (HR) of 0.73 (95% CI: 0.57, 0.95; p = 0.0177). This group also had a statistically significant improvement in modified event-free survival (HR 0.75; 95% CI: 0.58, 0.96; p = 0.0244). No significant difference in complete response rate or overall survival was observed (HR 0.94; 95% CI: 0.67, final analysis 1.33).
The most common adverse reactions (≥20%) in the experiment arm (excluding laboratory abnormalities), were peripheral neuropathy, nausea, fatigue, diarrhea, constipation, alopecia, and mucositis. Grade 3 to 4 laboratory abnormalities (≥10%) were lymphopenia, neutropenia, hyperuricemia, and anemia. Peripheral neuropathy developed or worsened in 53% of patients and resolved in 58% after a median of 4 months. Serious adverse reactions, including febrile neutropenia and pneumonia, occurred in 34% of patients.
The recommended dose of Polatuzumab vedotin is 1.8 mg/kg intravenously every 21 days in combination with R-CHP for 6 cycles. Patients should be premedicated with antihistamines and antipyretics, and receive prophylactic granulocyte colony-stimulating factor. The application was granted Orphan Drug Designation.
Editor’s note: Polatuzumab vedotin is a CD79b-directed antibody-drug conjugate that delivers monomethyl auristatin E (MMAE), an anti-mitotic agent, to cancer cells and inhibits their division.
参考文献 Reference
https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-polatuzumab-vedotin-piiq-previously-untreated-diffuse-large-b-cell-lymphoma-not
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阿比特龙和奥拉帕尼对相对于阿比特龙作为转移性去势抵抗性前列腺癌的一线疗法 (4/23/2023)
First line abiraterone plus olaparib vs abiraterone/placebo in metastatic castration-resistant prostate cancer
方法：PROpel 是一项随机, 双盲III期临床试验（NCT03732820），针对符合阿比特龙条件的转移性去势抵抗性前列腺癌患者进行一线治疗。 使用肿瘤组织和/或循环肿瘤 DNA (ctDNA) 测试对患者的同源重组修复突变 (HRRm) 状态进行前瞻性评估, 患者以1:1 随机分配至奥拉帕尼每天两次300 mg或安慰剂，两组都接受阿比特龙（每日一次1000 mg）加泼尼松/泼尼松龙（prednisone/prednisolone, 每天两次5 mg）。 治疗一直持续到影像学疾病进展、不可接受的毒性或撤回同意。 总生存期是一个关键的次要终点。 来自肿瘤组织和 ctDNA 检测的综合结果被用于将患者分配到 HRRm/BRCAm (BRCA突变)亚组。
结果：患者 (n = 796) 的特征（包括先前的多西他赛, 转移部位, 症状评分和 HRRm 状态）总体上是平衡的。 在意向治疗人群中, 阿比特龙+ 奥拉帕尼相对于阿比特龙 + 安慰剂显示总生存期获益趋势（成熟度 47.9%，HR 0.81，95% CI 0.67–1.00，P = 0.0544），中位总生存期分别为 42.1 个月和 34.7 个月。 HRRm, 非 HRRm, BRCAm 和非 BRCAm 亚组的中位总生存期中位数和 HR 均有利于阿比特龙+ 奥拉帕尼相对于阿比特龙+ 安慰剂。
在阿比特龙+ 奥拉帕尼组中，最常见的 ≥ 3 级不良事件是贫血 (16.1%)。
结论：在 PROpel 中预先指定的最终分析中，在意向治疗人群中，与标准治疗阿比特龙相比，阿比特龙+ 奥拉帕尼将总生存期延长 > 7 个月。 大于 42 个月的中位总生存期是迄今为止在一线转移性去势抵抗性前列腺癌的 3 期试验中报告的最长中位值。在 HRRm, 非 HRRm, , BRCAm 和非 BRCAm 亚组中观察到总生存期获益的趋势，其中 BRCAm 亚组获益最大。 没有发现新的长期安全问题。
Methods: PROpel is a randomized, double-blind phase III trial (NCT03732820) using first-line therapy in abiraterone-eligible patients with metastatic castration-resistant prostate cancer. Patients were prospectively assessed for homologous recombination repair mutation (HRRm) status using tumor tissue and/or circulating tumor DNA (ctDNA) testing, and patients were randomized 1:1 to olaparib 300 mg twice daily or placebo , both groups received abiraterone (1000 mg once daily) plus prednisone/prednisolone (5 mg twice daily). Treatment continued until radiographic disease progression, unacceptable toxicity, or withdrawal of consent. Overall survival is a key secondary endpoint. Combined results from tumor tissue and ctDNA testing were used to assign patients to the HRRm/BRCAm (BRCA-mutated) subgroup.
Results: Patient (n = 796) characteristics (including prior docetaxel, metastatic site, symptom score, and HRRm status) were overall balanced. In the intention-to-treat population, abiraterone + olaparib showed a trend toward overall survival benefit versus abiraterone + placebo (maturity 47.9%, HR 0.81, 95% CI 0.67–1.00, P = 0.0544), Median overall survival was 42.1 months and 34.7 months, respectively. Overall survival medians and HR in HRRm, non-HRRm, BRCAm and non-BRCAm subgroups favored abiraterone + olaparib versus abiraterone + placebo.
In the abiraterone plus olaparib arm, the most common grade ≥ 3 adverse event was anemia (16.1%).
Conclusions: In the prespecified final analysis, abiraterone + olaparib prolonged overall survival by >7 months compared with standard of care abiraterone in the intention-to-treat population. The median overall survival of greater than 42 months is the longest reported to date in a phase 3 trial in first-line metastatic castration-resistant prostate cancer. A trend for overall survival benefit was observed in the HRRm, non-HRRm, , BRCAm, and non-BRCAm subgroups, with the greatest benefit in the BRCAm subgroup. No new long-term safety issues were identified.
参考文献 Reference
Clarke NW et al. J Clin Onc 2023; 41 (suppl 6 LBA 16)
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Belzutifan 联合卡博替尼用于接受过免疫治疗的晚期透明细胞肾癌 (4/22/2023)
Belzutifan plus cabozantinib for advanced clear-cell renal cell cancer previously treated with immunotherapy
这是一项开放标签, 单组, II期临床试验（NCT03634540）。 患者被纳入两个队列。 队列 1 的病人患有未治疗过的疾病（结果将单独报告）。 队列 2 中的病人患有局部晚期或转移性透明细胞肾细胞癌，并且 之前接受过免疫治疗和最多两种全身治疗方案。 患者每天口服一次 120 毫克belzutifan(hypoxia inducing factor, HIF-2α 抑制剂)，每天一次口服卡博替尼(一种VEGFR、c-MET 和 AXL 的多靶点酪氨酸激酶抑制剂) 60 毫克，直至疾病进展, 或出现不可接受的毒性或患者停药。 主要终点是客观响应。 在接受至少一剂研究治疗的所有患者中评估了抗肿瘤活性和安全性。
发现: 2018 年 9 月 27 日至 2020 年 7 月 14 日期间，对 117 名患者进行了资格筛选，其中 52 名 (44%) 入组队列 2 并接受了至少一剂研究治疗。 52 名患者中有 16 名 (30.8% [95% CI 18.7–45.1]) 有确认的客观响应，其中 1 名 (2%) 有完全响应，15 名 (29%) 有部分响应。
最常见的 3-4 级治疗相关不良事件是高血压（52 名患者中有 14 名 [27%]）。 15 名 (29%) 患者发生严重的治疗相关不良事件。 研究人员认为 1 例死亡与治疗相关（呼吸衰竭）。
解释: Belzutifan 加卡博替尼在接受过治疗的透明细胞肾细胞癌患者中具有良好的抗肿瘤活性，为进一步随机试验提供了基本原理。
This is an open-label, single-arm, phase II clinical trial (NCT03634540). Patients were included in two cohorts. Patients in cohort 1 had untreated disease (results will be reported separately). Patients in cohort 2 had locally advanced or metastatic clear cell renal cell carcinoma and had previously received immunotherapy and up to two systemic regimens. Patients received belzutifan (hypoxia inducing factor, HIF-2α inhibitor) 120 mg orally once a day and cabozantinib (a multi-target tyrosine kinase inhibitor of VEGFR, c-MET and AXL) 60 mg orally once a day, until disease progression, unacceptable toxicity, or patient discontinuation. The primary endpoint was objective response. Antitumor activity and safety were assessed in all patients who received at least one dose of study treatment.
Findings: Between September 27, 2018, and July 14, 2020, 117 patients were screened for eligibility, and 52 (44%) were enrolled in cohort 2 and received at least one dose of study treatment. Sixteen of 52 patients (30.8% [95% CI 18.7–45.1]) had a confirmed objective response, with 1 (2%) having a complete response and 15 (29%) having a partial response.
The most common grade 3-4 treatment-related adverse event was hypertension (14 [27%] of 52 patients). Serious treatment-related adverse events occurred in 15 (29%) patients. Investigators considered 1 death to be treatment-related (respiratory failure).
Interpretation: Belzutifan plus cabozantinib demonstrated promising antitumor activity in patients with previously treated clear cell renal cell carcinoma, providing rationale for further randomized trials.
参考文献 Reference
Choueiri TK et a. Lancet Onc 2023; March 31. DOI:https://doi.org/10.1016/S1470-2045(23)00097-9
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鞘内注射纳武单抗治疗黑色素瘤软脑膜疾病(4/16/2023)
Intrathecal administration of nivolumab for leptomeningeal disease in melanoma patients
由于许多药物对脑脊液 的渗透性较差，研究者首先在免疫活性小鼠模型中评估了鞘内给抗 PD1 抗体的毒性。 然后，设计了一项鞘内和静脉同时注射抗 PD1的首次人体剂量探索研究。这是一项I/Ib期临床试验(NCT03025256)的中期分析结果，该研究在黑色素瘤和软脑膜疾病患者中同时进行鞘内注射和静脉注射纳武单抗。 主要终点是确定鞘内注射纳武单抗的安全性和推荐的剂量。 次要终点是总生存期。
患者在第 1 个周期中单独接受鞘内注射纳武单抗治疗，随后的周期中包括静脉注射纳武单抗。 研究者使用 5,10,20 和 50 mg 的鞘内纳武单抗治疗了 25 名转移性黑色素瘤患者。 在任何剂量水平下都没有剂量限制性毒性。 纳武单抗的推荐鞘内注射剂量为每 2 周 50 mg（静脉注射纳武单抗 240 mg）。 中位总生存期为 4.9 个月(历史中位总生存期约为 6 周)，26 周和 52 周时的总生存率分别为 44% 和 26%。
这些初步结果表明，同时进行鞘内注射和静脉注射纳武单抗治疗黑色素瘤软脑膜疾病是安全可行的，具有潜在疗效，包括先前接受过抗 PD1 治疗的患者。
Because many drugs are poorly permeable to CSF, researchers first assessed the toxicity of intrathecally administered anti-PD1 antibodies in an immunocompetent mouse model. Then, a first-in-human dose-finding study of simultaneous intrathecal and intravenous administration of anti-PD1 antibody was designed. This is the result of an interim analysis of a phase I/Ib trial (NCT03025256) of concurrent intrathecal and intravenous nivolumab in patients with melanoma and leptomeningeal disease. The primary endpoint was to determine the safety and recommended dose of intrathecal nivolumab. The secondary endpoint is overall survival.
Patients received intrathecal nivolumab alone in cycle 1, followed by intravenous nivolumab in subsequent cycles. The investigators treated 25 patients with metastatic melanoma with 5, 10, 20, and 50 mg of intrathecal nivolumab. There were no dose-limiting toxicities at any dose level. The recommended intrathecal dose of nivolumab is 50 mg every 2 weeks (240 mg intravenous nivolumab). Median overall survival was 4.9 months (historical median overall survival was approximately 6 weeks), and overall survival rates at 26 and 52 weeks were 44% and 26%, respectively.
These preliminary results suggest that concurrent intrathecal and intravenous nivolumab is safe, feasible and potentially effective in the treatment of melanoma leptomeningeal disease, including in patients who have previously received anti-PD1 therapy.
参考文献 Reference
Oliva, ICG et al. Nature Med 2023; March 30.
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睾酮抑制加恩杂鲁胺对比睾酮抑制加标准抗雄激素治疗转移性前列腺癌 (4/15/2023)
Enzalutamide or standard antiandrogen therapy plus testosterone suppression in metastatic prostate cancer
方法: ENZAMET 是一项国际性, 开放标签, 随机III 期试验，在多国的 83 个地点进行。 参与者是在 CT 或骨扫描中有转移性的激素敏感性前列腺癌, 被随机分配 (1:1) 接受睾酮抑制加口服恩杂鲁胺（Enzalutamide 160 mg 每天一次）或标准口服非甾体类抗雄激素药物（比卡鲁胺,尼鲁米特/bicalutamide, nilutamide, or flutamide；对照组），直至疾病进展或禁止性毒性。 睾酮抑制被允许在随机化前长达 12 周，并作为辅助治疗长达 24 个月。 根据参与者和医生的判断，允许每 3 周一次最多六个周期的同时使用多西紫杉醇（75 毫克/平方米静脉注射）。 主要终点是意向治疗人群的总生存期。 这项计划分析是在达到 470 (42%)人死亡时触发的。
发现: 2014 年 3 月 31 日至 2017 年 3 月 24 日期间，1,125 名参与者被随机分配接受非甾体抗雄激素（n = 562；对照组）或恩杂鲁胺（n = 563）治疗。 中位年龄为 69 岁 (IQR 63–74)。中位随访 68 个月 (IQR 67–69) 后，未达到中位总生存期（风险比 0.70 [95% CI 0.58–0.84]；p < 0.0001）， 对照组的 5 年总生存率为 57% (0.53–0.61)，恩杂鲁胺组为 67% (0.63–0.70)。 恩杂鲁胺的总体生存获益在预定义的预后亚组和计划同时使用多西紫杉醇方面是一致的。
最常见的 3-4 级不良事件是与使用多西紫杉醇相关的发热性中性粒细胞减少（对照组 558 例中有 33 例 [6%]相对于恩杂鲁胺组 563 例中有 37 例 [6%]）, 疲劳（4 例 [1%]相对于33 [6%]）和高血压（31 [6%]相对于59 [10%]）。 1-3 级记忆障碍的发生率分别为 25 例 (4%) 和 75 例 (13%)。没有死亡归因于研究治疗。
解释: 将恩杂鲁胺加入标准治疗改善转移性激素敏感性前列腺癌的总生存期。
Methods: ENZAMET was an international, open-label, randomized phase III trial conducted at 83 sites in multiple countries. Participants with metastatic hormone-sensitive prostate cancer as demonstrated on CT or bone scan were randomly assigned (1:1) to receive testosterone suppression plus oral enzalutamide (Enzalutamide 160 mg once daily) or standard oral nonsteroidal antiandrogens (bicalutamide, nilutamide, or flutamide; control group) until disease progression or prohibitive toxicity. Testosterone suppression was allowed for up to 12 weeks before randomization and as adjuvant therapy for up to 24 months. Concomitant docetaxel (75 mg/m2 IV) every 3 weeks was allowed for up to six cycles at the discretion of the participating physicians. The primary endpoint was overall survival in the intention-to-treat population. This planned analysis was triggered when 470 (42%) fatalities were reached.
Findings: Between March 31, 2014, and March 24, 2017, 1,125 participants were randomly assigned to receive standard oral non-steroidal antiandrogen (n = 562; control group) or enzalutamide (n = 563). The median age was 69 years (IQR 63–74). After a median follow-up of 68 months (IQR 67–69), the median overall survival was not reached (hazard ratio 0.70 [95% CI 0.58–0.84]; p < 0.0001), with a 5-year overall survival rate of 57% in the control group (0.53–0.61), compared to 67% (0.63–0.70) in the enzalutamide group. The overall survival benefit of enzalutamide was consistent across predefined prognostic subgroups and with planned concomitant docetaxel use.
The most common grade 3-4 adverse event was febrile neutropenia associated with docetaxel (33 [6%] of 558 in the control group vs 37 of 563 in the enzalutamide group) [6%]), fatigue (4 [1%] vs. 33 [6%]) and hypertension (31 [6%] vs. 59 [10%]). Grade 1-3 memory impairment occurred in 25 (4%) and 75 (13%) cases, respectively. No deaths were attributed to study treatment.
Interpretation: Adding enzalutamide to standard therapy improves overall survival in metastatic hormone-sensitive prostate cancer.
参考文献 Reference
Sweeny CR et al. Lancet Onc 2023; 24: 323
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PD-1抑制剂Dostarlimab 治疗原发性晚期或复发性子宫内膜癌 (4/9/2023)
PD-1 inhibitor Dostarlimabin primary advanced or recurrent endometrial cancer
这是一项 III期全球, 双盲, 随机, 安慰剂对照试验（NCT03981796）。 符合条件的原发性晚期 III 期或 IV 期或首次复发子宫内膜癌患者以 1:1 的比例随机分配接受 dostarlimab（靶向程序性细胞死亡 1 受体, 500 mg）或安慰剂，加卡铂（AUC=5 ）和紫杉醇（ 175 毫克/平方米），每 3 周一次（六个周期），随后每 6 周一次 dostarlimab（1000 毫克）或安慰剂，持续长达 3 年。 主要终点是由研究者评估的无进展生存期和总生存期。 还评估了安全性。
结果: 在接受随机分组的 494 名患者中，118 名 (23.9%) 患有错配修复缺陷 (dMMR)、高微卫星不稳定性 (MSI-H) 肿瘤。 在 dMMR–MSI-H 人群中，dostarlimab 组的 24 个月估计无进展生存率为 61.4%（95% 置信区间 [CI]，46.3 至 73.4），而在 安慰剂组（进展或死亡的风险比，0.28；95% CI，0.16 至 0.50；P < 0.001）。 在总体人群中，dostarlimab 组的 24 个月无进展生存率为 36.1%（95% CI，29.3 至 42.9），安慰剂组为 18.1%（95% CI，13.0 至 23.9）（风险比，0.64； 95% CI，0.51 至 0.80；P<0.001）。 dostarlimab 组的 24 个月总生存率为 71.3%（95% CI，64.5 至 77.1），安慰剂组为 56.0%（95% CI，48.9 至 62.5）（死亡风险比，0.64；95% CI，0.46 至 0.87）。
治疗期间最常见不良事件是恶心（dostarlimab 组患者占 53.9%，安慰剂组患者占 45.9%）、脱发（53.5% 和 50.0%）和疲劳（51.9% 和 54.5%） %)。 与安慰剂组相比，dostarlimab 组的严重不良事件发生率更高。
结论: Dostarlimab 联合卡铂-紫杉醇可显著提高原发性晚期或复发性子宫内膜癌患者的无进展生存期，对 dMMR-MSI-H 人群具有实质性益处。
This is a phase III global, double-blind, randomized, placebo-controlled trial (NCT03981796). Eligible patients with primary advanced stage III or IV or first recurrent endometrial cancer were randomly assigned in a 1:1 ratio to receive dostarlimab (targeting the PD-1 receptor, 500 mg) or placebo, plus carboplatinum (AUC=5) and paclitaxel (175 mg/m2) every 3 weeks (six cycles), followed by dostarlimab (1000 mg) or placebo every 6 weeks for up to 3 years. The primary endpoints were progression-free survival and overall survival as assessed by the investigator. Safety was also assessed.
Results: Of 494 patients who underwent randomization, 118 (23.9%) had mismatch repair deficient (dMMR), microsatellite instability-high (MSI-H) tumors. In the dMMR/MSI-H population, the estimated 24-month progression-free survival rate was 61.4% (95% confidence interval [CI], 46.3 to 73.4) in the dostarlimab group compared with 61.4% in the placebo group (hazard ratio for progression or death, 0.28; 95% CI, 0.16 to 0.50; P < 0.001). In the overall population, the 24-month progression-free survival rate was 36.1% (95% CI, 29.3 to 42.9) in the dostarlimab group and 18.1% (95% CI, 13.0 to 23.9) in the placebo group (hazard ratio, 0.64; 95 % CI, 0.51 to 0.80; P<0.001). The 24-month overall survival rate was 71.3% (95% CI, 64.5 to 77.1) in the dostarlimab group and 56.0% (95% CI, 48.9 to 62.5) in the placebo group (hazard ratio for death, 0.64; 95% CI, 0.46 to 0.87).
The most common adverse events during treatment were nausea (53.9% of patients in the dostarlimab group and 45.9% of patients in the placebo group), alopecia (53.5% and 50.0%), and fatigue (51.9% and 54.5%). Serious adverse events occurred more frequently in the dostarlimab group than in the placebo group.
Conclusions: Dostarlimab plus carboplatin-paclitaxel significantly improved progression-free survival in patients with primary advanced or recurrent endometrial cancer, with substantial benefit in the dMMR/MSI-H population.
参考文献 Reference
Mirza MR et al. N Engl J Med 2023; March 27. DOI: 10.1056/NEJMoa2216334
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Talazoparib 联合 enzalutamide作为转移性去势抵抗性前列腺癌的一线治疗 (4/8/2023)
Talazoparib in combination with enzalutamide as first-line therapy for metastatic castration-resistant prostate cancer
一项III期临床试验TALAPRO-2 (NCT03395197), 是第一个将聚（ADP-核糖）聚合酶抑制剂 Talazoparib （TALA） 与雄激素受体抑制剂 enzalutamide 结合的研究。 未经过事先选择 DNA 损伤修复途径的遗传改变, 直接或间接涉及同源重组修复 (HRR) 的病人, 接受 TALA + enzalutamide或安慰剂 + enzalutamide 作为转移性去势抵抗性前列腺癌的一线治疗。
方法： 患者以 1:1 的比例随机分配至 TALA 0.5 mg 或安慰剂（所有患者每天接受enzalutamide 160 mg），根据先前的阿比特龙或多西紫杉醇对去势敏感的前列腺癌和 HRR 基因改变状态进行分 层。 关键资格标准：在研究开始时轻度或无症状者, 正在进行雄激素剥夺治疗, 既往未接受去势抵抗性前列腺癌的延长生命治疗。 主要终点是基于成像的无进展生存期 (ibPFS)。
结果：402 名患者被随机分配接受 TALA 组和 403 名安慰剂组。基于成像的无进展生存期在 TALA 组中相比于安慰剂组显著改善（分别为未达到和 21.9 个月；HR，0.63；95% CI，0.51–0.78；P<0.001）。
TALA 组的ibPFS 在 HRR 缺陷（HR，0.46；95% CI，0.30-0.70；P<0.001）, HRR 非缺陷或未知（HR，0.70；95% CI，0.54-0.89；P=0.004）中都显著改善 。 总体生存数据不成熟； 30.6% (TALA组) 和 32.0% (安慰剂组) 患者死亡； HR（0.89 [95% CI，0.69–1.14；P= 0.35]）。 客观响应率, PSA 响应≥50%, PSA 进展时间以及后续使用化疗和抗肿瘤治疗显著有利于 TALA 组。
在患者中，71.9% (TALA 组) 和 40.6% (安慰剂组) 有 3-4 级治疗不良事件。 最常见的 ≥ 3 级 不良事件是贫血, 低中性粒细胞和低血小板计数 (TALA 组)，以及高血压, 贫血和疲劳 (安慰剂组)。 不良事件导致 19.1% 的患者停用 TALA（而安慰剂组为 12.2%）。 TALA 组的 enzalutamide 停药率为 10.8%，而安慰剂组为 11.0%。 TALA组与安慰剂组相比，生活质量恶化的中位时间明显更长（分别为 30.8 个月和 25.0 个月；HR，0.78；95% CI，0.62–0.99 ；P=0.04）。
结论： TALA + enzalutamide证明，无论 HRR 状态如何，在基于成像的无进展生存期上比enzalutamide标准护理作为一线治疗具有统计学意义的临床改善，毒性通常是可控的。
A phase III trial, TALAPRO-2 (NCT03395197), is the first study to combine the poly(ADP-ribose) polymerase inhibitor talazoparib (TALA) with the androgen receptor inhibitor enzalutamide. Patients with unselected genetic alterations in DNA damage repair pathways, directly or indirectly involved in homologous recombination repair (HRR), received TALA + enzalutamide or placebo + enzalutamide as first-line therapy for metastatic castration-resistant prostate cancer.
Methods: Patients were randomized 1:1 to TALA 0.5 mg or placebo (all patients received enzalutamide 160 mg daily) stratified by prior abiraterone or docetaxel for castration-sensitive prostate cancer and HRR gene alteration status. Key eligibility criteria: mild or asymptomatic status at study entry, ongoing androgen deprivation therapy, and no previous life-prolonging therapy for castration-resistant prostate cancer. The primary endpoint was imaging-based progression-free survival (ibPFS).
Results: 402 patients were randomly assigned to receive TALA and 403 placebo. Imaging-based progression-free survival was significantly improved in the TALA group compared with placebo (not reached vs. 21.9 months, respectively; HR, 0.63; 95% CI, 0.51–0.78; P<0.001). ibPFS in the TALA group was significant longer in both HRR deficient (HR, 0.46; 95% CI, 0.30-0.70; P<0.001), HRR non-deficient or unknown (HR, 0.70; 95% CI, 0.54-0.89; P=0.004) in the TALA group. Overall survival data were immature; 30.6% (TALA group) and 32.0% (placebo group) patients died; HR (0.89 [95% CI, 0.69–1.14; P=0.35]). The objective response rate, PSA response ≥50%, time to PSA progression, and subsequent use of chemotherapy and antineoplastic therapy were significant in favor of the TALA group.
Side-effects: 71.9% (TALA group) and 40.6% (placebo group) had grade 3-4 treatment-emergent adverse events. The most common grade ≥3 adverse events were anemia, low neutrophils, and low platelet count (TALA group), and hypertension, anemia, and fatigue (placebo group). Adverse events led to discontinuation of TALA in 19.1% of patients (compared with 12.2% in the placebo group). The enzalutamide discontinuation rate was 10.8% in the TALA group compared with 11.0% in the placebo group. The median time to quality-of-life deterioration was significantly longer in the TALA group compared with the placebo group (30.8 months vs. 25.0 months, respectively; HR, 0.78; 95% CI, 0.62–0.99; P=0.04).
Conclusions: TALA + enzalutamide as first-line therapy demonstrated a statistically significant clinical improvement in imaging-based progression-free survival over standard care with enzalutamide, regardless of HRR status, with generally manageable toxicity.
参考文献 Reference
Agarwal N et al. J Clin Onc 2023; 41 suppl 6 abstr LBA17
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循环肿瘤 DNA 分析用于脑淋巴瘤检测, 风险分层和分类 (4/2/2023)
Circulating DNA analyses for detection, risk stratification and classification of brain lymphoma
方法：研究者通过对136 名脑癌患者的总共 306 例肿瘤, 血浆和脑脊液标本, 应用超灵敏靶向下一代测序，探索了循环肿瘤 DNA (ctDNA) 在早期结果预测, 和可测量残留疾病监测中的价值。
结果：治疗前，在 78% 的血浆和 100% 的脑脊液样本中可检测到 ctDNA。 治疗前血浆中 ctDNA 阳性患者的无进展生存期（P < .0001，时序检验）和总生存期（P = .0001，时序检验）显著缩短。 在包括已确定的临床和影像学风险因素在内的多变量分析中，治疗前血浆 ctDNA 浓度是临床结果的独立预后因素（无进展生存期 HR，1.4；95% CI，1.0 至 1.9；P = .03；总生存期 HR，1.6；95% CI，1.1 至 2.2；P = .006）。 此外，在治疗期间通过血浆 ctDNA 监测可测量的残留疾病检测, 确定了治愈性免疫化疗后预后特别差的患者（无进展生存期，P = .0002；总生存期，P = .004，对数秩检验）。 最后，研究者开发了一种机器学习方法，用于从 ctDNA 中进行无活检脑淋巴瘤鉴定，显示出 59%（脑脊液）和 25%（血浆）的灵敏度，具有高阳性预测值。
结论：研究结果展示了 ctDNA 作为非侵入性生物标志物的作用及其对脑淋巴瘤患者风险分层和治疗指导的潜在价值。
Methods: Researchers explored the role of circulating tumor DNA (ctDNA) in early outcome prediction and measurable residual disease monitoring by applying ultrasensitive targeted next-generation sequencing to a total of 306 tumor, plasma, and CSF specimens from 136 brain cancer patients.
Results: Before treatment, ctDNA was detectable in 78% of plasma and 100% of CSF samples. Patients with ctDNA-positive plasma before treatment had significantly shorter progression-free survival (P < .0001, log-rank test) and overall survival (P = .0001, log-rank test). In a multivariate analyses including established clinical and radiographic risk factors, pretreatment plasma ctDNA concentration was an independent prognostic factor for clinical outcome (HR for progression-free survival, 1.4; 95% CI, 1.0 to 1.9; P = .03; HR for overall survival, 1.6; 95% CI, 1.1 to 2.2; P = .006). In addition, measurable residual disease detection monitored by plasma ctDNA during treatment identified patients who had a particularly poor prognosis after curative immunochemotherapy (progression-free survival, P = .0002; overall survival, P = .004, log rank test). Finally, the investigators developed a machine learning method for biopsy-free brain lymphoma identification from ctDNA, showing a sensitivity of 59% (cerebrospinal fluid) and 25% (plasma), with a high positive predictive value.
Conclusions: Findings demonstrate the role of ctDNA as a non-invasive biomarker and its potential value for risk stratification and treatment guidance in patients with brain lymphoma.
参考文献 Reference
Mutter JA et al. J Clin Onc 2023; 2041; 1684
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奥拉帕尼维持治疗相比于与安慰剂对卵巢癌的总生存期 (4/1/2023)
Olaparib maintenance vs placebo in overall survival among ovarian cancer
SOLO-1 试验（NCT01844986）研究了奥拉帕尼 (Olaparib) 维持治疗相比于安慰剂对新诊断的晚期高级浆液性或子宫内膜样卵巢癌, 输卵管癌和/或原发性腹膜癌患者的疗效，这些患者有 BRCA1 和/或 BRCA2 突变 疾病, 并对铂类治疗敏感的患者。
该试验的主要结果显示，在中位随访 41 个月时，奥拉帕利组的估计无进展生存率为 60%，而安慰剂组为 27%。 在总生存期数据成熟度达到 21% 时进行的中期总生存期分析显示，奥拉帕尼组的估计 3 年总生存率为 84%，而安慰剂组为 80%。 此外，在奥拉帕尼组和安慰剂组中，至首次后续治疗或死亡的中位时间分别为 51.8 个月和 15.1 个月，估计奥拉帕尼组和安慰剂组分别有 74% 和 56% 的患者在3年时仍存活并且不需要第二次后续治疗 。 SOLO-1 的 7 年总生存率分析显示奥拉帕尼组为 67.0%，而安慰剂组为 46.5%。 然而，这些总生存率数据没有达到统计学意义，因为该试验的总生存率统计是为最终分析设计的。
The SOLO-1 trial (NCT01844986) investigated maintenance olaparib versus placebo in patients with newly diagnosed advanced high-grade serous or endometrioid ovarian, fallopian tube and/or primary peritoneal cancer. These patients had BRCA1 and / or BRCA2 mutations and were sensitive to platinum therapy.
The primary endpoint of the trial showed that at a median follow-up of 41 months, the estimated progression-free survival rate was 60% in the olaparib group compared with 27% in the placebo group. An interim overall survival analysis performed at 21% maturity of overall survival data showed an estimated 3-year overall survival rate of 84% in the olaparib arm compared with 80% in the placebo arm. In addition, the median time to first subsequent treatment or death was 51.8 months in the olaparib group vs. 15.1 months in the placebo group. An estimated 74% in the olaparib group and 56% in the placebo group were alive at 3 years and did not require a second subsequent treatment. The 7-year overall survival analysis in SOLO-1 showed 67.0% in the olaparib group compared with 46.5% in the placebo group. However, these overall survival data did not reach statistical significance because the trial’s overall survival statistics were designed for the final analysis.
参考文献 Reference
Mathews CA (talk). 2023 Soc Gyn Oncol Ann Meeting, March 30
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新的ROS1 抑制剂对难治性实体瘤有响应 (3/26/2023)
A new ROS1 inhibitor generated responses in refractory solid tumors
这是一项 I 期临床试验（ARROS-1）, 研究药物 NVL-520 是一种新的 ROS1 酪氨酸激酶抑制剂 (TKI)，具有与第二代 ROS1 TKI 相当的抗癌特性，但大大降低了神经毒性。该试验研究NVL-520用于 ROS1 融合检测阳性的经多线治疗复发或难治性实体瘤。ARROS-1 试验中的所有患者都 为ROS1 融合阳性，所有非小细胞肺癌患者之前都曾接受过一个或多个疗程的 ROS1 TKI 治疗。既往抗癌治疗线的中位数为三线（1-9 线）。在参加试验时，55% 患者有脑转移病史。 20 名患者（19 名非小细胞肺癌，1 名胰腺癌）接受了每日一次口服剂量为 25-100 毫克的 NVL-520。
35 名患者在五个递增剂量水平下没有发现剂量限制性毒性，也没有导致剂量减少或停止治疗的不良事件。 大多数与治疗相关的副作用是轻微的。 >1 名患者中唯一的治疗相关的副作用为恶心 (n = 2)。
在12 名具有 ROS1 + NSCLC 疗效的可评估患者中（每天25-75 毫克），有 6 名确认的部分响应。 观察到颅内转移灶缩小或消退； 没有患者出现颅内进展。 在大多数 (n = 5/7) ROS1 G2032R （后者使对目前可用的 ROS1 抑制剂产生耐药性） 癌症中实现了部分响应，包括既往接受过lorlatinib 或 repotrectinib 治疗的肿瘤。 循环肿瘤 DNA 分析显示 ROS1 变异等位基因频率降低 。
This is a phase I clinical trial (ARROS-1) of the investigational drug NVL-520, a novel ROS1 tyrosine kinase inhibitor (TKI) with comparable anticancer properties to second-generation ROS1 TKIs, but significantly reduced neurotoxicity. The trial is investigating NVL-520 in patients with multiple lines of therapy for relapsed or refractory solid tumors that test positive for ROS1 fusions. All patients in the ARROS-1 trial were ROS1 fusion positive, and all NSCLC patients had previously received one or more courses of ROS1 TKI therapy. The median number of previous lines of anticancer therapy was three (1-9 ). At the time of trial entry, 55% of patients had a history of brain metastases. Twenty patients (19 with NSCLC, 1 with pancreatic cancer) received NVL-520 at oral doses of 25-100 mg once daily.
No dose-limiting toxicities or adverse events leading to dose reduction or discontinuation of treatment were noted in the 35 patients at five escalating dose levels. Most treatment-related side effects were mild. The only treatment-related side effect in >1 patient was nausea (n = 2).
Of 12 patients with ROS1+ NSCLC evaluable for efficacy (25-75 mg daily), there were 6 confirmed partial responses. Shrinkage or regression of intracranial metastases was observed; no patient experienced intracranial progression. Partial responses were achieved in the majority (n = 5/7) of ROS1 G2032R (the latter conferring resistance to currently available ROS1 inhibitors) cancers, including tumors previously treated with lorlatinib or repotrectinib. Circulating tumor DNA analysis revealed reduced ROS1 variant allele frequency
参考文献 Reference
Drilon A et al. Eur J Cancer 2022; 174: suppl 1 ((S6-S7)
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ASCO对晚期胃食管癌的免疫/靶向第一线治疗的指南 (3/25/2023)
ASCO guideline towards the firs-line immunotherapy and target therapy for advanced gastric and esophageal cancer
胃腺癌: HER2 阴性
- PD-L1联合阳性评分（CPS）≥ 5
纳武单抗（Nivolumab）联合化疗（氟嘧啶和铂类药）。
- CPS 1 – 5
逐案考虑是否使用纳武单抗联合化疗（氟嘧啶和铂类药）。
- CPS = 0
化疗（氟嘧啶和铂类药）。
食管/胃食管交界处腺癌: HER2 阴性
- CPS ≥ 5
纳武单抗（派姆单抗, pembrolizumab 若CPS ≥ 10）联合化疗（氟嘧啶和铂类药）。
- CPS 1 – 5
逐案考虑是否使用纳武单抗（派姆单抗 若CPS 1 – 10）联合化疗（氟嘧啶和铂类药）。
- CPS = 0
化疗（氟嘧啶和铂类药）。
食管鳞状细胞癌: HER2 阴性
- CPS ≥ 10,
派姆单抗联合化疗（氟嘧啶和铂类药）。
- PD-L1 肿瘤比例评分tumor proportion score (TPS)≥ 1% （或CPS≥ 1）
纳武单抗联合化疗（氟嘧啶和铂类药）; 或纳武单抗联合ipilimumab（易普利姆玛）。
胃/胃食管交界处腺癌: HER2 阳性
Trastuzumab （曲妥珠单抗）, 派姆单抗联合化疗（氟嘧啶和铂类药）
Gastric adenocarcinoma: HER2 negative
- PD-L1 Combined Positive Score (CPS) ≥ 5
Nivolumab combined with chemotherapy (fluoropyrimidine and platinum).
- CPS 1 – 5
The use of nivolumab in combination with chemotherapy (fluoropyrimidine and platinum) should be considered on a case-by-case basis.
- CPS = 0
Chemotherapy (fluoropyrimidine and platinum)
Esophagus/GEJ adenocarcinoma: HER2 negative
- CPS ≥ 5
Nivolumab (pembrolizumab, if CPS ≥ 10) combined with chemotherapy (fluoropyrimidine and platinum drugs).
- CPS 1 – 5
Consider using nivolumab (pembrolizumab when CPS 1 – 10) in combination with chemotherapy (fluoropyrimidine and platinum) on a case-by-case basis.
- CPS = 0
Chemotherapy (fluoropyrimidines and platinum).
Esophageal squamous cell carcinoma: HER2 negative
- CPS ≥ 10,
Pembrolizumab combined with chemotherapy (fluoropyrimidine and platinum).
- PD-L1 tumor proportion score (TPS) ≥ 1% (or CPS ≥ 1)
Nivolumab plus chemotherapy (fluoropyrimidine and platinum); or nivolumab plus ipilimumab.
Gastric/GEJ adenocarcinoma: HER2 positive
Trastuzumab, pembrolizumab plus chemotherapy (fluoropyrimidine and platinum)
参考文献 Reference
Shah MA et al. J Clin Onc 2023; 41: 1470
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Camizestrant 改善ER+/HER2- 晚期乳腺癌的无进展生存期 (3/19/2023)
Camizestrant improved PFS in advanced ER+/HER2- breast cancer
与氟维司群（fulvestrant）相比，口服选择性雌激素受体降解剂 (SERD) Camizestrant改善了先前接受过治疗的晚期乳腺癌绝经后妇女的无进展生存期。
这是一项II期临床试验（SERENA-2），240 名先前接受过治疗的晚期激素受体阳性/HER2 阴性晚期乳腺癌患者被随机分配接受每天 75 毫克或 150 毫克的口服Camizestrant或 500 毫克的氟维司群 每 4 周肌肉注射一次。大约三分之一的患者有雌激素受体1 （ESR1） 突变，近 60% 有内脏转移。 所有患者在晚期情况下至少接受过一次内分泌治疗后出现疾病进展，大约一半的患者还接受了 CDK4/6 抑制剂治疗。
在总体人群中, Camizestrant 改善了无进展生存期 ，为7.2个月（ 75 毫克）或7.7个月（ 150 毫克） 相对于3.7个月（氟维司群）, 具有统计学意义和临床意义的改善。 作为敏感性分析进行的盲法独立中央评估也显示，两种剂量均优于氟维司群，具有统计学意义，这与研究者的评估一致。Camizestrant 在有内脏转移的患者中, 无进展生存期分布析别为7.2个月（ 75 毫克）或5.6个月（ 150 毫克） 相对于2.0个月（氟维司群）。 在具有 ESR1 突变的患者中，75 毫克 Camizestrant的中位无进展生存期为 6.3 个月，150 毫克 为 9.2 个月，氟维司群为 2.2 个月。
服用75 毫克/天camizestrant的 3 级或更高级别事件的为 12.2%，接受 150 毫克/天 的患者为 21.9%，接受氟维司治疗的为 13.7% 。 接受 75 毫克/天 camizestrant的患者中有 12.2% 的患者和接受 150 毫克/天 的患者中有 24.7% 的患者（所有级别）观察到一种不寻常的眼部副作用: 闪光幻觉（视觉扭曲，例如飞蚊症和闪光）。 这些事件是 1 级, 不干扰视力或患者日常活动。 在接受氟维司群治疗的患者中未报告闪光幻觉。
Camizestrant, an oral selective estrogen receptor degrader (SERD), improved progression-free survival compared with fulvestrant in postmenopausal women with previously treated advanced breast cancer.
This is a phase II clinical trial (SERENA-2) in which 240 patients with previously treated advanced hormone receptor-positive/HER2-negative advanced breast cancer were randomly assigned to receive either 75 mg or 150 mg of oral camizestrant or 500 mg of fulvestrant intramuscularly every 4 weeks. About one-third of patients had estrogen receptor 1 (ESR1) mutations, and nearly 60% had visceral metastases. All patients had disease progression after at least one dose of endocrine therapy in the advanced setting, and about half of the patients also received a CDK4/6 inhibitor.
In the overall population, progression-free survival was 7.2 months (75 mg) or 7.7 months (150 mg) versus 3.7 months (fulvestrant), a statistically and clinically meaningful improvement. A blinded independent central assessment performed as a sensitivity analysis also showed statistically significant superiority at both doses over fulvestrant, which was consistent with the investigators’ assessment. Camizestrant in patients with visceral metastases, the progression-free survival was 7.2 months (75 mg) or 5.6 months (150 mg) versus 2.0 months (fulvestrant). Among patients with ESR1 mutations, the median progression-free survival was 6.3 months for 75 mg camizestrant, 9.2 months for 150 mg, and 2.2 months for fulvestrant.
Grade 3 or higher events occurred in 12.2% of patients taking camizestrant 75 mg/day, 21.9% of patients receiving 150 mg/day, and 13.7% of patients receiving fulvestrant. An unusual ocular side effect, photopsia (floaters and flasher) was observed in 12.2% of patients receiving 75 mg/day camizestrant and in 24.7% of patients receiving 150 mg/day (all grades). These events were grade 1 and did not interfere with vision or patient’s daily activities. Photopsia was not reported in patients treated with fulvestrant.
参考文献 Reference
Oliveira M et al. 2022 San Antonio Breast Cancer Symp abstr GS3-02
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氨基酸转运蛋白抑制剂,Nanvuranlat，治疗晚期难治性胆道癌 (3/18/2023)
Nanvuranlat, an L-type amino acid transporter inhibitor, for advanced refractory biliary tract cancer
这是一项随机,双盲,安慰剂对照的II期临床试验。Nanvuranlat是一种 L 型氨基酸转运蛋白 (LAT1) 抑制剂。 LAT1 在肿瘤中的高表达为各种癌症类型（包括胆道癌）预后不良的预测因子。
该试验纳入了四种不同亚型的晚期胆道癌患者：肝内, 肝外, 胆囊和壶腹部。 所有患者都对标准化疗和其他研究药物具有耐药性或不耐受性。通过 N-乙酰转移酶 2 (NAT2) 试验, 患者预分类为非快速乙酰化者，以最大限度地减少 nanvuranlat 的代谢来提高疗效/安全性。 主要终点是无进展生存期。
结果：在数据截止时（2022 年 2 月 28 日），日本 14 个中心的 211 名胆道癌患者通过 NAT2 测试进行分类，共有 106 名患者被随机 (2:1) 接受 nanvuranlat (n = 70) 或安慰剂 (n = 36)。 Nanvuranlat 达到了其主要终点，与安慰剂组相比，无进展生存期方面有统计学意义的显著改善（风险比 = 0.557；95% CI，0.3435 – 0.9029；单侧 p = 0.0164）。 在所有胆道癌亚型中，nanvuranlat 组的疾病控制率约为 25%（平均 = 24.6%），而安慰剂组为 11.4%。
Nanvuranlat 组报告的 3 级不良事件发生率为 30.0%，而安慰剂组为 22.9%。 Nanvuranlat 和安慰剂组的治疗相关不良事件发生率分别为 41.4% 和 57.1%。 没有患者出现导致 nanvuranlat 治疗中断,剂量减少或死亡的不良事件。
结论：LAT1 抑制剂 nanvuranlat 单药疗法对四种不同亚型的晚期难治性胆道癌患者显示出有用的临床疗效。 并具有安全和耐受性。
This is a randomized, double-blind, placebo-controlled phase II clinical trial. Nanvuranlat is an L-type amino acid transporter (LAT1) inhibitor. High tumor expression of LAT1 is a predictor of poor prognosis in various cancer types, including biliary tract cancer.
The trial enrolled patients with four different subtypes of advanced biliary tract cancer: intrahepatic, extrahepatic, gallbladder, and ampulla of Vater. All patients were resistant or intolerant to standard chemotherapy and other study drugs. Via N-acetyltransferase 2 (NAT2) test, patients were pre-classified as non-rapid acetylators to minimize the metabolism of nanvuranlat to improve efficacy and safety. The primary endpoint was progression-free survival.
Results: At data cutoff (February 28, 2022), a total of 211 patients with biliary tract cancer were classified by the NAT2 test at 14 centers in Japan, and 106 patients were randomized (2:1) to receive nanvuranlat (n = 70) or placebo (n = 36). Nanvuranlat met its primary endpoint, showing a statistically significant improvement in progression-free survival compared to placebo (hazard ratio = 0.557; 95% CI, 0.3435 – 0.9029; one-sided p = 0.0164). Across all biliary tract cancer subtypes, the disease control rate was approximately 25% in the nanvuranlat group (mean = 24.6%) compared to 11.4% in the placebo group.
Grade 3 adverse events were reported in 30.0% of the nanvuranlat group compared with 22.9% in the placebo group. Treatment-related adverse events occurred in 41.4% of the nanvuranlat and 57.1% of the placebo groups, respectively. No patient had adverse events leading to nanvuranlat discontinuation, dose reduction or death.
Conclusions: Monotherapy with the LAT1 inhibitor nanvuranlat demonstrated significant clinical efficacy in patients with four different subtypes of advanced refractory biliary tract cancer. and was safe and well tolerated.
参考文献 Reference
Furuse J. et al. J Clin Onc 2023; 41:4 suppl 494
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饮食干预以减少淋巴瘤幸存者的疲劳: 可行性试点研究的结果 (3/12/2023)
Food intervention to improve fatigue in lymphoma survivors: results of a Feasibility Pilot Study
对于许多淋巴瘤和癌症幸存者，慢性疲劳是最常见的治疗副作用。这项试点研究旨在确定为期 12 周的一项减少疲劳饮食（FRD）的干预在弥漫性大 B 细胞淋巴瘤幸存者中的可行性，并评估饮食干预对慢性疲劳的初步疗效。
参与者远程会见了营养师，进行了八次单独的会议。饮食计划根据每位患者的食物偏好和烹饪能力进行个性化设置, 以养成参加者能够坚持的习惯，并整合来自全谷物, 五颜六色的水果, 蔬菜以及富含 omega-3 脂肪酸（鱼）食物。 可接受性通过会议出勤率, FRD 目标达成情况和退出调查进行评估。 在基线和干预后分别使用健康饮食指数 2015 和 PROMIS 疲劳简表测量自我报告的饮食摄入量和疲劳程度。 十名 DLBCL 幸存者入组； 九人参加了所有会议并完成了干预。 在整个研究过程中，每周对目标食物摄入的遵守情况显著提高（所有 p < 0.05），到第 11 周, 参与者每周达到目标的时间超过 4 天。中位饮食质量从基线 (65.9[6.3]) 到干预后显著改善 (82.2[5.0], p < 0.001)。中位疲劳从基线 (50.41[9.18]) 显著降低 (45.79[6.97]，p < 0.05)。
为期 12 周的减少疲劳饮食干预是可行的, 并且有望改善弥漫性大 B 细胞淋巴瘤幸存者的饮食质量和疲劳。
For many lymphoma and cancer survivors, chronic fatigue is the most common side-effect of treatment. This pilot study aimed to determine the feasibility of a 12-week intervention of a fatigue-reducing diet (FRD) in diffuse large B-cell lymphoma survivors and to assess the preliminary efficacy of the dietary intervention on chronic fatigue.
Participants met with a nutritionist remotely for eight separate sessions. Meal plans were personalized to each patient’s food preferences and culinary abilities to build habits that participants can stick to, and food sources include whole grains, colorful fruits, vegetables, and foods rich in omega-3 fatty acids. Acceptability was assessed by meeting attendance, FRD goal achievement, and exit surveys. Self-reported dietary intake and fatigue were measured using the Healthy Eating Index 2015 and the PROMIS Fatigue Short Form at baseline and after the intervention, respectively. Ten DLBCL survivors were enrolled; nine attended all sessions and completed the intervention. Weekly adherence to food intake targets improved significantly throughout the study (all p < 0.05), with participants reaching their targets more than 4 days per week by week 11. Median diet quality improved significantly from baseline (65.9 [6.3]) to post-intervention (82.2 [5.0], p < 0.001). Median fatigue was significantly lower (45.79 [6.97], p < 0.05) from baseline (50.41 [9.18]).
A 12-week fatigue-reducing dietary intervention is feasible and holds promise for improving diet quality and fatigue in diffuse large B-cell lymphoma survivors.
参考文献 Reference
Weinhold KR et al. Nutrition and Cancer 2023; https://doi.org/10.1080/01635581.2023.2173259
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辅助紫杉醇和曲妥珠单抗治疗淋巴结阴性/HER2 阳性乳腺癌：10 年分析 (3/11/2023)
Adjuvant paclitaxel and trastuzumab for node-negative/HER2-positive breast cancer: final 10-year analysis
研究者报告了一项II期临床试验的10 年生存结果: ≤3 cm, 淋巴结阴性/HER2 阳性乳腺癌患者接受紫杉醇和曲妥珠单抗辅助治疗。患者每周接受静脉注射紫杉醇 (80 毫克/平方米) 和曲妥珠单抗（负荷剂量为 4 毫克/公斤，后续剂量为 2 毫克/公斤），持续 12 周，随后接受曲妥珠单抗（每周 2 毫克/公斤注射一次, 或每3周 6 毫克/公斤) 以完成一整年的曲妥珠单抗。 主要终点是 3 年无侵袭性疾病生存期。
发现: 2007 年 10 月 29 日至 2010 年 9 月 3 日期间，410 名患者入组，其中 406 名患者接受紫杉醇和曲妥珠单抗辅助治疗并纳入分析。 入组时的平均年龄为 55 岁，272 人 (67.0%) 患有激素受体阳性疾病。 在中位随访 10.8 年 (IQR 7.1–11.4) 后，在分析人群中的 406 名患者中，观察到 31 起侵袭性无病生存事件，其中 6 起 (19.4%) 是局部同侧复发，9 例 (29.0%) 是新的对侧乳腺癌，6 例 (19.4%) 是远处复发，10 例 (32.3%) 是全因死亡。 10 年无侵袭性疾病生存率为 91.3%（95% CI 88.3–94.4），10 年无复发间隔为 96.3%（95% CI 94.3–98.3）, 10 年总生存率为 94.3% (95% CI 91.8–96.8),10 年乳腺癌特异性生存率为 98.8% (95% CI 97.6–100)。 作为连续变量的 HER2DX* 风险评分与无侵袭性疾病生存显著相关（风险比 [HR] 每 10 个单位增量 1.24 [95% CI 1.00–1.52]；p = 0.047）和 无复发间隔 (1.45 [1.09–1.93]; p = 0.011)。
解释 辅助紫杉醇和曲妥珠单抗是≤3 cm,淋巴结阴性/HER2 阳性乳腺癌患者的合理治疗标准。
*HER2DX 是一种监督学习算法，将肿瘤大小、淋巴结分期和跟踪免疫浸润、肿瘤细胞增殖、管腔分化和 HER2 扩增子表达的 4 个基因表达特征整合到一个评分中。
The investigators reported the 10-year survival outcomes of a phase II trial using adjuvant paclitaxel and trastuzumab in patients with ≤3 cm, node-negative/HER2-positive breast cancer. Patients received intravenous paclitaxel (80 mg/m2) and trastuzumab (loading dose 4 mg/kg followed by 2 mg/kg) weekly for 12 weeks, followed by trastuzumab (2 mg/kg weekly, or 6 mg/kg every 3 weeks) to complete a full year of trastuzumab. The primary endpoint was 3-year invasive disease-free survival.
Findings: Between October 29, 2007, and September 3, 2010, 410 patients were enrolled, of whom 406 received adjuvant paclitaxel and trastuzumab and were included in the analysis. The mean age at enrollment was 55 years, and 272 (67.0%) had hormone receptor-positive disease. After a median follow-up of 10.8 years (IQR 7.1–11.4), among the 406 patients in the analyzed population, 31 invasive disease-free survival events were observed, of which 6 (19.4%) were local ipsilateral recurrences and 9 (29.0%) were new contralateral breast cancers, 6 (19.4%) were distant recurrences, and 10 (32.3%) were all-cause deaths. The 10-year invasive disease-free survival rate was 91.3% (95% CI 88.3–94.4), the 10-year recurrence-free interval was 96.3% (95% CI 94.3–98.3), and the 10-year overall survival rate was 94.3% (95% CI 91.8 –96.8), and the 10-year breast cancer-specific survival rate was 98.8% (95% CI 97.6–100). HER2DX* risk score as a continuous variable was significantly associated with invasive disease-free survival (hazard ratio [HR] 1.24 [95% CI 1.00–1.52] per 10-unit increment; p = 0.047) and recurrence-free interval (1.45 [1.09 –1.93]; p = 0.011).
Interpretation Adjuvant paclitaxel and trastuzumab are a reasonable standard of care for patients with small (≤3 cm), node-negative/HER2-positive breast cancer.
*HER2DX is a supervised learning algorithm that integrates 4 gene expression signatures of tumor size, lymph node staging and tracking immune infiltration, tumor cell proliferation, luminal differentiation and HER2 amplicon expression into a single score.
参考文献 Reference
Tolany SM et al. Lancet Onc 2023; 24:273Prat A et al. Lancet 2022; 75. DOI:https://doi.org/10.1016/j.ebiom.2021.103801
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靶向CLDN18.2 的zolbetuximab加上化疗有利于不可切除或转移性胃或胃食管交界处腺癌 (3/5/2023)
Zolbetuximab （targeting CLDN18.2） plus chemotherapy benefited patients with unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma
CLDN18.2 在正常胃粘膜细胞中表达，并保留在转移性胃或胃食管交界处肿瘤细胞中。 在 FAST 研究中，靶向 CLDN18.2 的 zolbetuximab 联合化疗可延长局部晚期不可切除或转移性胃或胃食管交界处腺癌患者的生存期。 SPOTLIGHT (NCT03504397) 是一项 3 期全球双盲研究，比较 zolbetuximab + 亚叶酸、5-FU 和奥沙利铂 (mFOLFOX6) 与安慰剂 + mFOLFOX6 作为第一线治疗 CLDN18.2+/ HER2−, 局部晚期不可切除或转移性胃或胃食管交界处腺癌。
方法： 既往未经治疗的 CLDN18.2+（IHC 检测 ≥75% 肿瘤细胞中度至强阳性）/HER2- 局部晚期不可切除或转移性胃或胃食管交界处腺癌以 1:1 的比例随机分配至 zolbetuximab 经静脉 800 毫克/平方米（周期 1，第1 天）之后是 600 毫克/平方米（周期 1，第22 天; 以后为每 3 周的第一天）+ mFOLFOX6 （第1, 15, 29天）, 每 6 周为一个周期, 共四个周期，对照组为安慰剂 + mFOLFOX6； 没有疾病进展的患者继续使用 zolbetuximab 或安慰剂+ 亚叶酸和 5-FU 治疗 > 4 个周期（由研究者决定），直到达到疾病进展或停药标准。 主要终点是无进展生存期。 次要终点包括总生存期, 客观响应率和安全性。
结果： 在筛选的 2,735 名患者中，565 名患者以 1:1 的比例随机分配至 zolbetuximab + mFOLFOX6 (N = 283) 或安慰剂 + mFOLFOX6 (N = 282)。 Zolbetuximab + mFOLFOX6 在统计学上显著改善了 无进展生存期（中位数 10.61 相对于 8.67 个月，HR 0.751，P = 0.0066）。 总生存期也得到显著改善（中位数 18.23 相对于 15.54 个月，HR 0.750，P =0.0053，< 0.0135 作为界限）。 治疗组之间的客观响应率相似。
Zolbetuximab + mFOLFOX6 最常见治疗相关的副作用是恶心（82.4% 相对于安慰剂组的60.8%）, 呕吐（67.4% 相对于35.6%）和食欲下降（47.0% 相对于33.5%）； 两组严重副作用 的发生率相似（44.8% 对 43.5%）。
结论： 靶向 CLDN18.2 的第一线 zolbetuximab 联合 mFOLFOX6 在 CLDN18.2+/ HER2-, 局部晚期不可切除或转移性胃或胃食管交界处腺癌患者中显著延长了无进展生存期和总生存期。治疗相关的副作用与之前的研究一致。
CLDN18.2 is expressed in normal gastric mucosal cells and is still retained in metastatic gastric or GEJ tumor cells. In the FAST study, zolbetuximab targeting CLDN18.2 in combination with chemotherapy prolonged survival in patients with locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma. SPOTLIGHT (NCT03504397) is a phase 3 global double-blind study comparing zolbetuximab + folinic acid, 5-FU and oxaliplatin (mFOLFOX6) vs placebo + mFOLFOX6 as first-line treatment for CLDN18.2+/ HER2−, locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma.
Methods: Previously untreated CLDN18.2+ (moderately to strongly positive in ≥75% tumor cells by IHC)/HER2- locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma randomized 1:1 assigned to zolbetuximab IV 800 mg/m2 (cycle 1, day 1) followed by 600 mg/m2 (cycle 1, day 22; thereafter every 3 weeks on day 1) + mFOLFOX6 (days 1, 15 , 29), every 6 weeks as a cycle, for a total of four cycles. The control group received placebo + mFOLFOX6. Patients without disease progression continued to use zolbetuximab or placebo + leucovorin and 5-FU treatment > 4 cycles (per Investigators’ decision), until disease progression or discontinuation criteria were reached. The primary endpoint was progression-free survival. Secondary endpoints included overall survival, objective response rate, and safety.
Results: Of 2,735 patients screened, 565 patients were randomized 1:1 to zolbetuximab + mFOLFOX6 (N = 283) or placebo + mFOLFOX6 (N = 282). Zolbetuximab plus chemotherapy statistically significantly improved progression-free survival (median 10.61 vs 8.67 months, HR 0.751, P = 0.0066). Overall survival was also significantly improved (median 18.23 vs. 15.54 months, HR 0.750, P = 0.0053, < 0.0135 as cutoff). Objective response rates were similar between treatment groups.
The most common treatment-related side effects of Zolbetuximab + mFOLFOX6 were nausea (82.4% vs. 60.8% in the placebo group), vomiting (67.4% vs. 35.6%), and decreased appetite (47.0% vs. 33.5%). The incidence of severe treatment-related side effects was similar (44.8% vs 43.5%).
Conclusions: First-line zolbetuximab combined with mFOLFOX6 significantly prolonged progression-free survival and overall survival in patients with CLDN18.2+/HER2-, locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma. Treatment-related side effects were consistent with previous studies.
参考文献 Reference
Shitara K et al. 2023 ASCO GI Cancers Symp Abstr LBA292.
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Tucatinib 联合曲妥珠单抗和卡培他滨治疗既往治疗过的 HER2 阳性转移性乳腺癌脑转移 (3/4/2023)
Tucatinib in combination with trastuzumab and capecitabine for HER2-Positive breast cancer with brain metastases
高达 50% 的 HER2 阳性转移性乳腺癌患者会发生脑转移，这与预后不良有关。 HER2CLIMB 是一项国际, 多中心, 随机, 双盲, 安慰剂对照临床试验，评估Tucatinib联合曲妥珠单抗和卡培他滨对 HER2 阳性乳腺癌并脑转移患者的疗效。 612 名患者，包括患有活动性或稳定脑转移的患者，之前曾接受过曲妥珠单抗, 帕妥珠单抗和曲妥珠单抗 emtansine 治疗的 HER2阳性转移性乳腺癌。 该研究于 2016 年 2 月 23 日至 2019 年 5 月 3 日进行。分析了 2016 年 2 月 23 日至 2021 年 2 月 8 日的数据。患者按 2:1 随机分配接受 tucatinib（300 毫克 口服，每日两次）或安慰剂（口服，每日两次），两者联合曲妥珠单抗（6 毫克/公斤 静脉内或皮下注射，每 3 周一次，初始负荷剂量为 8 毫克/公斤）和卡培他滨（1000 毫克/平方米，在每个 3 周周期的第 1-14 天口服，每天两次）。 该探索性亚组分析中的主要结果和测量评估包括脑转移患者的总生存期和颅内无进展生存期 , 患者（在基线时具有可测量的颅内疾病）确认的颅内客观响应率和颅内响应持续时间，以及所有患者的无新脑损伤生存期。 在主要数据锁定之前仅预先指定了总生存期。
结果: 在基线时，612 名患者中有 291 名 (47.5%) 患有脑转移。 中位年龄为 52 岁（范围 22-75 岁），289 名 (99.3%) 为女性。 在中位随访 29.6 个月（范围，0.1-52.9 个月）时，Tucatinib联合组的中位总生存期（21.6 个月；95% CI，18.1-28.5）比安慰剂联合组（12.5 个月）长 9.1 个月 ；95% CI，11.2-16.9）。Tucatinib联合治疗组的颅内响应持续时间为 8.6 个月（95% CI，5.5-10.3 个月），安慰剂联合治疗组为 3.0 个月（95% CI，3.0-10.3 个月）。 Tucatinib联合治疗组与安慰剂联合治疗组相比，作为首次进展或死亡部位出现新脑损伤的风险降低了 45.1%（风险比，0.55 [95% CI，0.36-0.85]）。
结论: 亚组分析发现，tucatinib 联合曲妥珠单抗和卡培他滨可改善总生存期，同时降低发生新脑损伤的风险。
Up to 50% of patients with HER2-positive metastatic breast cancer develop brain metastases. This is associated with poor prognosis. HER2CLIMB is an international, multicenter, randomized, double-blind, placebo-controlled clinical trial evaluating the efficacy of tucatinib combined with trastuzumab and capecitabine in patients with HER2-positive breast cancer and brain metastases. Six-hundred and twelve patients, including those with active or stable brain metastases, had previously been treated with trastuzumab, pertuzumab, and trastuzumab emtansine for HER2-positive metastatic breast cancer. The study was conducted from February 23, 2016 to May 3, 2019. Data from February 23, 2016 to February 8, 2021 were analyzed. Patients were randomized 2:1 to receive tucatinib (300 mg orally twice a day) or placebo (oral twice daily) in combination with trastuzumab (6 mg/kg intravenously or subcutaneously, every 3 weeks with an initial loading dose of 8 mg/kg) and capecitabine (1000 mg/m2 orally twice a day on days 1-14 of each 3-week cycle). The main outcomes and measures evaluated in this exploratory subgroup analysis included overall survival and intracranial progression-free survival in patients with brain metastases, confirmed intracranial objective response rate in patients and duration of intracranial response in patients with measurable intracranial disease at baseline, and new brain injury-free survival in all patients. Only overall survival was prespecified before the primary data lock.
Results: At baseline, 291 (47.5%) of 612 patients had brain metastases. The median age was 52 years (range, 22-75 years), and 289 (99.3%) were female. At a median follow-up of 29.6 months (range, 0.1-52.9 months), the median overall survival in the tucatinib combination arm (21.6 months; 95% CI, 18.1-28.5) was longer than that in the placebo combination arm (12.5 months) by 9.1 months; 95% CI, 11.2-16.9). The duration of intracranial response was 8.6 months (95% CI, 5.5-10.3 months) in the tucatinib-combination arm and 3.0 months (95% CI, 3.0-10.3 months) in the placebo-combination arm. The risk of new brain lesions as the site of first progression or death was reduced by 45.1% in the tucatinib-combination group compared with the placebo-combination group (hazard ratio, 0.55 [95% CI, 0.36-0.85]).
Conclusions: Subgroup analysis demonstrated that adding tucatinib to trastuzumab and capecitabine improved overall survival while reducing the risk of new brain injury.
参考文献 Reference
Lin NU et al. JAMA Onc 2023; 9:197.
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抗体-药物偶联物（Enfortumab Vedotin*） 加 Pembrolizumab 治疗晚期尿路上皮癌 (2/26/2023)
Antibody-drug conjugate （Enfortumab Vedotin*）and pembrolizumab for advanced urothelial cancer
这是一项正在进行的Ib/II期多中心,开放标签临床试验（EV-103/KYENOTE-869），参加者为第一线顺铂治疗不适合的, 局部晚期或转移性尿路上皮癌患者。他们在第 1 天接受pembrolizumab 200 毫克静脉注射，在第 1 天和第 8 天接受 enfortumab vedotin （每次1.25 毫克/公斤），以每 3 周为一个周期。 主要终点是安全性。 关键的次要终点包括确认的客观响应率, 响应持续时间和总生存期。 共有 45 名患者接受了 enfortumab vedotin 联合 pembrolizumab。
最常见的治疗相关不良事件是周围感觉神经病变 (55.6%)、疲劳 (51.1%) 和脱发 (48.9%)。 29 名患者 (64.4%) 有 3 级或更高级别的治疗相关不良事件； 最常见的是脂肪酶增加 (17.8%)、斑丘疹 (11.1%) 和疲劳 (11.1%)。 1 例死亡 (2.2%) 被归类为治疗相关不良事件。 中位数九个周期后确认的客观响应率为 73.3%，完全响应为 15.6%。 中位响应持续时间和中位总生存期分别为 25.6 个月和 26.1 个月。
结论 Enfortumab vedotin 加 pembrolizumab 显示出可控的安全性。 大多数患者经历了肿瘤缩小。 在不适合顺铂的患者人群中，中位响应持续时间和中位总生存期超过 2 年，这组合目前正在 III 期研究中进行。
*Enfortumab vedotin （Padcev ），它是一种针对 Nectin-4 的单克隆抗体（Enfortumab）,和微管抑制剂偶联物通过化学接头（vedotin）连接到抗体。
This is an ongoing phase Ib/II multicenter, open-label clinical trial (EV-103/KYENOTE-869) in patients with locally advanced or metastatic urothelial cancer ineligible for first-line cisplatin. They received pembrolizumab 200 mg intravenously on day 1 and enfortumab vedotin (1.25 mg/kg) on days 1 and 8 every 3 weeks. The primary endpoint is safety. Key secondary endpoints included confirmed objective response rate, duration of response and overall survival. A total of 45 patients received enfortumab vedotin plus pembrolizumab.
The most common treatment-related adverse events were peripheral sensory neuropathy (55.6%), fatigue (51.1%), and alopecia (48.9%). Twenty-nine patients (64.4%) had grade 3 or higher treatment-related adverse events; the most common were increased lipase (17.8%), maculopapular rash (11.1%), and fatigue (11.1%). One death (2.2%) was classified as a treatment-related adverse event. The confirmed objective response rate after a median of nine cycles was 73.3%, with a complete response rate of 15.6%. Median duration of response and median overall survival were 25.6 months and 26.1 months, respectively.
Conclusion Enfortumab vedotin plus pembrolizumab showed a manageable safety profile. Most patients experienced tumor shrinkage. In a patient population ineligible for cisplatin, the median duration of response and median overall survival exceeded 2 years, and the combination is currently being studied in a phase III study.
*Enfortumab vedotin (Padcev), is a monoclonal antibody against nectin-4 (Enfortumab), and a microtubule inhibitor conjugate linked to the antibody via a chemical linker (vedotin). (NIH website)
参考文献 Reference
Hoimes CJ et al. J Clin Onc 2023; 41: 22-31
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对早期乳腺癌进行或不进行放疗的保乳手术 (2/25/2023)
Breast-conserving surgery with or without radiation in early breast cancer
研究者进行了一项关于省略放疗的 III 期随机试验（由苏格兰政府首席科学家办公室和爱丁堡西部总医院乳腺癌研究所资助: ISRCTN95889329）。试验人群包括 65 岁或以上的女性，她们患有激素受体阳性、淋巴结阴性、T1 或 T2 原发性乳腺癌（肿瘤最大尺寸≤3 cm）, 接受了保乳手术, 切除边缘阴性，并且接受了辅助内分泌治疗。 患者被随机分配接受全乳照射（40 至 50 Gy）或不接受照射。 主要终点是局部乳腺癌复发。 还评估了区域复发, 乳腺癌特异性生存, 作为首发事件的远处复发和总生存。
结果: 共有 1,326 名女性入组；658 人被随机分配接受全乳照射，668 人不接受照射。 中位随访时间为 9.1 年。 非放疗组 10 年内局部乳腺癌复发的累积发生率为 9.5%（95% 置信区间 [CI]，6.8 至 12.3），放疗组为 0.9%（95% CI，0.1 至 1.7）。风险比，10.4；95% CI，4.1 至 26.1；P < 0.001）。 尽管局部复发在未接受放疗组中更为常见，但作为首发事件的远处复发的 10 年发生率在未放疗组中并不高于放疗组，为 1.6%（95% CI， 0.4 至 2.8）和 3.0%（95% CI，1.4 至 4.5）。 两组的 10 年总生存率几乎相同，未接受放疗的为 80.8%（95% CI，77.2 至 84.3），接受放疗的为 80.7%（95% CI，76.9 至 84.3）。 区域复发率和乳腺癌特异性生存率在两组之间也没有显著差异。
结论: 不接受放疗与局部复发率增加有关，但对 65 岁或以上患有低风险、激素受体阳性早期乳腺癌的女性的首次事件远处复发或总生存期没有不利影响。
The investigators conducted a phase III randomized trial of the omission of radiation (funded by the Chief Scientist Office of the Scottish Government and the Breast Cancer Institute, Western General Hospital, Edinburgh: ISRCTN95889329). The trial population included women aged 65 years or older with hormone-receptor-positive, node-negative, T1 or T2 primary breast cancer (maximum tumor size ≤ 3 cm), who had undergone breast-conserving surgery with negative resection margins, and received adjuvant endocrine therapy. Patients were randomly assigned to receive whole breast irradiation (40 to 50 Gy) or no irradiation. The primary endpoint was local breast cancer recurrence. Regional recurrence, breast cancer-specific survival, distant recurrence as a first event, and overall survival were also assessed.
Results: A total of 1,326 women were enrolled; 658 were randomly assigned to receive whole breast radiation and 668 not to receive radiation. Median follow-up was 9.1 years. The 10-year cumulative incidence of local breast cancer recurrence was 9.5% (95% confidence interval [CI], 6.8 to 12.3) in the non-radiation group and 0.9% (95% CI, 0.1 to 1.7) in the radiation group. Hazard ratio, 10.4; 95% CI, 4.1 to 26.1; P < 0.001). Although local recurrence was more common in the no-radiation group, the 10-year incidence of distant recurrence as the first event was no higher in the no-radiation group than in the radiation group, at 1.6% (95% CI, 0.4 to 2.8) and 3.0% (95% CI, 1.4 to 4.5). The 10-year overall survival rates were nearly identical in the two groups, 80.8% (95% CI, 77.2 to 84.3) for those who did not receive radiation and 80.7% (95% CI, 76.9 to 84.3) for those who received radiation. Regional recurrence rates and breast cancer-specific survival rates were also not significantly different between the two groups.
Conclusions: Not receiving radiotherapy was associated with increased rates of local recurrence but had no adverse effect on first-event distant recurrence or overall survival in women 65 years or older with low-risk, hormone-receptor-positive early breast cancer.
参考文献 Reference
Hunkler IH et al. N Engl J Med 2023; 388:585
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Sotorasib 对比地西紫杉醇治疗 KRASG12C 突变非小细胞肺癌 (2/19/2023)
Sotorasib v Docetaxel in KRASG12C mutant Non-small cell lung cancer (NSCLC)
这是一项随机,开放标签的 III期临床试验（NCT04303780）, 在 22 个国家/地区的 148 个中心招募了 KRASG12C 突变晚期 NSCLC 患者，这些患者在先前的铂类化疗和 PD-1 或 PD-L1 抑制剂后出现疾病进展。 以开放标签的方式将患者随机分配 (1:1) 口服 sotorasib（960 毫克 每天一次）或静脉注射多西紫杉醇（75 毫克/平方米，每 3 周一次）。治疗一直持续到疾病进展, 不耐受,开始另一种抗癌治疗, 撤回同意或死亡。 主要终点是无进展生存期。 在所有接受治疗的患者中评估了安全性。
发现: 2020 年 6 月 4 日至 2021 年 4 月 26 日期间，345 名患者被随机分配接受 sotorasib (n=171 [50%]) 或多西紫杉醇 (n = 174 [50%])。 Sotorasib 组的 169 名 (99%) 患者和多西紫杉醇组的 151 名 (87%) 患者接受了至少一剂治疗。 在中位随访 17.7 个月 (IQR 16.4–20.1) 后，该研究达到了主要终点，即与多西紫杉醇相比，sotorasib 的无进展生存期有统计学意义的显著增加（中位无进展生存期 生存 5.6 个月 [95% CI 4.3–7.8] 相对于 4.5 个月 [3.0–5.7]；风险比 0.66 [0.51–0.86]；p = 0.0017) 。
Sotorasib 耐受性良好，与多西紫杉醇相比，3 级或更严重的事件（n = 56 [33%] 相对于 n = 61 [40%]）和严重的治疗相关不良事件较少（n = 18 [11%] 相对于 n = 34 [23%]）。 对于 sotorasib，最常见的 3 级或更严重的治疗相关不良事件是腹泻 (n = 20 [12%])、谷丙转氨酶升高 (n = 13 [8%]) 和天冬氨酸转氨酶升高 (n = 9 [ 5%])。 对于多西紫杉醇，最常见的 3 级或更严重的治疗相关不良事件是中性粒细胞减少症 (n = 13 [9%])、疲劳 (n = 9 [6%]) 和发热性中性粒细胞减少症 (n = 8 [5%] ) 。
解释: 与多西紫杉醇相比，Sotorasib在具有 KRASG12C 突变且之前接受过其他抗癌药物治疗的晚期 NSCLC 患者中显著增加了无进展生存期, 并具有更有利的安全性。
This is a randomized, open-label, phase III clinical trial (NCT04303780), which enrolled patients with KRASG12C -mutated advanced NSCLC at 148 centers in 22 countries. Their disease progressed following prior platinum-based chemotherapy and PD-1 or PD-L1 inhibitors. Patients were randomized (1:1) in an open-label fashion to either oral sotorasib (960 mg once daily) or intravenous docetaxel (75 mg/m2 every 3 weeks). Treatment continued until disease progression, intolerance, initiation of another anticancer therapy, withdrawal of consent, or death. The primary endpoint was progression-free survival. Safety was assessed in all treated patients.
Findings: Between June 4, 2020, and April 26, 2021, 345 patients were randomly assigned to receive either sotorasib (n =171 [50%]) or docetaxel (n =174 [50%]). 169 (99%) patients in the sotorasib group and 151 (87%) in the docetaxel group received at least one dose. After a median follow-up of 17.7 months (IQR 16.4–20.1), the study met its primary endpoint with a statistically significant increase in progression-free survival with sotorasib compared to docetaxel (median progression-free survival was 5.6 months [95% CI 4.3–7.8] vs 4.5 months [3.0–5.7]; hazard ratio 0.66 [0.51–0.86]; p = 0.0017).
Sotorasib was well tolerated, with fewer grade 3 or worse events (n = 56 [33%] vs. n = 61 [40%]) and serious treatment-related adverse events (n = 18 [11%] versus n = 34 [23%]). For sotorasib, the most common grade 3 or worse treatment-related adverse events were diarrhea (n = 20 [12%]), increased alanine aminotransferase (n = 13 [8%]), and increased aspartate aminotransferase (n = 9 [5%]). For docetaxel, the most common grade 3 or worse treatment-related adverse events were neutropenia (n = 13 [9%]), fatigue (n = 9 [6%]), and febrile neutropenia Granulocytopenia (n = 8 [5%]).
Interpretation: Sotorasib significantly increased progression-free survival compared with docetaxel and had a more favorable safety profile in advanced NSCLC patients with a KRASG12C mutation who had been previously treated with other anticancer drugs.
参考文献 Reference
Johannes de Langen A et al. Lancet 2023; Feb. 3. DOI:https://doi.org/10.1016/S0140-6736(23)00221-0
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新辅助 T-DXd 用于 HER2-低表达的 乳腺癌（2/18/2023）
Neoadjuvant T-DXd in HER2-low breast cancer
TALENT是一项II期临床试验（TRIO-US B-12，NCT04553770）, 主要目标是评估新辅助 T-DXd 单独或与内分泌治疗联合在雌激素受体阳性/HER2-低表达的早期乳腺癌的临床活性和安全性。
方法: 患有先前未治疗的,可手术的侵入性, 雌激素受体阳性/HER2-低表达（IHC 1+ 或 2+/FISH-）, > 2 厘米的早期乳腺癌符合条件。 在临床试验的第 1 阶段，参与者以 1:1 的比例随机接受1) A 组: 单独使用T-DXd（5.4 mg/kg IV 每21 天）; 2) B 组: T-DXd与阿那曲唑（1 mg 每天口服）联合使用。
最初治疗为 6 周期，但在 02/2022，一项修正案对于新入组的患者或尚未接受手术的患者增加了治疗周期的数量到8周期。 随机分配到 B 组的男性和绝经前/围绝经期女性还接受了促性腺激素释放激素激动剂。 分层因素是 HER2 表达（1+ 与 2+）和绝经状态（男性为绝经后）。基线肿瘤组织在第 1 周期的第 17-21 天和手术时收集。基线乳腺造影于第2 周期和术前。 主要终点是手术时的 病理性完全响应率。其他终点包括安全性,客观响应率, Ki67 表达的变化, 残余癌症负担指数,探索性生物标志物分析，以及与健康相关的生活质量。
结果： 从 09/21/2020 到 10/13/2022，58 名患者（A 组 29 名，B 组 29 名）在试验的第一阶段。 5 名患者在完成研究治疗前退出研究。 截至数据截止 (10/05/2022)，33 名患者完成了研究治疗并接受了 手术（A 组 17 名，B 组 16 名），13 名正在接受治疗，7 名正在等待手术； 27名完成 6 个周期，13 名完成 8 个周期。46/58 名患者的基线 HER2 表达为 1+，4/58 为 0，6/58 为 2+，1/58 有多中心病变 1+ 和 2+，1/58 有单一病变 1+ 和 2+。 在A组，1/17 患者在 8 周期后获得病理性完全响应，2/17 患者在 6 周期后获得残余癌症负担指数-I（17.6% ）。 在 B 组中，1/16 患者 8 个周期后有获得残余癌症负担指I (6.3%)。 A 组中响应可评估患者的客观响应率为 75% (12/16, 1例完全响应，11 例部分响应）和 B 组为 63.2%（12/19，2 例完全响应，10 例部分响应）； 1 名患者（B 组）疾病进展。
间质性肺病（2 级）发生在 1 名患者 (1.7%)，并在停止治疗后 11 天消退。 最常见的 A 组和 B 组中与治疗相关的 ≥ 3 级副作用分别包括低钾血症（1.7%， 5.2%）、腹泻（3.4%、3.4%）, 中性粒细胞减少（3.4%、1.7%）, 疲劳（1.7%、3.4%）,头痛 (3.4%, 1.7%)，呕吐 (3.4%, 1.7%)，脱水 (1.7%, 1.7%) 和恶心 (3.4%, 0%)。
结论： 这是评估 HER2低表达乳腺癌新辅助 T-DXd 试验的第一份报告。作者认为T DXd +/- 内分泌治疗对雌激素受体阳性/HER2-低表达的乳腺癌出有临床活性。
TALENT is a phase II clinical trial (TRIO-US B-12, NCT04553770). The main goal is to evaluate the clinical activity and safety of neoadjuvant T-DXd alone or in combination with endocrine therapy in estrogen receptor positive / HER2-low early breast cancer.
Methods: Patients with previously untreated, operable invasive, estrogen receptor-positive /HER2-low expressing (IHC 1+ or 2+/FISH-), >2 cm early breast cancer were eligible. In phase 1 of the clinical trial, participants were randomized in a 1:1 ratio to receive 1) Arm A: T-DXd alone (5.4 mg/kg IV every 21 days); 2) Arm B: T-DXd with anastrozole (1 mg orally daily). The initial treatment was 6 cycles; in 02/2022, an amendment increased the number of treatment to 8 cycles for newly enrolled patients or patients who had not yet undergone surgery. Men and premenopausal/perimenopausal women randomized to arm B also received a GnRH agonist. Stratification factors were HER2 expression (1+ vs 2+) and menopausal status (postmenopausal in men). Baseline tumor tissue was collected on days 17-21 of cycle 1 and at surgery. Baseline mammography was performed in cycle 2 and preoperatively. The primary endpoint was pathological complete response rate at the time of surgery. Additional endpoints included safety, objective response rate, change in Ki67 expression, residual cancer burden index, exploratory biomarker analysis, and health-related quality of life.
Results: From 09/21/2020 to 10/13/2022, 58 patients (29 in arm A and 29 in arm B) were in the first phase of the trial.Five patients withdrew from the study before completing study treatment.As of the data cut-off (10/05/2022), 33 patients completed the study treatment and underwent surgery (17 in group A, 16 in group B), 13 were receiving treatment, and 7 were waiting for surgery; 27 completed 6cycles,13 completed 8 cycles.Baseline HER2 expression was 1+ in 46/58 patients, 0 in 4/58, 2+ in 6/58, 1/58 with multicentric lesions 1+ and 2+, and 1/58 with single lesions 1+ and 2+. In arm A, 1/17 patients achieved pathological complete response after 8 cycles, and 2/17 patients achieved residual cancer burden index-I after 6 cycles (17.6%).In arm B, 1/16 patients had achieved residual cancer burden index I after 8 cycles (6.3%).The objective response rate in response-evaluable patients was 75% in Arm A (12/16, 1 complete response, 11 partial responses) and 63.2% in Arm B (12/19, 2 complete responses, 10 partial responses); 1 patient (group B) had disease progression.
Interstitial lung disease (grade 2) occurred in 1 patient (1.7%) and resolved 11 days after stopping treatment. The most common treatment-related grade ≥ 3 side effects in Arms A and B included hypokalemia (1.7%, 5.2%), diarrhea (3.4%, 3.4%), neutropenia (3.4%, 1.7%) %), fatigue (1.7%, 3.4%), headache (3.4%, 1.7%), vomiting (3.4%, 1.7%), dehydration (1.7%, 1.7%) and nausea (3.4%, 0%).
Conclusions: This is the first report of a trial evaluating neoadjuvant T-DXd in HER2-low expressing breast cancer. The authors believed that T DXd +/- endocrine therapy had clinical activity for estrogen receptor positive/HER2-low breast cancer.
参考文献 Reference
Hurvitz SA et al. 2022 San Antonio Breast Cancer Symp abstr GS2-03
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Talquetamab，用于多发性骨髓瘤的 T 细胞重定向双特异性抗体 (2/12/2023)
Talquetamab，A T-cell-redirecting bispecific antibody for multiple myeloma
Talquetamab 是一种针对 CD3 （T 细胞）和 GPRC5D （G 蛋白偶联受体，C 家族，第 5 组，成员 D）的双特异性抗体，可重定向 T 细胞以介导杀死表达 GPRC5D 的骨髓瘤细胞。
在一项 I 期研究中（NCT03399799），研究者评估了在接受过大量治疗的复发性或难治性多发性骨髓瘤患者中, 每周或每隔一周静脉注射一次（0.5 至 180 微克/公斤）.或每周、每隔一周或每月一次皮下注射（5 至 1600 微克/公斤）的Talquetamab。主要终点为剂量限制性毒性作用的频率和类型（仅限研究第 1 部分）,不良事件和实验室异常, 以便为 II 期研究选择推荐剂量。
结果：在数据截止日期，232 名患者接受了 talquetamab（102 名静脉注射，130 名皮下注射）。 在 II 期研究推荐的两种皮下剂量下（每周 405 微克/公斤 [30 名患者] 和每隔一周 800 微克/公斤 [44 名患者]），常见的不良事件是细胞因子释放综合征（77% 和 80% 的患者） 患者）, 皮肤相关事件（分别为 67% 和 70%）和味觉障碍（分别为 63% 和 57%）； 除一次细胞因子释放综合征事件外，所有事件均为 1 级或 2 级。一名接受 800 微克剂量水平的患者报告了 3 级皮疹的剂量限制毒性作用。 在中位随访 11.7 个月（在接受 405 微克剂量水平的 talquetamab 的患者中）和 4.2 个月（在接受 800 微克剂量水平的患者中）时，有响应的患者百分比为 分别为 70%（95% 置信区间 [CI]，51 至 85）和 64%（95% CI，48 至 78）。 中位响应持续时间分别为 10.2 个月和 7.8 个月。
结论：细胞因子释放综合征,皮肤相关事件和味觉障碍在 talquetamab 治疗中很常见，但主要是低级别的。 Talquetamab 在经过大量预处理的复发性或难治性多发性骨髓瘤患者中引起了实质性反应。
Talquetamab is a bispecific antibody against CD3 (T cells) and GPRC5D (G protein-coupled receptors, family C, group 5, member D) that redirects T cells to mediate killing of GPRC5D-expressing myeloma cells.
In a phase I study (NCT03399799), investigators evaluated weekly or every other week intravenous injections (0.5 to 180 μg/kg ), or Talquetamab given subcutaneously (5 to 1600 μg/kg) weekly, every other week, or monthly. The primary endpoints were the frequency and type of dose-limiting toxic effects (study part 1 only), adverse events and laboratory abnormalities to allow selection of the recommended dose for the phase II study.
Results: At the data cutoff date, 232 patients received talquetamab (102 intravenously, 130 subcutaneously). A common adverse event was cytokine release syndrome (77 % and 80% of patients), skin-related events (67% and 70%, respectively) and dysgeusia (63% and 57%, respectively); all but one cytokine release syndrome event were grade 1 or grade 2. A dose-limiting toxic effect of grade 3 rash was reported in one patient receiving the 800 μg dose level. At a median follow-up of 11.7 months (in patients receiving talquetamab at the 405 μg dose level) and 4.2 months (in patients receiving the 800 μg dose level), the percentages of patients who responded were 70% (95% [CI], 51 to 85) and 64% (95% CI, 48 to 78). The median duration of response was 10.2 months and 7.8 months, respectively.
Conclusions: Cytokine release syndrome, skin-related events, and dysgeusia were common with talquetamab treatment, but mainly of low-grade. Talquetamab elicited substantial responses in heavily pretreated patients with relapsed or refractory multiple myeloma.
参考文献 Reference
Chari a. et al. N Engl J Med 2022; 387:2232
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服用Ibrutinib而有心脏毒性患者的心血管磁共振表现 (2/11/2023)
Cardiovascular MRI of patients with Ibrutinib-associated cardiotoxicity
在具有Ibrutinib相关心脏毒性作用的患者中，心肌纤维化很常见，并且似乎与较高的心脏毒性风险相关。在临床前模型中，这些事件与弥漫性心肌损伤（炎症和纤维化）并行。在这项队列研究中，连续 33 名患者接受了心脏磁共振成像检查，因为怀疑有Ibrutinib相关的心脏毒性作用，近三分之二的患者有心肌损伤的证据，包括超过 50% 的患者有疤痕。 即使考虑到传统的心脏危险因素，这种模式仍然存在，并且那些受伤的人未来的心脏毒性事件增加了 5 倍。
这项队列研究纳入了 2012 年至 2019 年连续接受Ibrutinib治疗的患者，这些患者使用心血管磁共振 (CMR) 进行了表型分析。主要结果是晚期钆增强 (LGE) 纤维化的存在。 次要结局是主要不良心脏事件（MACE）的发生，定义为心房颤动、心力衰竭、有症状的室性心律失常，以及 CMR 后可能或明确与Ibrutinib相关的猝死。 还评估了参数映射亚临床纤维化（天然-T1，细胞外体积分数）和炎症/水肿（max-T2）措施。 将心血管磁共振测量值与在未接受Ibrutinib治疗的类似连续癌症患者（治疗前对照）中获得的测量值进行比较。 研究者还将观察到的指标与相似年龄的广泛人群比率（一般人群对照）和更广泛的心血管疾病（CVD）风险匹配的癌症对照进行了比较。 多变量回归用于评估 CMR 指标与 MACE 之间的关联。 结果 总体而言，确定了 49 名接受Ibrutinib治疗的患者，其中 33 名在治疗开始后进行了成像（平均 [SD] 年龄，65 [10] 岁，9 名 [27%] 患有高血压，23 名 [69.7%] 患有指数心律失常； Ibrutinib使用的中位持续时间为 14 个月。 平均 (SD) 治疗前天然 T1 为 977.0 (73.0) ms，max-T2 为 56.5 (4.0) ms，4 (13.3%) 有 LGE。 治疗开始后，平均 (SD) 天然 T1 为 1033.7 (48.2) ms，max-T2 为 61.5 (4.8) ms，17 例 (54.8%) 患有 LGE（Ibrutinib治疗前和治疗后的 P 分别为P < .001，P = .01，P < .001）。 9 例 (28.6%) 的天然 T12SD 升高，21 例 (63.0%) 的最大 T22SD 升高。 心血管磁共振测量值在疑似毒性作用的患者中最高（分别为 P = .01 和 P = .01）。 传统的 CVD 风险或癌症治疗状态与异常 CMR 测量值之间没有关联。 在没有传统 CVD 的人群中，16 人 (58.6%) 有 LGE，而匹配对照中有 38 人 (13.3%)（相对风险，4.8；P < .001）。 在 19 个月的中位随访期间，13 人 (39.4%) 经历了 MACE。 在包含传统 CVD 风险因素的多变量模型中，LGE（风险比 [HR]，4.9；P = .04）和天然 T12SD（HR，3.3；P = .05）与较高的 MACE 风险相关。
结论和相关性: 在这项队列研究中，心肌损伤在Ibrutinib使用者中很常见，并且其存在与较高的心脏毒性风险相关。
In patients with ibrutinib-related cardiotoxic effects, myocardial fibrosis was common and appeared to be associated with a higher risk of cardiotoxicity. In preclinical models, these events paralleled or preceded by diffuse myocardial injury (inflammation and fibrosis). In this cohort study, 33 consecutive patients underwent cardiac magnetic resonance imaging because of suspected ibrutinib-related cardiotoxic effects, and nearly two-thirds of patients had evidence of myocardial injury, including more than 50% of patients with scarring . This pattern persisted even after accounting for traditional cardiac risk factors, and those injured had a 5-fold increase in future cardiotoxic events.
This cohort study included consecutive patients who received ibrutinib between 2012 and 2019 and were phenotyped using cardiovascular magnetic resonance (CMR). The primary outcome was the presence of late gadolinium-enhancing (LGE) fibrosis. The secondary outcome was the occurrence of major adverse cardiac events (MACE), defined as atrial fibrillation, heart failure, symptomatic ventricular arrhythmias, and sudden death of prpbable or definite association with ibrutinib after CMR. Also assessed were parameters mapping subclinical fibrosis (native-T1, extracellular volume fraction) and inflammation/edema (max-T2) measures. Cardiovascular magnetic resonance measurements were compared with those obtained in similar consecutive cancer patients not receiving ibrutinib treatment (pretreatment controls). The observed indicators were also compared to broad population rates of similar age (general population controls) and to broader cardiovascular disease (CVD) risk-matched cancer controls. Multivariate regression was used to assess the association between CMR indicators and MACE. Results: Overall, 49 patients treated with ibrutinib were identified, of whom 33 underwent imaging after initiation of treatment (mean [SD] age, 65 [10] years, nine [27%] had hypertension, 23 [69.7%] had index arrhythmias; median duration of ibrutinib use was 14 months. Mean (SD) pre-treatment natural T1 was 977.0 (73.0) ms, max-T2 was 56.5 (4.0) ms, 4 ( 13.3%) had LGE. After treatment initiation, mean (SD) natural T1 was 1033.7 (48.2) ms, max-T2 was 61.5 (4.8) ms, and 17 patients (54.8%) had LGE (P < .001, P = .01, P < .001, pre- vs post-ibrutinib treatment respectively). Nine (28.6%) had elevated native T12SD and 21 (63.0%) had elevated maximal T22SD. Cardiovascular MRI measurements in suspected Toxic effects were highest among patients (P = .01 and P = .01, respectively). There was no association between traditional CVD risk or cancer treatment status and abnormal CMR measurements. Among those without traditional CVD, 16 (58.6 %) had LGE, compared with 38 (13.3%) of matched controls (relative risk, 4.8; P < .001). During a median follow-up of 19 months, 13 (39.4%) experienced MACE. In a multivariate model inclusive of traditional CVD risk factors, LGE (hazard ratio [HR], 4.9; P = .04) and native T12SD (HR, 3.3; P = .05) were associated with higher risk of MACE.
Conclusions and relevance: Myocardial injury was common among ibrutinib users in this cohort, and its presence was associated with a higher risk of cardiotoxicity.
参考文献 Reference
Buck B et al. JAMA Onc 2023; February 2, 2023. doi:10.1001/jamaoncol.2022.6869
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炎症生物标志物与 III 期结肠癌患者生存的关联 (2/6/2023)
Association of inflammatory biomarkers and the survival of stage III colon cancer
该试验于 2010 年 6 月 22 日至 2015 年 11 月 20 日期间进行,共纳入 1,494 名血浆样本可用于炎症生物标志物检测的患者（CALGB/SWOG 80702）。血浆炎症生物标志物包括细胞介素 6 [IL-6],可溶性肿瘤坏死因子α受体 2 [sTNF-αR2] 和高敏 C 反应蛋白 [hsCRP]；五分位数）在手术后 3 至 8 周但 化疗随机化之前进行检测。该试验主要结果是无病生存期，定义为从随机分组到结肠癌复发或因任何原因死亡的时间。 次要结局是无复发生存期和总生存期。 通过 Cox 比例风险回归估计炎症生物标志物与生存相关的风险比。
结果: 1,494 名患者（中位随访 5.9 年 [IQR，4.7-6.1 岁]），中位年龄为 61.3 岁（IQR，54.0-68.8 岁），828 名 (55.4%) 为男性，327 名复发，244 名死亡和 387 起无病生存事件。 手术后中位 6.9 周（IQR，5.6-8.1 周）收集血浆样本。 IL-6 的中位血浆浓度为 3.8 pg/mL（IQR，2.3-6.2 pg/mL），sTNF-αR2 为 2.9 × 103 pg/mL（IQR，2.3-3.6 × 103 pg/mL）和 2.6 mg /L（IQR，1.2-5.6 mg/L）用于 hsCRP。 与炎症最低五分之一的患者相比，炎症最高五分之一的患者复发或死亡的风险显著增加（IL-6 的调整后风险比：1.52 [95% CI, 1.07-2.14]；对趋势的P =.01；对于 sTNF-αR2：1.77 [95% CI，1.23-2.55]；对趋势的 P < .001；对于 hsCRP：1.65 [95% CI，1.17-2.34]；对于趋势的P = .006）。 此外，在炎症生物标志物和celecoxib干预之间没有观察到对无病生存有显著的相互作用。 无复发生存期和总生存期也观察到了类似的结果。
结论和相关性: 该队列研究发现，诊断后较高的炎症与 III 期结肠癌患者较差的生存结果显著相关。 这一发现值得进一步研究，以评估抗炎干预是否可以改善结肠癌的预后。
The trial was conducted between June 22, 2010, and November 20, 2015, and included 1,494 patients ( from CALGB/SWOG 8070)2) with plasma samples available for detection of inflammatory biomarkers. The latter included interleukin 6 [IL-6], soluble tumor necrosis factor alpha receptor 2 [sTNF-αR2], and high-sensitivity C-reactive protein [hsCRP]; quintiles). The samples were measured at 3 to 8 weeks after surgery but before randomization. The primary outcome of the trial was disease-free survival, defined as the time from randomization to colon cancer recurrence or death from any cause. Secondary outcomes were recurrence-free survival and overall survival. Hazard ratios of inflammatory biomarkers associated with survival were estimated by Cox proportional hazards regression.
Results: 1,494 patients (median follow-up 5.9 years [IQR, 4.7-6.1 years]), median age 61.3 years (IQR, 54.0-68.8 years), 828 (55.4%) were male, 327 relapsed, 244 deaths and 387 disease-free survival events ocurred. Plasma samples were collected a median of 6.9 weeks (IQR, 5.6-8.1 weeks) after surgery. The median plasma concentration of IL-6 was 3.8 pg/mL (IQR, 2.3-6.2 pg/mL), sTNF-αR2 was 2 .9 × 103 pg/mL (IQR, 2.3-3.6 × 103 pg/mL) and 2.6 mg/L (IQR, 1.2-5.6 mg/L) for hsCRP. Patients in the highest quintile of inflammation had a significantly increased risk of relapse or death compared with patients in the lowest quintile of inflammation (adjusted hazard ratio for IL-6: 1.52 [95% CI, 1.07-2.14]; P = .01 for trend; for sTNF-αR2: 1.77 [95% CI, 1.23-2.55]; P < .001 for trend; for hsCRP: 1.65 [95% CI, 1.17-2.34] P = .006 for trend. Furthermore, no significant interaction was observed between biomarkers and celecoxib intervention for disease-free survival. Similar results were observed for recurrence-free survival and overall survival.
Conclusions and relevance This cohort study found that higher inflammation after diagnosis was significantly associated with poorer survival outcomes in patients with stage III colon cancer. This finding warrants further study to assess whether anti-inflammatory interventions can improve colon cancer outcomes.
参考文献 Reference
Cheng, E et al. JAMA Onc 2023; doi:10.1001/jamaoncol.2022.6911
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ctDNA分析相关于ripretinib与舒尼替尼在胃肠道间质瘤的疗效 (1/29/2023)
ctDNA analysis in relationship to efficacy of ripretinib vs sunitinib in GIST
Ripretinib 是一种开关控制酪氨酸激酶抑制剂 (TKI)，适用于既往接受过≥3 种 TKI（包括伊马替尼, Imatinib）治疗的胃肠道间质瘤 (GIST) 患者。 伊马替尼失败后，舒尼替尼 (Sunitinib) 被批准用于晚期 GIST。 循环肿瘤 DNA (ctDNA) 分析可以深入了解这些药物在二线晚期 GIST 中的疗效。
INTRIGUE (NCT03673501) 是一项开放标签的 3 期研究，招募了患有晚的成年患者，这些患者对伊马替尼有进展或不耐受。 患者随机分为 1：1 每天一次Ripretinib 150 mg 或舒尼替尼 50 mg （服用 4 周/停药 2 周）。 基线外周全血由 Guardant360 分析，这是一种基于 74 基因 ctDNA 下一代测序 (NGS) 的检测方法。 这里只报告了 KIT 突变。
结果： 在总体意向治疗人群的 453 名患者中，对 362 (80%) 个样本进行了分析。 在 280/362 (77%) 中检测到 ctDNA，在 213/280 (76%) 中检测到 KIT 突变。 常见的耐药突变位于 KIT 激活环（AL；外显子 17/18；89/213，42%）和 ATP 结合口袋（ATP-BP；外显子 13/14；81/213，38%）。 在 KIT 外显子 11 和整体意向治疗人群人群中检测到 ctDNA 的患者的疗效与基于用于随机化的肿瘤数据的初步分析一致。 具有 KIT 外显子 11 + 17/18 (−9/13/14) 突变的患者使用 ripretinib 与舒尼替尼相比具有更好的无进展生存期（14.2 vs 1.5 个月）,客观响应率（44.0 vs 0）和中位总生存期（不可估计 vs 17.5 个月，HR = 0.34），而外显子 11 + 13/14 (−9/17/18) 突变，舒尼替尼与ripretinib相比具有更好的无进展生存期（15.0 对 4.0个月）, 客观响应率（15.0 对 9.5）和中位总生存期（不可估计对 24.5个月，HR=0.25）。亚组安全概况与主要分析一致。
结论：这项研究证明了基于 ctDNA NGS 的 KIT 突变测序的价值，以预测 ripretinib 或舒尼替尼作为晚期 GIST 患者的二线治疗的临床益处。
Ripretinib is a switch-controlled tyrosine kinase inhibitor (TKI) indicated for patients with gastrointestinal stromal tumor (GIST) who have been previously treated with ≥3 TKIs, including imatinib. After progression on imatinib, sunitinib was approved for advanced GIST. Circulating tumor DNA (ctDNA) analysis can provide insight into the efficacy of these agents in second-line advanced GIST.
INTRIGUE (NCT03673501) is an open-label phase 3 study enrolling adult patients with advanced disease who had progressed on or were intolerant to imatinib. Patients were randomized 1:1 to daily ripretinib 150 mg or sunitinib 50 mg once daily (4 weeks on/2 weeks off). Baseline peripheral whole blood was analyzed by Guardant360, a 74-gene ctDNA next-generation sequencing (NGS)-based assay. Only KIT mutations are analyzed here.
Results: Of the 453 patients in the overall intent-to-treat population, 362 (80%) samples were analyzed. ctDNA was detected in 280/362 (77%) and KIT mutations in 213/280 (76%). Common resistance mutations were located in the KIT activation loop (AL; exons 17/18; 89/213, 42%) and the ATP-binding pocket (ATP-BP; exons 13/14; 81/213, 38%). Efficacy in patients with detectable ctDNA in KIT exon 11 and the overall intention-to-treat population was consistent with the primary analysis based on tumor data used for randomization. Patients with KIT exon 11 + 17/18 (−9/13/14) mutations had better progression-free survival (14.2 vs 1.5 months), objective response rate (44.0 vs 0), and median overall survival (not estimable vs 17.5 months, HR = 0.34), with ripretinib compared with sunitinib, whereas those with exon 11 + 13/14 (−9/17/18) mutations, sunitinib had better progression-free survival (15.0 vs 4.0), objective response rate (15.0 vs 9.5) and median overall survival (not estimable vs 24.5, HR=0.25) compared with ripretinib. The subgroup safety profiles were consistent with the primary analysis.
Conclusions: This study demonstrates the value of ctDNA NGS-based sequencing of KIT mutations to predict the clinical benefit of ripretinib or sunitinib as second-line therapy in patients with advanced GIST.
参考文献 Reference
Bauer S et al. J Clin Oncol 2023; 41: suppl. 36 abstr 397784
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Zanubrutinib用于慢性淋巴细胞白血病/小淋巴细胞淋巴瘤 (1/28/2023)
Zanubrutinib for chronic lymphocytic leukemia/small lymphocytic lymphoma
2023年1月19日FDA批准zanubrutinib（Brukinsa）用于治疗慢性淋巴细胞白血病或小淋巴细胞淋巴瘤患者。
对初治患者的试验（SEQUOIA）: 在包含无 17p 缺失患者的随机队列中，共有 479 名患者按 1:1 随机分配至接受 zanubrutinib 直至疾病进展或出现不可接受的毒性，或接受苯达莫司汀（bendamustine）加利妥昔单抗治疗六个周期。 主要疗效结果指标是由独立审查委员会确定的无进展生存期。 Zanubrutinib 组尚未达到中位无进展生存期（95% 置信区间 [CI] = 不可评估至不可评估），苯达莫司汀加利妥昔单抗组为 33.7 个月（95% CI = 28.1 个月至不可评估）（ 风险比 [HR] = 0.42，95% CI = 0.28–0.63，P ≤ .0001）。 估计无进展生存期的中位随访时间为 25.0 个月。 在 SEQUOIA 的一个单独的非随机队列中，zanubrutinib 在 110 名先前未治疗的 CLL/SLL 和 17p 缺失患者中进行了评估。 每个独立审查委员会的总体响应率为 88%（95% CI = 81%–94%）。 在中位随访 25.1 个月后，未达到中位响应持续时间。
对复发或难治性患者的试验（ALPINE）: 共有 652 名患者按 1:1 的比例随机分配接受 zanubrutinib 或 ibrutinib。 既往治疗线的中位数为 1（范围 = 1–8）。 主要疗效结果是总体响应率和响应持续时间。 Zanubrutinib 组的总响应率为 80%（95% CI = 76%–85%），而伊布替尼组的总反应率为 73%（95% CI = 68%–78%）（响应率比 = 1.10，95% CI） = 1.01–1.20，P = .0264）。 在中位随访 14.1 个月后，两组均未达到中位响应持续时间。
在 zanubrutinib 的临床试验中，最常见的不良反应（发生在 ≥ 30% 的患者中）是中性粒细胞计数减少 (42%)、上呼吸道感染 (39%)、血小板计数减少 (34%)、出血 (30%) ), 和肌肉骨骼疼痛 (30%)。 13% 的患者发生第二原发性恶性肿瘤，包括非皮肤癌。 3.7% 的患者报告心房颤动或扑动，0.2% 的患者发生 3 级或更高级别的室性心律失常。
推荐的 zanubrutinib 剂量为 160 mg，每天口服两次或 320 mg，每天口服一次，直至疾病进展或出现不可接受的毒性。
On January 19, 2023, FDA approved zanubrutinib (Brukinsa) for the treatment of patients with chronic lymphocytic leukemia or small lymphocytic lymphoma.
Trial in treatment-naïve patients (SEQUOIA): In this randomized cohort of patients without the 17p deletion, a total of 479 patients were randomized 1:1 to receive zanubrutinib until disease progression or unacceptable toxicity, versus bendamustine plus rituximab for six cycles. The primary efficacy outcome measure was progression-free survival as determined by an independent review committee. Median progression-free survival had not yet been reached with Zanubrutinib (95% confidence interval [CI] = not evaluable to not evaluable), compared with 33.7 months for bendamustine plus rituximab (95% CI = 28.1 months) (hazard ratio [HR] = 0.42, 95% CI = 0.28–0.63, P ≤ .0001). The median follow-up time for estimated progression-free survival was 25.0 months. In a separate nonrandomized cohort of SEQUOIA, zanubrutinib was evaluated in 110 patients with previously untreated CLL/SLL and 17p deletion. The overall response rate per independent review committee was 88% (95% CI = 81%–94%). After a median follow-up of 25.1 months, the median duration of response was not reached.
Trial in relapsed or refractory patients (ALPINE): A total of 652 patients were randomized 1:1 to receive zanubrutinib or ibrutinib. The median number of prior lines of therapy was 1 (range = 1–8). The primary efficacy outcomes were overall response rate and duration of response. The overall response rate was 80% (95% CI = 76%–85%) in the zanubrutinib arm and 73% (95% CI = 68%–78%) in the ibrutinib arm (response rate ratio = 1.10, 95% CI) = 1.01–1.20, P = .0264). After a median follow-up of 14.1 months, neither group reached the median duration of response.
In clinical trials of zanubrutinib, the most common adverse reactions (occurring in ≥ 30% of patients) were decreased neutrophil count (42%), upper respiratory tract infection (39%), decreased platelet count (34%), bleeding (30%) ), and musculoskeletal pain (30%). Second primary malignancies, including non-skin cancers, occurred in 13% of patients. Atrial fibrillation or flutter was reported in 3.7% of patients, and grade 3 or higher ventricular arrhythmias occurred in 0.2% of patients.
The recommended dose of zanubrutinib is 160 mg orally twice daily or 320 mg orally once daily until disease progression or unacceptable toxicity.
参考文献 Reference
https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-zanubrutinib-chronic-lymphocytic-leukemia-or-small-lymphocytic-lymphoma
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Atezolizumab 加贝伐单抗作为一线治疗具有高肿瘤突变负担的转移性非鳞状非小细胞肺癌(1/22/2023)
Atezolizumab plus bevacizumab as first-line therapy for metastatic non-squamous NSCLC with high tumor mutation burden
这是一项期多中心、单臂、开放标签的临床II试验, 招募38 名IIIB-IV 期的初治患者参加, 他们具有 > 10 个突变/兆碱基的 TMB 且无 EGFR、ALK、STK11、MDM2 或 ROS1 改变。 从 2019 年 5 月到 2021 年 1 月，在西班牙的 13 个地点对患者进行了评估，并随访至 2022 年 2 月 28 日。 在每 21 天周期的第 1 天，参与者接受 atezolizumab 1200 毫克 加贝伐珠单抗 15 毫克/公斤。 治疗一直持续到疾病进展,不可接受的毒性作用,患者退出,研究者决定或死亡。主要终点是 12 个月无进展生存期；定义为从入组到疾病进展或死亡的时间。38 名患者（28 名 [73.7%] 男性；平均年龄，63.7 [8.3] 岁）。
12 个月无进展生存率为 51.3%（95% CI，34.2%-66.0%），达到主要终点。 12 个月总生存率为 72.0%（95% CI，54.1%-83.9%）。中位无进展生存期为 13.0 个月（95% CI，7.9-18.0 个月），未达到中位总生存率。 38 例患者中，16 例（42.1%）取得客观响应，30 例（78.9%）取得疾病控制。 中位响应时间为 2.8 个月（IQR，2.8-3.58 个月），中位响应持续时间为 11.7 个月（范围，3.57-22.4 个月；响应在截止时持续）。 大多数不良事件为 1 级或 2 级。对于 atezolizumab，最常见的不良事件是疲劳 (6 [15.8%]) 和瘙痒 (6 [15.8%])。对于贝伐珠单抗，它们是高血压 (10 [26.3%]) 和蛋白尿 (4 [10.5%])。 2 名接受阿替利珠单抗治疗的患者 (5.3%) 和 3 名接受贝伐珠单抗治疗的患者 (7.9%) 停药。 PD-L1 水平与响应, 中位无进展生存期或总生存期无关。
结论: atezolizumab 联合贝伐珠单抗是高肿瘤突变负担的非鳞状非小细胞肺癌的潜在治疗方法。
This is a phase II, multicenter, single-arm, open-label clinical trial, that recruited 38 stage IIIB-IV treatment-naïve patients with TMB > 10 mutations/megabase and no EGFR, ALK, STK11 , MDM2 or ROS1 mutations. Patients were recruited at 13 sites in Spain from May 2019 to January 2021 and followed until February 28, 2022. On Day 1 of each 21-day cycle, participants received atezolizumab 1200 mg plus bevacizumab 15 mg/kg. Treatment continued until disease progression, unacceptable toxic effects, patient withdrawal, investigators’ decision, or death. The primary endpoint was 12-month progression-free survival; defined as the time from enrollment to disease progression or death.
Thirty-eight patients (28 [73.7%] were men; median age, 63.7 [8.3] years). The 12-month progression-free survival rate was 51.3% (95% CI, 34.2%-66.0%), meeting the primary endpoint. The 12-month overall survival rate was 72.0% (95% CI, 54.1%-83.9%). Median progression-free survival was 13.0 months (95% CI, 7.9-18.0 months), and median overall survival was not reached. Of the 38 patients, 16 (42.1%) achieved an objective response and 30 (78.9%) achieved disease control. Median time to response was 2.8 months (IQR, 2.8-3.58 months), and median duration of response was 11.7 months (range, 3.57-22.4 months; response was ongoing at cutoff). Most adverse events were grade 1 or 2. For atezolizumab, the most common adverse events were fatigue (6 [15.8%]) and pruritus (6 [15.8%]). For bevacizumab, they were hypertension (10 [26.3%]) and proteinuria (4 [10.5%]). Drug discontinuation occurred in two patients (5.3%) who received atezolizumab and three patients (7.9%) who received bevacizumab. PD-L1 levels were not associated with response, median progression-free survival or overall survival.
Conclusions: Atezolizumab combined with bevacizumab is a potential treatment for nonsquamous NSCLC with high tumor mutation burden.
参考文献 Reference
Provendo M et al. JAMA Onc 2022; Dec. 15.
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FDA加速批准 tucatinib与曲妥珠单抗联合用于 RAS 野生型 HER2 阳性晚期结直肠癌 (1/21/2023)
FDA approved tucatinib in combination with Herceptin in wild type RAS and HER2-positive advanced stage colorectal cancer
在一项开放标签,多中心试验 MOUNTAINEER (NCT03043313) 中，对 84 名患者的疗效进行了评估。 患者必须患有 HER2 阳性, RAS 野生型、不可切除或转移性结直肠癌，并且之前接受过氟嘧啶、奥沙利铂、伊立替康和抗血管内皮生长因子单克隆抗体治疗。 肿瘤缺乏错配修复 (dMMR) 蛋白或微卫星不稳定性高 (MSI-H) 的患者也必须接受抗程序性细胞死亡蛋白-1 单克隆抗体。 之前接受过抗 HER2 靶向治疗的患者被排除在外。 患者接受口服 tucatinib 300 毫克，每天两次，曲妥珠单抗在第 1 周期的第 1 天以 8 毫克/公斤 的负荷剂量静脉内给药，随后在每21天（为一周期）接受维持剂量为 6 毫克/公斤。 患者接受治疗直至疾病进展或出现不可接受的毒性。 主要疗效指标是通过盲法独立中央审查评估的总体响应率和响应持续时间。
总体响应率为 38%（95% CI：28、49），中位响应持续时间为 12.4 个月（95% CI：8.5、20.5）。 最常见的不良事件（≥20%）是腹泻,疲劳,皮疹,恶心,腹痛,输液相关反应和发热。 最常见的实验室异常 (≥20%) 是肌酐升高,葡萄糖升高,ALT/AST 升高、血红蛋白降低, 胆红素升高,碱性磷酸酶升高,淋巴细胞减少,白蛋白减少,白细胞减少和钠减少。
FDA在 2023 年 1 月 19 日加速批准 tucatinib与曲妥珠单抗联合用于 RAS 野生型 HER2 阳性并在氟嘧啶,奥沙利铂和伊立替康为基础的化疗后进展的晚期结直肠癌，推荐的 tucatinib 剂量为 300 毫克，每天口服两次，与曲妥珠单抗联合使用，直至疾病进展或出现不可接受的毒性。
In an open-label, multicenter clinical trial MOUNTAINEER (NCT03043313), 84 patients were enrolled. Patients had to be HER2-positive, of RAS wild-type, unresectable or metastatic colorectal cancer and had been previously treated with fluoropyrimidines, oxaliplatin, irinotecan, and anti-vascular endothelial growth factor monoclonal antibodies. Patients whose tumors lack mismatch repair (dMMR) proteins or were microsatellite instability-high (MSI-H) must also receive anti-programmed cell death protein-1 monoclonal antibodies. Patients who had previously received anti-HER2 targeted therapy were excluded. Patients received tucatinib 300 mg orally twice daily and trastuzumab intravenously at a loading dose of 8 mg/kg on day 1 of cycle 1, followed by a maintenance dose of 6 mg/kg every 21 days. Patients were treated until disease progression or unacceptable toxicity. The major efficacy measures were overall response rate and duration of response assessed by blinded independent central review.
The overall response rate was 38% (95% CI: 28, 49), and the median duration of response was 12.4 months (95% CI: 8.5, 20.5). The most common adverse events (≥20%) were diarrhea, fatigue, rash, nausea, abdominal pain, infusion-related reactions, and pyrexia. The most common laboratory abnormalities (≥20%) were increased creatinine, increased glucose, increased ALT/AST, decreased hemoglobin, increased bilirubin, increased alkaline phosphatase, decreased lymphocytes, decreased albumin, leukopenia and decreased sodium.
On January 19, 2023 FDA granted accelerated approval of tucatinib in combination with trastuzumab for RAS wild-type, HER2-positive advanced colorectal cancer that has progressed after fluoropyrimidine, oxaliplatin, and irinotecan-based chemotherapy. Recommended Tucatinib dose was 300 mg orally twice daily in combination with trastuzumab until disease progression or unacceptable toxicity.
参考文献 Reference
https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-tucatinib-trastuzumab-colorectal-cancer
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Adagrasib 联合或不联合西妥昔单抗治疗 KRAS G12C 突变结直肠癌 (1/15/2023)
Adagrasib alone or plus cetuximab in colorectal cancer with mutated KRAS G12C
这是一项期临床 I-II 开放标签试验（NCT03785249），招募接受过多线治疗的 KRAS G12C 突变型转移性结直肠癌患者接受Adagrasib单药治疗（600 毫克，每天两次口服）或Adagrasib（相同剂量）与 每周一次静脉注射西妥昔单抗（初始负荷剂量为400 毫克/平方米，随后剂量为250 毫克/平方米）或每 2 周一次（剂量为500 毫克/平方米）。 主要终点是客观响应和安全性。
结果: 截至 2022 年 6 月 16 日，共有 44 名患者接受了Adagrasib，32 名患者接受了Adagrasib和西妥昔单抗的联合治疗，中位随访时间分别为 20.1 个月和 17.5 个月。 在单药治疗组（43 名可评估患者）中，19% 的患者报告有响应（95% 置信区间 [CI]，8 至 33）。 中位反应持续时间为 4.3 个月（95% CI，2.3 至 8.3），中位无进展生存期为 5.6 个月（95% CI，4.1 至 8.3）。 在联合治疗组（28 名可评估患者）中，响应率为 46%（95% CI，28 至 66）。 中位反应持续时间为 7.6 个月（95% CI，5.7 至不可估计），中位无进展生存期为 6.9 个月（95% CI，5.4 至 8.1）。 单药治疗组 3 级或 4 级治疗相关不良事件的百分比为 34%，联合治疗组为 16%。 未观察到 5 级不良事件。
结论: Adagrasib 在接受过多线治疗的 KRAS G12C 突变型转移性结直肠癌患者中具有抗肿瘤活性，无论是作为口服单一疗法还是与西妥昔单抗联合使用。 联合治疗组的中位响应持续时间超过 6 个月。不良事件在两组中都常见及可逆。
This is a phase I-II open-label trial (NCT03785249), enrolling patients with KRAS G12C-mutant metastatic colorectal cancer patients, who had received multiple lines of prior therapy, to receive either adagrasib monotherapy (600 mg orally twice daily) or adagrasib ( same dose) with intravenous cetuximab once weekly (initial loading dose of 400 mg/m2 followed by 250 mg/m2) or every 2 weeks (500 mg/m2). The primary endpoints were objective response and safety.
Results: As of June 16, 2022, a total of 44 patients had received adagrasib and 32 patients had received a combination of adagrasib and cetuximab, with median follow-ups of 20.1 and 17.5 months, respectively. In the monotherapy arm (43 evaluable patients), 19% of patients reported a response (95% confidence interval [CI], 8 to 33). The median duration of response was 4.3 months (95% CI, 2.3 to 8.3), and the median progression-free survival was 5.6 months (95% CI, 4.1 to 8.3). In the combination arm (28 evaluable patients), the response rate was 46% (95% CI, 28 to 66). The median duration of response was 7.6 months (95% CI, 5.7 to not estimable), and the median progression-free survival was 6.9 months (95% CI, 5.4 to 8.1). The percentage of grade 3 or 4 treatment-related adverse events was 34% in the monotherapy arm and 16% in the combination arm. No grade 5 adverse events were observed.
Conclusions: Adagrasib has antitumor activity in patients with KRAS G12C-mutant metastatic colorectal cancer who have received multiple lines of therapy, either as oral monotherapy or in combination with cetuximab. The median duration of response in the combination arm was more than 6 months. Adverse events were common and reversible in both groups.
参考文献 Reference
Yeger R et al. N Engl J Med 2023; 388: 44
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针对 MAGE-A4+ 的自体 T 细胞疗法治疗HLA-A*02+实体癌患者 (1/14/2023) Autologous T cell therapy for MAGE-A4+ solid cancers in HLA-A*02+ patients
T 细胞受体疗法，如 afamiresgene autoleucel，可以靶向通常在细胞内发现的蛋白质。 使用 T 细胞的天然受体，这种类型的疗法可以识别与细胞表面免疫相关蛋白结合的蛋白质片段, 如MAGE-A4（melanoma-associated antigen A4）。
这是一项I期临床试验（NCT03132922），共有 38 名平均接受过 3 线治疗的患者接受了 afamitresgene autoleucel 治疗。 58% 为男性，92% 为白人； 其余为亚洲人。 该研究包括 16 名滑膜肉瘤患者； 9 名患有卵巢癌； 3 名患有头颈癌；食管癌、非小细胞肺癌、尿路上皮癌和粘液样/圆形细胞脂肪肉瘤各 2 例； 胃癌和黑色素瘤各 1 例。 所有患者都经历了与治疗相关的≥3 级血液学 不良事件: 55% 的患者（90% ≤ 2 级）出现细胞因子释放综合征; 最常见的是淋巴细胞减少症、白细胞减少症、中性粒细胞减少症、贫血和血小板减少症。 45% 的患者 (n = 17) 在 afamitresgene autoleucel 治疗后 4 周持续出现长期血细胞减少。 有两例发现生与试验相关的死亡，这导致筛选时的最大年龄降低和大剂量环磷酰胺淋巴细胞清除方案的停止使用。
所有患者的中位反应持续时间为 26 周，滑膜肉瘤亚组为 28 周。 这些发现在滑膜肉瘤患者亚组中尤其值得注意，在这些亚组中，接受 afamitresgene autoleucel 治疗的患者有 44% 的客观响应率，而所有癌症类型的总体响应率为 24%——这导致了一项正在进行的研究 II 期试验进一步检查 afamitresgene autoleucel 治疗晚期滑膜肉瘤或粘液样/圆细胞脂肪肉瘤患者的疗效。
这些早期结果证明了多种实体瘤新型细胞治疗方法的概念验证。Afamitresgene autoleucel 具有干扰素-γ 驱动的作用机制并触发适应性免疫反应。总体毒性是可控的。
T cell receptor therapies, such as afamitresgene autoleucel, target proteins normally found inside cells. Using T cells’ natural receptors, this type of therapy recognizes protein fragments that bind to immune-related proteins on the cell surface, such as MAGE-A4 （melanoma-associated antigen A4） in this case.
This is a phase I clinical trial （NCT03132922）. A total of 38 patients who had received an average of 3 prior lines of therapy received afamitresgene autoleucel. 58% were male, 92% were white; the remainder were Asian. The study included 16 patients with synovial sarcoma; 9 with ovarian cancer; 3 with head and neck cancer; 2 each with esophageal, non-small cell lung, urothelial, and myxoid/round cell liposarcoma; and 1 case of melanoma. All patients experienced treatment-related grade ≥3 hematologic adverse events: 55% of patients (90% Grade ≤2) experienced cytokine release syndrome; most commonly lymphopenia, leukopenia, neutropenia, anemia, and thrombocytopenia. Long-term cytopenias persisted 4 weeks after afamitresgene autoleucel treatment in 45% of patients (n = 17). Two trial-related deaths were found, which resulted in a reduction in the maximum age at screening and discontinuation of the high-dose cyclophosphamide lymphodepletion regimen.
The median duration of response was 26 weeks for all patients and 28 weeks for the synovial sarcoma subgroup. These findings were particularly noteworthy in the subgroup of patients with synovial sarcoma, in which patients treated with afamitresgene autoleucel had an objective response rate of 44%, compared with an overall response rate of 24% for all cancer type. This has led to an ongoing phase II trial that further examines the efficacy of afamitresgene autoleucel in patients with advanced synovial sarcoma or myxoid/round cell liposarcoma.
These early results demonstrate a proof-of-concept for a novel cell therapy approach for multiple solid tumors. Afamitresgene autoleucel has an interferon-γ-driven mechanism of action and triggers adaptive immune responses. The overall toxicity was manageable.
参考文献 Reference
Hong DS et al. Nature Med 2023; Jan 9
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Patritumab deruxtecan 在表达 HER3 的转移性乳腺癌患者中的研究结果 (1/8/2023)
Results of a clinical trial using Patritumab deruxtecan in HER3-expressing metastatic breast cancer
Patritumab deruxtecan (HER3-DXd) 是一种新型的研究性抗体药物偶联物，由人类抗 HER3 单克隆抗体组成，与拓扑异构酶 I 抑制剂有效负载共价结合。
方法：U31402-A-J101 （NCT02980341） 是一项临床1/2 期、多中心、开放标签、首次人体研究, 对表达 HER3 的转移性乳腺癌患者（n = 182）进行的 HER3-DXd研究。招募了剂量递增 (3.2-8.0 mg/kg 每3星期静脉给药) 和跨分子亚型的剂量探索部分的患者（n = 66；包括 HER2+ 转移性乳腺癌患者，n = 14），随后在以下亚型中进行剂量扩展： HER3 高 (4.8 mg/kg [n = 33] 或 6.4 mg/kg [n = 31])，HER3 低 (6.4 mg/kg [n = 21]) 雌激素受体+/HER2- 转移性乳腺癌 或 HER3高的三阴性乳腺癌 (6.4 mg/kg [n = 31]）。 HER3高被定义为≥75%, HER3低被定义为25% ‒ < 75% 的膜阳性。 主要目标是评估安全性和有效性; 次要目标包括确定疗效和 HER3 表达之间的关系。
结果：在数据截止时（2021 年 8 月 16 日），中位研究持续时间为 31.9 个月（范围，15-56）。 中位年龄为 57 岁（范围 30-83）。患者之前接受的局部晚期/转移性疾病治疗线的中位数为 5（范围，1-13）。 HER3-DXd 的中位治疗持续时间为 5.9 个月（范围，0.7-30.6）。总体而言，130 名患者 (71.4%) 的治疗相关的副作用等级≥3； 最常见的 (≥15%) 是中性粒细胞计数减少 (39.6%)、血小板计数减少 (30.8%)、贫血 (18.7%) 和白细胞计数减少 (18.1%)。 根据中央裁定，12 名患者 (6.6%) 经历了与治疗相关的间质性肺病，包括 1 起 5 级事件。 在剂量递增/发现和扩展的汇总评估中, 没有完全响应。在雌激素受体+/HER2-, HER3高/低患者（n = 113, 所有剂量）中, 部分响应和病情稳定分别为34(30.1) 和57 (50.4); 在HER3高的三阴性乳腺癌患者（n = 53, 所有剂量）中, 部分响应和病情稳定分别为12(22.6) 和30 (56.6); 在HER3高的HER2+乳腺癌患者（n = 14, 所有剂量）中, 部分响应和病情稳定分别为6(42.9) 和7 (50) 。 在这三组中，中位响应持续时间分别为7.2 (5.3-未达到), 5.9 (3.0-8.4) 和8.3 (2.8-26.4) 。
结论：在这个经过大量治疗的人群中进行的汇总分析显示，在雌激素受体+/HER2- 和 HER2+ 转移性乳腺癌以及三阴性乳腺癌患者中具有良好的疗效, 并显示出足够的安全性和耐受性。
本栏编辑:: HER3是ERBB 家族一员, 包括表皮生长因子受体 (EGFR)，ERBB2/HER2/Neu、ERBB3/HER3 和 ERBB4/HER4。由于HER3在肿瘤中的表达相对较低，它的治疗潜力长期以来一直被低估。近年来受到关注，因为它具有调节 EGFR/HER2 介导的耐药性的潜力, 对治疗失败有影响（通过激活 PI3K/AKT、MAPK/ERK 和 JAK/STAT 通路）。HER3 的上调与多种恶性肿瘤相关，它通过与不同受体酪氨酸激酶的相互作用促进肿瘤进展。
Patritumab deruxtecan (HER3-DXd) is a novel investigational antibody-drug conjugate consisting of a human anti-HER3 monoclonal antibody covalently attached to a topoisomerase I inhibitor payload.
Methods: U31402-A-J101 (NCT02980341) is a phase 1/2, multicenter, open-label, first-in-human study of HER3-DXd in patients with HER3-expressing metastatic breast cancer (n = 182). Patients were enrolled in a dose-escalation (3.2-8.0 mg/kg IV every 3 weeks) and dose-finding portion across molecular subtypes (n = 66; including patients with HER2+ metastatic breast cancer, n = 14), followed by dose expansion which was performed in subtypes: HER3 high (4.8 mg/kg [n = 33] or 6.4 mg/kg [n = 31]), HER3 low (6.4 mg/kg [n = 21]) ER+/ HER2-metastatic breast cancer or HER3-high triple-negative breast cancer (6.4 mg/kg [n = 31]). HER3 high was defined as ≥75% and HER3 low was defined as 25% ‒ <75% of membrane positivity. Primary objectives were to assess safety and efficacy; secondary objectives included determining the relationship between efficacy and HER3 expression.
Results: At data cutoff (August 16, 2021), the median study duration was 31.9 months (range, 15-56). Median age was 57 years (range 30-83). Patients had received a median of 5 (range, 1-13) lines of prior treatment for locally advanced/metastatic disease. The median treatment duration for HER3-DXd was 5.9 months (range, 0.7-30.6). Overall, 130 patients (71.4%) had grade ≥3 treatment-related side effects; the most common (≥15%) were decreased neutrophil count (39.6%), decreased platelet count (30.8%), anemia ( 18.7%) and decreased white blood cell count (18.1%). According to central adjudication, 12 patients (6.6%) experienced treatment-related interstitial lung disease, including 1 grade 5 event. There were no complete responses at the pooled assessment of dose escalation/discovery and expansion. In estrogen receptor+/HER2-, HER3 high/low patients (n = 113, all doses), partial response and stable disease were 34 (30.1) and 57 (50.4); in HER3-high triple-negative breast cancer patients (n = 53, all doses), partial response and stable disease were 12 (22.6) and 30 (56.6); in HER3-high HER2+ breast cancer patients (n = 14, all doses), partial response and stable disease were 6 (42.9) and 7 (50), respectively. In the three groups, the median duration of response was 7.2 months (5.3-not reached), 5.9 (3.0-8.4) and 8.3 (2.8-26.4), respectively.
Conclusions: Pooled analysis in this heavily treated population showed favorable efficacy and demonstrated an adequate safety profile in patients with estrogen receptor+/HER2-, HER2+ and triple-negative metastatic breast cancer patients with good tolerance.
Editor of this column: HER3 is a member of the ERBB family, including epidermal growth factor receptor (EGFR), ERBB2/HER2/Neu, ERBB3/HER3 and ERBB4/HER4.Due to the relatively low expression of HER3 in tumors, its therapeutic potential has long been underestimated.It has received attention in recent years because of its potential to modulate EGFR/HER2-mediated drug resistance, with implications for treatment failure (via activation of PI3K/AKT, MAPK/ERK, and JAK/STAT pathways).Upregulation of HER3 is associated with a variety of malignancies, and it promotes tumor progression through interactions with different receptor tyrosine kinases.
参考文献 Reference
Krop IE et al. J Clin Onc 2022; 40 (16)_suppl 1002
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口服米诺地尔用于治疗化疗后的晚期脱发 (1/7/2023)
Oral Minoxidil treating late alopecia following chemotherapy
晚期脱发定义为细胞毒性化疗或内分泌治疗后 6 个月以上的不完全毛发再生, 据报道，这发生在多达 25-30% 的患者中, 它与生活质量下降和癌症治疗剂量强度降低有关。米诺地尔可导致血管舒张和静息毛囊进入生长期。
方法：这项研究回顾性评估了在 2018 年 1 月至 2021 年 5 月期间在肿瘤学转诊计划中接受口服米诺地尔（每天 1.25 毫克）治疗的所有晚期脱发女性。 通过标准化摄影（4 个视图）和毛发镜检查（HairMetrix，Canfield Scientific，Inc.）评估结果。 毛发镜检查在均匀的额叶和枕骨目标区域（分别距离眉间 12 厘米和 36 厘米中线）记录头发密度（头发数量/cm2）和头发厚度（轴径）。 使用 CTCAE v5.0 记录和分级不良事件。 描述性统计用于总结患者的人口统计学和临床特征。 使用配对 t 检验估计从基线到随访的毛发镜测量值的变化。
结果：216 名患者（平均年龄 57.8±13.7）被纳入分析。 31 例 (14%) 仅接受化疗，65 例 (30%) 接受内分泌单药治疗，120 例 (56%) 接受化疗后进行内分泌治疗。 大多数患者 (n = 170, 79.1%) 有乳腺癌病史。 口服米诺地尔中位数 105 天（IQR = 70）后的标准化摄影评估（n = 119）显示 88 人（74%）的临床改善。 中位数 91 天 (IQR = 126) 后的毛发检查评估 (n = 42) 显示额毛密度增加（124.2 对 153.2 根头发/cm2，p = 0.008）和枕部毛发密度（100.3 对 123.5 根头发/cm2，p = 0.004 ). 平均额叶或枕骨毛发厚度在统计学上没有显著差异（分别为 69.3 和 67.3 μm，p = 0.22，以及 70.3 和 69.9 μm，p = 0.84）。
没有患者报告因不良反应而停止口服米诺地尔。
结论：口服米诺地尔可能有益于接受细胞毒性和/或内分泌治疗的患者的额叶和枕叶晚期脱发。 该方案被患者很好地耐受。 需要进行前瞻性对照研究来证实这些观察结果。
Late alopecia is defined as incomplete hair regrowth more than 6 months after cytotoxic chemotherapy or endocrine therapy, which has been reported in up to 25-30% of patients, and it is associated with decreased quality of life and reduced dose intensity of cancer therapy. Minoxidil causes vasodilation and entry of resting hair follicles into growth.
Methods: This study retrospectively evaluated all women with advanced alopecia treated with oral minoxidil (1.25 mg per day) in an oncology referral program between January 2018 and May 2021. Results were evaluated by standardized photography (4 views) and trichoscopy (HairMetrix, Canfield Scientific, Inc.). Trichoscopic examination recorded hair density (number of hairs/cm2) and hair thickness (shaft diameter) at uniform frontal and occipital target areas (12 cm from the brow and 36 cm from the midline, respectively). Adverse events were recorded and graded using CTCAE v5.0. Descriptive statistics were used to summarize the demographic and clinical characteristics of the patients. Changes in trichoscopic measurements from baseline to follow-up were estimated using paired t-tests.
Results: 216 patients (median age 57.8±13.7) were included in the analysis. Thirty-one patients (14%) received chemotherapy alone, 65 patients (30%) received endocrine monotherapy, and 120 patients (56%) received chemotherapy followed by endocrine therapy. Most patients (n = 170, 79.1%) had a history of breast cancer. Standardized photographic assessment (n = 119) after a median of 105 days (IQR = 70) of oral minoxidil showed clinical improvement in 88 (74%). Trichoscopic assessment (n = 42) after a median of 91 days (IQR = 126) showed increased frontal (124.2 vs 153.2 hairs/cm2, p = 0.008) and occipital (100.3 vs 123.5 hairs/cm2, p = 0.004 ). There was no statistically significant difference in average frontal or occipital hair thickness (69.3 and 67.3 μm, p = 0.22, and 70.3 and 69.9 μm, p = 0.84, respectively).
No patient reported discontinuing oral minoxidil due to adverse effects.
Conclusions: Oral minoxidil may be beneficial for advanced frontal and occipital alopecia in patients receiving cytotoxic and/or endocrine therapy. This regimen was well tolerated by patients. Prospective controlled studies are needed to confirm these observations.
参考文献 Reference
Kuo, A MS et al. J Clin Onc 2022; 40 (16)_ suppl
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第一个MYC 靶向疗法Omomyc完成 I 期临床试验 (1/1/2023)
The first MYC-targeted inhibitor completed phase I trial
MYC 是一种致癌基因, 与驱动和维持癌症有关。Omomyc (OMO-103) 是一种治疗性微型蛋白质。已经在小鼠模型中展示了这种新型细胞穿透微型蛋白的临床前疗效和安全性。
这项 I 期临床试验招募了 22 名患者参加，以确定 OMO-103 的安全性,耐受性,药代动力学和药效学以及概念验证。 这些接受过至少三种治疗治疗的患者, 患多种实体瘤，包括胰腺癌、肠癌和非小细胞肺癌。 最常见的治疗相关不良事件包括对静脉输液的轻度反应，如寒战、发烧、恶心、皮疹和低血压。 更高的剂量水平与更多的输液反应有关，但很容易治疗。 该研究的另一个重要方面侧重于评估 OMO-103 的药代动力学，并确定该药物在体内的吸收和加工方式，以及它在肿瘤中的停留时间。 分析表明 OMO-103 在血液中至少可保留 50 小时，在肿瘤中的保留时间可能更长。
17 名可评估患者的 CT 扫描结果显示，8 名病情稳定，治疗阻止了肿瘤生长。值得注意的是，一名胰腺癌患者在研究中持续了六个月以上，他的肿瘤缩小了 8%，血液中循环肿瘤 DNA 的数量减少了 83%。另一名唾液腺肿瘤患者在 15 个月后仍在治疗中，其疾病保持稳定，而另一名肉瘤患者此前对其他治疗响应非常差，其病情稳定了 8 个月。
MYC致癌蛋白一直被认为是不可药治的。 OMO-103 是第一个成功完成 I 期临床试验的 MYC 抑制剂，并准备在未来进入 II 期研究。
MYC is an oncogene implicated in driving and maintaining cancer growth. Omomyc (OMO-103) is a therapeutic peptides. The preclinical efficacy and safety of this novel cell-penetrating peptides has been demonstrated in mouse models.
The phase I clinical trial enrolled 22 patients to determine the safety, tolerability, pharmacokinetics and pharmacodynamics of OMO-103 as well as proof of concept. These patients, who had received at least three lines of therapy, had a variety of solid tumors, including pancreatic, bowel, and non-small cell lung cancer. The most common treatment-related adverse events included mild reactions to intravenous injections such as chills, fever, nausea, rash, and hypotension. Higher dose levels were associated with more infusion reactions, but were easily manageable. Another important aspect of the study focused on assessing the pharmacokinetics of OMO-103 and determining how the drug is absorbed and processed in the body, as well as how long it stays in tumors. Analysis showed that OMO-103 was retained in blood for at least 50 hours and possibly longer in tumors.
CT scans of the 17 evaluable patients showed stable disease in eight, implicating treatment stopped tumor growth. Of note, one pancreatic cancer patient remained in the study for more than six months. He had 8% reduction in tumor size and 83% reduction in the amount of circulating tumor DNA in the blood. Another patient with a salivary gland tumor remained on treatment for 15 months with stable disease, while another patient with sarcoma who had previously responded very poorly to other treatments had stable disease for 8 months.
MYC has long been considered undruggable. OMO-103 is the first MYC inhibitor to successfully complete phase I clinical trials and is poised to enter Phase II studies in the future.