NanoTherm 治疗中危前列腺癌 (12/26/2021)
NanoTherm therapy for intermediate-risk prostate cancer
根据药公司宣布, 一项使用 NanoTherm 治疗系统对中危前列腺癌进行局灶性消融的 2b 阶段的临床试验. 已为FDA 批准, 将招募 100 名被诊断患有中度风险前列腺癌且已发展到需要进行临床审查和治疗的男性。第 2b 阶段建立在早期研究的结果之上，这些结果证明了安全性和有效性，而且没有其他疗法经常遇到的与治疗相关的副作用，例如性,泌尿或胃肠功能障碍或能量损失。
NanoTherm 治疗系统通过激活超顺磁性纳米粒子在肿瘤内产生热量，从而实现对实体瘤的靶向治疗。 单臂研究的第 2b 阶段计划评估 NanoTherm 消融在治疗中级病变的前列腺癌患者中的应用，并在更大的患者群体中确认第 2a 阶段看到的有利结果。旨在证明 NanoTherm 治疗系统可以最小的副作用局部消融靶向前列腺癌病变。随后，患可以在没有确定性治疗（例如外照射或前列腺切除术）的情况下恢复主动监测。
A drug company has announced that FDA approved a phase 2b clinical trial of focal ablation of intermediate-risk prostate cancer using the NanoTherm treatment system. The trial plans to recruit 100 patients diagnosed with intermediate-risk prostate cancer and they need clinical review and treatment. Phase 2b builds on the results of earlier studies that have demonstrated safety and effectiveness without treatment-related side effects often encountered with other therapies, such as sexual, urinary or gastrointestinal dysfunction or energy loss.
The NanoTherm treatment system activates superparamagnetic nanoparticles to generate heat in the tumor, thereby achieving targeted therapy for solid tumors. Phase 2b of the single-arm study plans to evaluate the use of NanoTherm ablation in the treatment of prostate cancer patients with intermediate-risk disease and confirm in a larger patient population the favorable results seen in phase 2a. It aims to prove that the NanoTherm treatment system can target prostate cancer lesions by local ablation with minimal side effects. Subsequently, these patients can resume active monitoring without definitive treatment (external beam radiation or prostatectomy).
参考文献 Reference U.S. Clinical trial: https://clinicaltrials.gov/ct2/show/NCT05010759 https://www.magforce.com/en/news/?article=325
Elacestrant 改善了转移性乳腺癌的无进展生存期 (12/25/2021)
Elacestrant improved progression-free survival in metastatic breast cancer
Elacestrant 是第一个口服选择性雌激素受体降解剂，在二线和三线环境中，ER 阳性/HER2 阴性转移性乳腺癌患者的无进展生存期有统计学意义和临床意义的改善，包括对于肿瘤携带 ESR1 突变的患者。
这是一项多中心, 开放标签III期临床试验（EMERALD），共有477 名 ER 阳性、HER2 阴性转移性乳腺癌的绝经后患者，这些患者在转移性环境中接受了一种或两种既往内分泌治疗而未接受化疗。所有患者均在先前的 CDK 4/6 抑制剂治疗中出现进展。 研究人员将 239 名患者随机分配到每天 400 毫克elacestrant。其他 238 人接受了标准护理（包括研究人员选择氟维司群或芳香酶抑制剂）。 研究人员根据 ESR1 突变状态（已确认，n = 228；未检测到，n = 249）, 先前的氟维司群治疗和内脏疾病的存在进行分层。 Elacestrant 和标准治疗组在中位年龄（63 岁与 63.5 岁）、ESR1 突变阳性状态（48.1% 与 47.4%）和接受过两种先前治疗的患者百分比（46%与40.8%）方面保持平衡。盲法独立审查委员会评估的ESR1 突变患者, 以及所有患者（无论 ESR1 突变状态如何）的无进展生存期，作为主要终点。总生存期, 安全性、耐受性和生活质量作为次要终点。
该研究达到了两个主要终点。所有患者（HR = 0.69；95% CI，0.55-0.88）和 ESR1 突变患者（HR = 0.54；95% CI，0.38-0.76）中，elacestrant 的疾病进展或死亡风险降低。 根据先前的治疗线数、内脏转移、先前的氟维司群治疗和地理区域，elacestrant 的益处在预先指定的关键亚组中持续存在。 12 个月无进展生存率在所有患者（22.3% 对 9.4%）和具有 ESR1 突变的患者（26.7% 对 8.1%）中更高。 一项预先指定的中位总生存期分析显示，所有患者（HR = 0.75；95% CI，0.54-1）和 ESR1 突变阳性组（HR = 0.59；95% CI，0.36-0.95）中都存在有利于 elacestrant 的趋势。最终的结果预计将在 2022 年。
Elacestrant 治疗组的治疗相关不良事件发生率与标准治疗组相比更高, 包括恶心（25.3% 对 8.7%）、呕吐（11% 对 2.6%）和疲劳（11% 对 7.9%）。这些事件中的大多数是 1 级或 2 级。 接受 elacestrant 治疗的 3 级或更高级别的治疗相关不良事件的患者人数大约是其两倍（7.2% 对 3.1%），其结果主要由恶心引起（2.1% 对 0.9%）。 治疗中出现的不良事件导致 6.3% 分配给 elacestrant 的患者和 4.4% 分配标准治疗的患者停止治疗。两组均未发生与治疗相关的死亡。
这项研究存在的局限性是所有入组的患者都接受了之前的 CDK 4/6 抑制剂治疗，因此对于未接受 CDK 4/6 抑制剂治疗的患者，elacestrant 的临床益处仍不清楚。
Elacestrant is the first oral selective estrogen receptor degrading agent, that showed statistically and clinically significant improvement in PFS in the second-line and third-line settings, in patients with ER-positive/HER2-negative metastatic breast cancer including patients with ESR1 mutations.
This is a multi-center, open-label phase III clinical trial (EMERALD) with a total of 477 postmenopausal patients with ER-positive and HER2-negative metastatic breast cancer. These patients received one or two previous endocrine therapies (without chemotherapy) in metastatic setting. All patients had progressed on previous CDK 4/6 inhibitor therapy. The researchers randomly assigned 239 patients to 400 mg of elacestrant per day. The other 238 people received standard care (including fulvestrant or aromatase inhibitor per researchers’ choice). They were stratified the ESR1 mutation status (confirmed, n = 228; undetected, n = 249), previous fulvestrant treatment and the presence of visceral disease. Elacestrant and the standard treatment group were balanced in terms of median age (63 years and 63.5 years), ESR1 mutation positive status (48.1% and 47.4%), and the percentage of patients who had received two previous treatments (46% and 40.8%). PFS in patients with ESR1 mutations and all patients (regardless of ESR1 mutation status was evaluated by the blinded independent review board, and used as the primary endpoint. Overall survival, safety, tolerability and quality of life were secondary endpoints.
The study reached two main endpoints. In all patients (HR = 0.69; 95% CI, 0.55-0.88) and patients with ESR1 mutations (HR = 0.54; 95% CI, 0.38-0.76), elacestrant achieved a reduced risk of disease progression or death. Based on the number of previous treatment lines, visceral metastases, previous fulvestrant treatment, and geographic area, the benefits of elacestrant persistrf in key pre-specified subgroups. The 12-month progression-free survival rate was higher in all patients (22.3% vs. 9.4%) and patients with ESR1 mutations (26.7% vs. 8.1%). A pre-specified median overall survival analysis showed that all patients (HR = 0.75; 95% CI, 0.54-1) and the ESR1 mutation-positive group (HR = 0.59; 95% CI, 0.36-0.95) revealed a trend in favor of elacestrant. The final results are anticipated in 2022.
The incidence of treatment-related adverse events in the elacestrant treatment group was higher than that in the standard treatment group, including nausea (25.3% vs. 8.7%), vomiting (11% vs. 2.6%), and fatigue (11% vs. 7.9%). Most of these events were level 1 or level 2. Approximately twice the number of patients with treatment-related adverse events of grade 3 or higher who received elacestrant (7.2% vs. 3.1%) was mainly caused by nausea (2.1% vs. 0.9%). Adverse events during treatment caused 6.3% of patients assigned to elacestrant and 4.4% of patients assigned to standard treatment to discontinue treatment. There were no treatment-related deaths in either group.
The limitation of this study is that all enrolled patients have received previous CDK 4/6 inhibitor treatment. So for patients who have not received CDK 4/6 inhibitor treatment, the clinical benefit of elacestrant is still unclear.
参考文献 Reference Bardia A et al. 2021 San Antonio Breast Cancer Symposium
派姆单抗加化疗对持续性、复发性或转移性宫颈癌的疗效 (12/19/2021)
Pembrolizumab plus chemotherapy in persistent, recurrent or metastatic cervical cancer
这是一项双盲III期临床试验（KEYNOE-826），患有持续性、复发性或转移性宫颈癌的患者，以 1:1 的比例随机分配每 3 周接受派姆单抗（200 mg）或安慰剂治疗，同时加铂类药物化疗，以及根据研究者的判断，联合或不联合贝伐珠单抗, 最多 35 个周期。双重主要终点是无进展生存期和总生存期，所有结果均来自方案指定的第一次中期分析。
结果: 在 548 名 PD-L1 综合阳性评分为 1 或更高的患者中，派姆单抗组的中位无进展生存期为 10.4 个月，安慰剂组为 8.2 个月（疾病进展或死亡的风险比为 0.62；95% CI, 0.50 至 0.77；P < 0.001)。在意向治疗人群中的 617 名患者中，无进展生存期分别为 10.4 个月和 8.2 个月（风险比，0.65；95% CI，0.53 至 0.79；P < 0.001）。在 317 名 PD-L1 综合阳性评分为 10 或更高的患者中，无进展生存期分别为 10.4 个月和 8.1 个月（风险比，0.58；95% CI，0.44 至 0.77；P < 0.001）。帕博利珠单抗组 24 个月时的总生存率为 53.0%，安慰剂组为 41.7%（死亡风险比，0.64；95% CI，0.50 至 0.81；P < 0.001）。
最常见的 3 至 5 级不良事件是贫血（派姆单抗组为 30.3%，安慰剂组为 26.9%）和中性粒细胞减少症（分别为 12.4% 和 9.7%）。
结论: 在同时接受化疗（联合或不联合贝伐单抗）的持续性, 复发性或转移性宫颈癌患者中，帕博利珠单抗的无进展生存期和总生存期显着长于安慰剂。
This is a double-blind phase III clinical trial (KEYNOE-826). Patients with persistent, recurrent or metastatic cervical cancer were randomly assigned at a ratio of 1:1 to receive pembrolizumab (200 mg) or placebo, plus platinum-based chemotherapy, and, with or without bevacizumab as per investors’ choice, up to 35 cycles. The dual primary endpoints were progression-free survival and overall survival. All results are from the first interim analysis specified by the protocol.
Results: Among 548 patients with a PD-L1 comprehensive positive score of 1 or higher, the median progression-free survival of the pembrolizumab group was 10.4 months, and that of the placebo group was 8.2 months (hazard ratio for risk of disease progression or death, 0.62; 95% CI, 0.50 to 0.77; P < 0.001). In 617 patients in the intention-to-treat population, progression-free survival was 10.4 months and 8.2 months, respectively (hazard ratio, 0.65; 95% CI, 0.53 to 0.79; P <0.001). Among 317 patients with a PD-L1 composite positive score of 10 or higher, progression-free survival was 10.4 months and 8.1 months, respectively (hazard ratio, 0.58; 95% CI, 0.44 to 0.77; P <0.001). Overall survival at 24 months was 53.0% in the pembrolizumab group and 41.7% in the placebo group (hazard ratio for death, 0.64; 95% CI, 0.50 to 0.81; P <0.001).
The most common grade 3 to 5 adverse events were anemia (30.3% in the pembrolizumab group and 26.9% in the placebo group) and neutropenia (12.4% and 9.7%, respectively).
Conclusion: In patients with persistent, recurrent or metastatic cervical cancer who received concurrent chemotherapy (with or without bevacizumab), both progression-free survival and overall survival with pembrolizumab were significantly longer than with placebo.
参考文献 Reference Columbo N. et al. NEJM 2021; 385: 1856
抗组胺药增加免疫疗法对癌症的效果 (12/18/2021)
Antihistamines drugs may influence efficacy of checkpoint inhibitor in cancer therapy
一项回顾性分析显示，在免疫治疗期间服用抗组胺药可提高癌症患者的生存率。在黑色素瘤或肺癌患者中，同时使用靶向组胺受体 H1 (HRH1) 的抗组胺药与生存改善相关。乳腺癌或结肠癌患者也表现出类似的趋势，尽管由于样本量相对较小，数据没有达到统计显著性。
研究者进而发现组胺和HRH1在肿瘤微环境中经常增加并诱导 T 细胞功能障碍。HRH1 激活的巨噬细胞转化为免疫抑制表型，导致 T 细胞功能失调。 抗组胺药治疗可恢复巨噬细胞免疫抑制，恢复 T 细胞的细胞毒功能，并恢复免疫治疗反应。过敏通过组胺-HRH1 轴促进小鼠和人类的肿瘤生长并诱导免疫治疗抵抗。研究人员还发现了癌症患者血浆组胺水平与免疫检查点抑制剂反应之间的相关性。这些发现表明组胺水平升高, 无论是过敏还是癌细胞的产生, 可能有助于抑制抗肿瘤反应。与血浆组胺水平高的患者相比，血浆组胺水平低的癌症患者对抗 PD-1 治疗的客观反应率高出三倍以上。这个发现值得前瞻性地探索抗组胺药作为组合免疫治疗的辅助剂。
A retrospective analysis showed that taking antihistamines during immunotherapy could improve survival of cancer patients. In patients with melanoma or lung cancer, simultaneous use of antihistamines targeting histamine receptor H1 (HRH1) was associated with improved survival. Patients with breast or colon cancer also showed a similar trend, although the data did not reach statistical significance due to the relatively small sample size.
The researchers found that histamine and HRH1 often increase in the tumor microenvironment and induce T cell dysfunction. Macrophages activated via HRH1 transform into an immunosuppressive phenotype, leading to dysfunction of T cells. Antihistamine treatment could restore macrophage immunosuppression, the cytotoxic function of T cells, and immunotherapy response. Allergy promotes tumor growth in mice and humans through the histamine-HRH1 axis and induces immunotherapy resistance. Researchers also found a correlation between plasma histamine levels in cancer patients and immune checkpoint inhibitor responses. These findings suggest that elevated levels of histamine, whether it is due to allergies or production by cancer cells, may help suppress anti-tumor responses. Compared with patients with high plasma histamine levels, cancer patients with low plasma histamine levels had more than three times the objective response rate to anti-PD-1 treatment. This finding is worthy of prospective studies of antihistamines as adjuvants in combination immunotherapy.
参考文献 Reference Li H et al. Cancer Cell 2021; Nov. 18 DOI: 10.1016/j.ccell.2021.11.002
Mirvetuximab soravtansine对耐铂类药卵巢癌的治疗 (12/12/2021)
Mirvetuximab soravtansine in platinum-refractory ovarian cancer
Mirvetuximab soravtansine (MIRV)是一种抗体-药物偶联物，包含结合叶酸受体α (FRα)的抗体和美登木素生物碱（maytansinoid） DM4，一种有效的微管蛋白靶向剂。 这是一项随机,开放标签,III期临床试验（FORWARD I）。旨在研究耐铂类药上皮性卵巢癌患者中MIRV相对于化疗的疗效。
接受过 1-3线先前治疗且其肿瘤对FRα表达呈阳性的患者以 2:1的比例随机分配接受MIRV（6mg/kg）或化疗（紫杉醇、脂质体多柔比星或拓扑替康）。主要终点是意向治疗人群和预先指定的FRα高人群（≥75%的肿瘤细胞在≤×10显微镜物镜下可见任何FRα膜染色）中的无进展生存期。 次要终点包括客观缓解率,总生存期和患者报告结果。
结果：共有366名患者被随机分组； 243人接受MIRV，109人接受化疗。主要终点无进展生存期在意向治疗人群[风险比 (HR)，0.98，P= 0.897]或 FRα 高人群（HR，0.69，P = 0.049）中均未达到统计学显着性。在FRα高人群的所有次要终点中均观察到MIRV优于化疗的结果，包括改善的客观反应率（24%对 10%）,CA-125反应（53%对 25%）和患者报告的结果（27%对 13%）。
与化疗相比，MIRV治疗相关的 3级或更高级别的不良事件更少（25.1%对 44.0%），导致剂量减少（19.8%对 30.3%）和治疗中断（4.5%对 8.3%）的事件更少。
结论：在耐铂类药的上皮性卵巢癌患者中，与化疗相比，MIRV并未显着改善无进展生存期。次要终点始终有利于 MIRV，尤其是在高 FRα表达的患者中。与化疗相比，MIRV显示出更易于管理的安全性。
Mirvetuximab soravtansine (MIRV) is an antibody-drug conjugate consisting of an antibody that binds to folate receptor alpha (FRα) and maytansinoid DM4, an effective tubulin targeting agent. This is a randomized, open label, phase III clinical trial (FORWARD I). The study was to evaluate the efficacy of MIRV compared to chemotherapy in patients with platinum-resistant epithelial ovarian cancer.
Patients who had received 1-3 lines of previous treatment and whose tumors were positive for FRα expression were randomly assigned to MIRV (6 mg/kg) or chemotherapy (paclitaxel, liposomal doxorubicin or topotecan) at a 2:1 ratio. The primary endpoint was progression-free survival in the intent-to-treat population and the pre-specified FRα high population (≥75% of tumor cells with any FRα membrane staining visible at ≤×10 microscope objective). Secondary endpoints included objective response rate, overall survival, and patient-reported outcome.
Results: A total of 366 patients were randomized; 243 received MIRV and 109 received chemotherapy. The primary endpoint of PFS did not reach statistical significance in the intention-to-treat population [hazard ratio (HR), 0.98, P = 0.897] or the FRα high population (HR, 0.69, P = 0.049). Superior results of MIRV compared with chemotherapy were observed in all secondary endpoints of patients with high FRα, including improved objective response rate (24% vs. 10%), CA-125 response (53% vs. 25%), and patient-reported outcome (27% vs. 13%).
Compared with chemotherapy, MIRV treatment had fewer grade 3 or higher adverse events (25.1% vs. 44.0%), fewer events of dose reduction (19.8% vs. 30.3%) and treatment interruptions (4.5% vs. 8.3%).
Conclusion: In patients with platinum-resistant epithelial ovarian cancer, MIRV did not significantly improve PFS compared with chemotherapy. Secondary endpoints favored MIRV, especially in patients with high FRα expression. Compared with chemotherapy, MIRV shows safety profile that was easier to manage.
参考文献 Reference Moore KN et al. Ann Onc 2021; 32; 757-765
个性化癌症疫苗用于胶质母细胞瘤 (12/11/2021)
A personalized cancer vaccine used in glioblastoma
一项II期研究结果显示，个性化癌症疫苗使一部分新诊断的胶质母细胞瘤患者获得了无进展生存期率的益处。这些患者除了标准的积极治疗外（包括手术切除，然后联合放疗和替莫唑胺（Temodar）），还接受了AV-GMB（一种自体疫苗）。该疫苗包含自体树突状细胞，其负载自体肿瘤相关抗原。
该研究在意向治疗的基础上招募了 60名患者（中位年龄为 59岁；范围为 29-70），患者在第 1、2、3、8、12、16、20和 24周接受皮下注射, 57名患者至少接受了一次注射。意向治疗入组后 14.6个月的总生存率为 75%或更高是该研究的主要终点。意向治疗入组和首次疫苗注射的无进展生存期率作为次要终点。 最短随访时间为 15.2个月。
研究人员报告了 16个月的意向治疗入组的中位总生存率（95%CI，13-21.3）。意向治疗入组的总生存率在 12个月时为 71.5%，在 18个月时为 44.2%，在 24个月时为 24.3%。与历史结果相比，该方案并未显着提高总生存期。意向治疗入组的中位无进展生存期为 10.3个月（95%CI，8.5-11.6）,比具有可比标准的随机临床试验报告的时间长约 50%。第一次注射疫苗的中位无进展生存期为 8.3个月（95%CI，6.5-9），比随机试验报告的时间长约 107%。研究中近四分之一的患者在治疗后 30个月或更长时间仍然存活。
安全性结果显示没有与疫苗接种相关的 3级或 4级治疗相关不良事件。最常见的疫苗相关不良事件包括注射部位反应 (15.8%)和流感样症状 (10.5%)。最常见的治疗相关不良事件包括疲劳 (54.4%)、头痛 (36.8%)和癫痫发作 (33%)。 研究人员表示，该研究中的癫痫发作率似乎高于使用可比标准治疗组的其他随机试验中观察到的癫痫发作率。研究者认为疫苗可能诱发了一种免疫反应，增加了肿瘤部位的炎症，并导致一些患者癫痫发作。
The results of a phase II study showed that a personalized cancer vaccines benefited some newly diagnosed glioblastoma patients in progression-free survival (PFS). These patients received AV-GMB (an autologous vaccine) in addition to standard active treatment (including surgical resection, followed by combined radiotherapy and temozolomide (Temodar)). The vaccine contains autologous dendritic cells loaded with autologous tumor-associated antigens.
The study recruited 60 intent-to-treat patients (median age 59 years; range 29-70). They received subcutaneous injections at 1, 2, 3, 8, 12, 16, 20, and 24 weeks. Fifty-seven patients received at least one injection. An overall survival rate of 75% or higher at 14.6 months after enrollment in the intent-to-treat group was the primary endpoint. PFS of intent-to-treat patients and those who receive first vaccination was used as a secondary endpoint. The shortest follow-up time was 15.2 months.
The researchers reported the 16-month median overall survival rate (95% CI, 13-21.3) of the intent-to-treat patients. It was 71.5% at 12 months, 44.2% at 18 months, and 24.3% at 24 months. Compared with historical results, this therapy did not significantly improve overall survival. The median PFS for the intent-to-treat group was 10.3 months (95% CI, 8.5-11.6), which was about 50% longer than the reported time in randomized clinical trials with comparable standards. The median PFS from the first vaccination group was 8.3 months (95% CI, 6.5-9), which was about 107% longer than the time reported in the randomized trial. Nearly a quarter of the patients in the study were still alive 30 months or more after treatment.
The safety data showed that there were no grade 3 or 4 treatment-related adverse events related to the vaccination. The most common vaccine-related adverse events included injection site reactions (15.8%) and flu-like symptoms (10.5%). The most common treatment-related adverse events included fatigue (54.4%), headache (36.8%), and seizures (33%). The seizure rate in this study appeared to be higher than that observed in other randomized trials using comparable standard treatment groups. Researchers thought that the vaccine may induce an immune response, which increased inflammation at the tumor site, and caused seizures in some patients.
参考文献 Reference Bota DA, et al. Soc for Immunotherapy of Cancer Ann Meeting 2021; abstr 331 & 952Piccioni DE, et al. Soc for Immunotherapy of Cancer Ann Meeting 2021; abstr 336
NC201 对复发性具有 H3 K27M 突变的弥漫性中线胶质瘤的疗效 (12/5/2021)
NC201 in treating relapsed diffuse midline glioma with H3 K27M mutation
H3 K27M 突变型弥漫性中线胶质瘤 (DMG) 主要影响儿童和年轻人。 ONC201 是同类药物中第一个抗癌的 DRD2 拮抗剂和 ClpP 激动剂。研究人员评估了ONC201在儿科和成年患者具有复发性H3 K27M突变的DMG 的安全性和有效性。
50 名患者（不包括脑桥和脊髓肿瘤）注册并在临床试验中接受口服 ONC201 单药治疗, 中位数患者年龄为30岁（范围，8-70岁），大多数（88％）患者已接受过先前的temozolomide治疗。主要终点是 RANO-HGG 标准的总体响应率。次要终点包括响应持续时间, 无进展生存期, 和总生存期。放射学终点通过双读者盲法独立中央审查进行评估。数据截止日期为 2021 年 5 月 31 日。中位随访时间为18.8个月。
根据RANO-HGG标准，总体响应率为 20.0%（95%CI：10.0-33.7%）。中位响应持续时间为 11.2个月（95%CI：3.8 -未达到），中位响应开始时间为 8.3个月（范围 1.9-15.9）。 6个月时的无进展生存期为 35.1%（95%CI：21.2-49.3%）。中位总生存期为 13.7个月（95%CI：8.0-20.3），24个月时的总生存期为 34.7%（95%CI：20.7-49.2%）。
有25名患者（50%）发生严重不良事件，其中一名患者可能与ONC201相关，肺栓塞被认为与治疗有关。
结论ONC201单一疗法在复发性H3 K27M突变型 DMG中表现出持久且具有临床意义的疗效。
H3 K27M mutant diffuse midline glioma (DMG) mainly affects children and young people. ONC201 is the first-in-class anti-cancer DRD2 antagonist and ClpP agonist. Researchers evaluated the safety and effecacy of ONC201 in pediatric and adult patients with recurrent H3 K27M mutant DMG.
Fifty patients (excluding pontine and spinal cord tumors) were registered and received oral ONC201 monotherapy in clinical trials. The median age was 30 years (range, 8-70 years), and most (88%) patients had received prior temozolomide treatment. The primary endpoint was overall response rate by RANO-HGG criteria. Secondary endpoints included response duration, time to response, progression-free survival, and overall survival. The radiology endpoints were evaluated by a dual-reader blinded independent central review. The data deadline was May 31, 2021. The median follow-up time was 18.8 months.
According to RANO-HGG criteria, the overall response rate was 20.0% (95% CI: 10.0-33.7%). The median response duration was 11.2 months (95% CI: 3.8-not reached), and median time to response was 8.3 months (range 1.9-15.9). Progression-free survival at 6 months was 35.1% (95% CI: 21.2-49.3%). Median overall survival was 13.7 months (95% CI: 8.0-20.3), and overall survival at 24 months was 34.7% (95% CI: 20.7-49.2%).
Twenty-five patients (50%) experienced serious adverse events. One of them may be related to ONC201. Pulmonary embolism was considered to be related to treatment.
Conclusion: ONC201 monotherapy shows long-lasting and clinically significant effects in recurrent H3 K27M mutant DMG.
参考文献 Reference Arrillaga-Romany I et al. Neuro-Oncol 2021; 23: Suppl_6, vi230
Ibrutinib与利妥昔单抗联合作为第一线治疗老年套细胞淋巴瘤 (12/4/2021)
Ibrutinib and rituximab combination as first-line chemotherapy-free regime for elderly mantel cell lymphoma
多数套细胞淋巴瘤（mantel cell lymphoma）患者是老年人。这项II期临床试验（NCT01880567）研究了Ibrutinib与利妥昔单抗联合初治老年患者（年龄≥65岁）的疗效和安全性。
该试验入选50例套细胞淋巴瘤患者。Ki-67％≥50％和母细胞（blastoid）形态的患者被排除。Ibrutinib与利妥昔单抗治疗长达2年，然后,Ibrutinib单独继续治疗。试验主要目的是总响应率和安全性。在可评估的样品中，进行了全外显子组从基线组织样品测序和RNA测序。患者中位年龄为71岁。 16％的患者有高风险的简化套细胞淋巴瘤的国际预后指数。有38位患者（76％）的Ki-67是低的％（<30％）,有12位患者（24％）的Ki-67中度增高（≥30％-50％）。 总响应率为96％（71％完全缓解）。在中位随访45个月后, 28位（56％）患者由于各种原因离开了试验（包括4个疾病进展，21位由于毒性和三个其它原因）。中位无进展生存期和总生存期都没有达到; 3年中位无进展生存率和总生存率分别为87％和94％。
没有患者在研究治疗中死亡。值得注意的是，11个（22％）患者有3级房颤。 3-4级的骨髓抑制患者<5％。与完全缓解者相比,在部分响应者中,CCND1，BIRC3，BANK1，SETBP1，AXIN2和IL2RA有过表达。
结论: Ibrutinib与利妥昔单抗组合是有效的老年患者套细胞淋巴瘤第一线治疗。若使用Ibrutinib,须要心血管风险基线评估。
Most mantel cell lymphoma (MCL) patients are elderly. The phase II clinical trial (NCT01880567) studied the efficacy and safety of Ibrutinib and rituximab combination as first-line therapy for older patients (age ≥ 65 years).
The trial enrolled 50 cases of MCL patients. Patients with Ki-67% ≥ 50% and blastoid cell morphology were excluded. Ibrutinib and rituximab administration were up to 2 years, with continuation of Ibrutinib alone. The primary objective of the trial was overall response rate and safety. In evaluable samples, whole-exome were performed from baseline tissue samples. The median age was 71 years. Sixteen percent of patients had high-risk simplified international MCL prognostic index. The Ki-67% was low (<30%) in 38 patients (76%), and moderately high (> 30%-50%) in 12 patients (24%).
The best overall response rate was 96% (71% complete remission). After a median follow-up of 45 months, 28 (56%) patients came off the trial due to various reasons, including 4 disease progression, 21 toxicity and three other reasons. There is no progressive life and total survival period; 3 years no progressive survival rate and total survival rate are 87% and 94%, respectively.
No patient died on study drugs. Of note, 11 (22%) patients had grade 3 atrial fibrillation. Grade 3-4 myelosuppression occurred in <5% of patients. Compared with those the complete response, differential overexpression of CCND1, BIRC3, BANK1, SETBP1, AXIN2 and IL2RA was noted in partial responders.
Conclusion: Ibrutinib and rituximab combination is effective as a first line treatment for older patients with MCL. If Ibrutinib is used in the future, a cardiovascular risk baseline is required.
参考文献 Reference Jain P et al. J Clin Onc 2021; Published online November 19, 2021. DOI: 10.1200/JCO.21.01797
Durvalumab联合化疗与单独化疗相比改善了晚期胆道癌生存率 (11/28/2021)
Durvalumab and chemotherapy combination showed better overall survival in advanced biliary tract cancer than chemotherapy alone
这是一项全球,随机、双盲的III期临床试验（TOPAZ-1），有685名不可切除的晚期或转移性胆道癌参加,包括肝内和肝外胆管癌和胆囊癌（排除壶腹癌）。 该试验正在美国、欧洲、南美等 17个国家的 145多个中心以及韩国、泰国、日本和中国等亚洲几个国家进行。主要终点是总生存率，关键次要终点包括无进展生存期、客观缓解率和安全性。
在预定的中期分析中，独立数据监测委员会得出结论，作为一线晚期胆道癌的治疗,durvalumab联合化疗与单独化疗相比改善了总生存率，达到了主要终点。该组合还证明了无进展生存期和总体反应率的改善。Durvalumab加化疗耐受性良好，与对照组相比具有相似的安全性，并且与单独化疗相比，不会增加因不良事件导致的停药率。这是首个免疫疗法组合证明了优于标准护理。根据制药公司,这些数据将在未来的癌症会议上公布。
This is a global, randomized, double-blind phase III clinical trial (TOPAZ-1), involving 685 unresectable advanced or metastatic biliary tract cancer patients, including intrahepatic and extrahepatic cholangiocarcinoma and gallbladder cancer (excluding ampullary cancer). The test is being conducted in more than 145 centers in 17 countries including the United States, Europe, and South America, as well as several Asian countries such as South Korea, Thailand, Japan, and China. The primary endpoint is overall survival, and key secondary endpoints include progression-free survival, objective response rate, and safety.
At a predefined interim analysis, the Independent Data Monitoring Committee concluded that durvalumab combined with chemotherapy, as a treatment for first-line advanced biliary tract cancer, improved overall survival compared with chemotherapy alone, reaching the primary endpoint. The combination also demonstrated improvement in progression-free survival and overall response rate. Durvalumab plus chemotherapy is well tolerated, and has similar safety profile compared with the control group, and does not increase the withdrawal rate due to adverse events compared with chemotherapy alone. This is the first immunotherapy combination that has shown superiority to standard care. According to the pharmaceutical company, these data will bepresented at a forthcoming medical meeting.
参考文献 Reference https://www.astrazeneca.com/media-centre/press-releases/2021/imfinzi-improved-survival-in-biliary-tract-cancer.html
DNX-2401 治疗弥漫性内在性脑桥胶质瘤 (11/27/2021)
DNX-2401 treating diffuse intrinsic pontine glioma （DIPG）
DIPG是一种进展迅速预后差的儿科肿瘤，接受放射治疗患者的中位总生存期通常在 8-11个月。DNX-2401是一种溶瘤腺腺病毒的免疫疗法，专门设计用于感染、复制和直接杀死癌细胞并触发抗肿瘤免疫反应。DNX-2401对成人复发性胶质母细胞瘤患者具有良好的耐受性并延长了生存期。DNX-2401已被FDA授予复发性恶性胶质细胞瘤孤儿药。
今年十月的神经肿瘤学会年会上,报告了DNX-2401治疗弥漫性内在性脑桥胶质瘤 (DIPG)的I期研究数据。第一阶段研究包括 12名新诊断的 DIPG患者,先接受了DNX-2401，然后进行了常规放射治疗。其中9名患者 (75%)的肿瘤减少，截至数据截止，中位总生存期为 17.8个月,包括三名正在进行随访的患者。没有观察到剂量限制性毒性，治疗方案耐受性良好。
Diffuse intrinsic pontine glioma (DIPG) is a rapidly progressing pediatric brain tumor with poor prognosis. Nedian overall survival of patients receiving radiotherapy is usually 8-11 months.DNX-2401 is an oncolytic adenovirus immunotherapy, specifically designed to infect, replicate and directly kill cancer cells and trigger an anti-tumor immune response.DNX-2401 is well tolerated and has been shown to prolong survival in adult recurrent glioblastoma.DNX-2401 has been granted orphan drug designation for recurrent malignant glioma by FDA.
At the annual Society of Neuro-Oncology meeting in October this year, data was presented in a phase I study of DNX-2401 in the treatment of DIPG.The first phase of the study included 12 newly diagnosed DIPG patients who first received DNX-2401 and then received conventional radiotherapy.Nine patients (75%) had tumor reductions. As of the data cutoff, median overall survival was 17.8 months, including three patients still undergoing follow-up.No dose-limiting toxicity was observed, and the treatment regimen was well tolerated.
参考文献 Reference https://markets.businessinsider.com/news/stocks/dnatrix-announces-oral-presentation-of-positive-overall-survival-data-with-dnx-2401-in-dipg-at-the-society-for-neuro-oncology-sno-annual-meeting-1030996160 https://ascopost.com/News/18662
Tisotumab vedotin 对先前治疗过的复发性或转移性宫颈癌中的疗效 (11/21/2021)Efficacy of Tisotumab vedotin in previously treated recurrent of metastatic cervical cancer
这是一项多中心、开放标签、单臂II期临床试验(innovaTV 204, NCT03438396)。Tisotumab vedotin是一种组织因子导向的抗体-药物偶联物,该研究旨在评估它在先前治疗过的复发性或转移性宫颈癌中的疗效和安全性。
这项研究在欧洲和美国的 35个学术中心、医院和社区实践中完成。该研究包括患有复发性或转移性鳞状细胞癌、腺癌或腺鳞癌的患者,这些患者在复发性或转移性环境中接受过不超过两种既往全身性治疗方案，包括至少一种既往含铂化疗方案。其中69%的患者曾接受贝伐单抗作为先前全身治疗的一部分。 患者每 3周静脉内接受 2 mg/kg（最多 200 mg）tisotumab vedotin，直至疾病进展或不可接受的毒性。主要终点是根据独立审查委员会评估的RECIST（1.1版）确认的客观反应率。在接受至少一剂药物的患者中进行活性和安全性分析。该研究正在进行中，招募已完成。
从2018年6月12日至2019年4月11日期间招募了102名患者； 101名患者接受了至少一剂tisotumab vedotin。分析时的中位随访时间为 10个月（IQR 6.1–13.0）。经确认的客观缓解率为 24% (95%CI 16–33)，其中 7个 (7%)完全缓解和 17个 (17%)部分缓解。
最常见的不良反应（≥25%），包括实验室检查异常，有血红蛋白降低,疲劳,淋巴细胞减少,恶心,周围神经病变,脱发,鼻衄,结膜不良反应,出血,白细胞减少,肌酐升高,干眼症,凝血酶原国际标准化比率增加，活化部分凝血活酶时间延长，腹泻和皮疹。28名 (28%)患者报告了 3级或更严重的治疗相关不良事件，包括中性粒细胞减少症（三名 [3%]患者）、疲劳（两名 [2%]）、溃疡性角膜炎（两名 [2%]）和周围神经病变（两个 [2%]）。 13名 (13%)患者发生了严重的治疗相关不良事件，其中最常见的包括周围感觉运动神经病（两名 [2%]）和发热（两名 [2%]）。研究人员认为 1例因感染性休克导致的死亡与治疗有关。
Tisotumab vedotin在既往接受过治疗的复发性或转移性宫颈癌女性中显示出具有临床意义和持久的抗肿瘤活性，并且具有可控和可耐受的安全性。FDA已授予加速批准。
This is a multi-center, open-label, single-arm phase II clinical trial (innovaTV 204, NCT03438396). Tisotumab vedotin is a tissue factor-oriented antibody-drug conjugate. This study aimed to evaluate its efficacy and safety in previously treated recurrent or metastatic cervical cancer.
This study was conducted in 35 academic centers, hospitals and community practices in Europe and the United States. The study included patients with recurrent or metastatic squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma. These patients had received no more than two lines of previous systemic treatment in a recurrent or metastatic setting, including at least one prior platinum-containing chemotherapy regimen. Among them, 69% had received bevacizumab as part of the systemic therapy. In the trial, patients received 2 mg/kg (up to 200 mg) tisotumab vedotin intravenously every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint is objective response rate confirmed by RECIST (version 1.1) evaluated by the independent review board. Efficacy and safety analysis were conducted in patients receiving at least one dose of the drug. The study is ongoing and recruitment has been completed.
From June 12, 2018 to April 11, 2019, 102 patients were recruited;. Among them, 101 patients received at least one dose of tisotumab vedotin. The median follow-up time at the time of analysis was 10 months (IQR 6.1–13.0). Confirmed objective response rate was 24% (95% CI 16–33), with 7 (7%) complete remission and 17 (17%) partial remission.
The most common adverse reactions (≥25%) including abnormal laboratory tests, were decreased hemoglobin, fatigue, lymphopenia, nausea, peripheral neuropathy, alopecia, epistaxis, conjunctival adverse reactions, bleeding, leukopenia, and increased creatinine , dry eye, increased INR, prolonged aPTT, diarrhea and skin rash. A total of 28 (28%) patients reported treatment-related adverse events of grade 3 or more, including neutropenia (three [3%]), fatigue (two [2%]), ulcerative cornea Inflammation (two [2%]) and peripheral neuropathy (two [2%]). Thirteen (13%) patients experienced serious treatment-related adverse events, the most common of which included peripheral sensorimotor neuropathy (two [2%]) and fever (two [2%]). Researchers believed that one death due to septic shock was related to treatment.
Tisotumab vedotin has shown clinically significant and long-lasting anti-tumor activity in women with recurrent or metastatic cervical cancer who have previously received treatment. It has a controllable and tolerable safety. FDA has granted accelerated approval.
参考文献 Reference Coleman RL et al. Lancet Onc 2021; 22: 609
携带CDH1变异的遗传性小叶乳腺癌和隐匿性胃癌 (11/20/2021)CDH1 variant-associated hereditary lobular breast cancer and occult gastric cancer
一项前瞻性队列研究了因CDH1致病性或可能致病性变异导致的遗传性小叶乳腺癌患者（2017年 10月至 2021年 1月入组）,数据分析于 2021年 5月进行。关联分析对这 3个患者组进行了检查：（1）遗传性小叶乳腺癌组有乳腺癌家族史且无胃癌； （2）遗传性弥漫性胃癌组有胃癌家族史且无乳腺癌； (3)混合组有乳腺癌和胃癌家族史。使用Pearsonχ2检验比较分类变量。研究的主要终点是遗传性小叶乳腺癌患者的隐匿性印戒细胞胃癌的患病率。研究者检查了这个人群的个人/家族病史、基因型和（降低风险的）全胃切除术和监测内窥镜检查的病理数据。
结果:共有 283名CDH1致病性或可能致病性变异患者（199名 [70.3%]为女性，259名 [91.5%]为白人；中位年龄，48岁 [范围，18-81岁]）被纳入前瞻性研究遗传性弥漫性胃癌。该队列由 151个家庭组成。根据乳腺癌和/或胃癌家族史对患者进行分类：遗传性小叶乳腺癌15.5% [283名患者中的 44名],遗传性弥漫性胃癌（16.2% [283名患者中的 46名]和混合型（68.2% [283名患者中的 193名]）。遗传性小叶乳腺癌 组包括 31个不同的家族，具有 19个 CDH1变体；这些变体中的 10个也存在于遗传性弥漫性胃癌和混合组中（52.6% [19个变体中的 10个]）。几乎所有的遗传性小叶乳腺癌患者（93.8% [16个变体中的 15个]）由于其潜在的CDH1致病性或可能致病性变异而选择降低风险的全胃切除术后的病理结果显示隐匿性印戒细胞胃腺癌（中位年龄，50岁） [范围，21-67岁]）。 遗传性弥漫性胃癌组中无症状患者的隐匿性胃癌患病率相似（94.7% [19个变体中的 18个]；P= .98）。
结论:无胃癌家族史的携带CDH1致病性或可能致病性变异者表现出较高的隐匿性印戒细胞胃癌发生率。这些数据可用于为遗传性小叶乳腺癌患者的家庭咨询提供参考。
A prospective cohort study examined patients with hereditary lobular breast cancer in association of pathogenic or likely pathogenic variants in CDH1. Patients were enrolled from October 2017 to January 2021. Data analysis was conducted in May 2021. Association analysis examined three patient groups: (1) hereditary lobular breast cancer group had a family history of breast cancer and no gastric cancer; (2)family history of gastric cancer and no breast cancer in the hereditary diffuse gastric cancer group; (3) family history of both breast and gastric cancer in the mixed group. Pearson χ2 test was used to compare categorical variables. The primary endpoint of the study was the prevalence of occult signet ring cell gastric cancer in patients with hereditary lobular breast cancer. The researchers examined personal and family medical history, genotype, and pathological data from risk-reducing total gastrectomy and surveillance endoscopy.
Results: A total of 283 patients with CDH1 pathogenic or likely pathogenic variants (199 [70.3%] were women, 259 [91.5%] were white; median age, 48 years [range, 18-81 years]) were enrolled in this prospective study of hereditary diffuse gastric cancer. The cohort consisted of 151 families. Classification of patients based on family history of breast and/or gastric cancer: hereditary lobular breast cancer 15.5% [44 of 283 patients]), hereditary diffuse gastric cancer (16.2% [46 of 283 patients]) and mixed type (68.2% [193 of 283 patients]). The hereditary lobular breast cancer group included 31 different families with 19 CDH1 variants; 10 of these variants were also present in hereditary diffuse gastric cancer and mixed group (52.6% [10 of 19 variants]). Almost all patients with hereditary lobular breast cancer (93.8% [15 of 16 variants]) who elected for risk-reducing total gastrectomy, due to their potential CDH1 pathogenic or likely pathogenic variants, harbored occult signet ring cell gastric adenocarcinoma on final pathology (median age, 50 years [range, 21-67]). The prevalence of occult gastric cancer in asymptomatic patients in the hereditary diffuse gastric cancer group was similar (94.7% [18 of 19 variants]; P = .98).
Conclusion: Those with CDH1 pathogenic or likely pathogenic variants with no family history of gastric cancer demonstrated a higher incidence of occult signet ring cell gastric cancer. These data may be used as reference for counseling family with hereditary lobular breast cancer.
参考文献 Reference Gamble LA et al. JAMA Surg 2021; October 13, 2021. doi:10.1001/jamasurg.2021.5118
III 期临床试验测试Nemvaleukin α用于铂类耐药卵巢癌 (11/14/2021)
Nemvaleukin alfa for platinum-resistant ovarian cancer in phase III clinical trial
Nemvaleukin是一种工程化融合蛋白，由修饰的白介素 2 (IL-2)和高亲和力IL-2 α受体链组成，旨在优先扩增杀伤肿瘤的免疫细胞，同时通过与IL-2受体复合物结合避免免疫抑制细胞的激活。
这是一项多中心、开放标签、随机III期临床试验（ARTISTRY-7, NCT05092360）,大约 376名铂类耐药的上皮性卵巢癌、输卵管癌或原发性腹膜癌患者将入组,并以 3:1:1:3的比例接受1) Nemvaleukin 6µg/kg/天与 200 mg派姆单抗（pembrolizumab）; 2)单独派姆单抗; 3)单独nemvaleukin;或4)研究人员选择的联合化疗。 在实验组中，nemvaleukin将通过静脉输注在 21天周期的第 1天至第 5天给药。派姆单抗在 21天周期的第 1天给药。在对照组中，化疗选择包括脂质体阿霉素（在 28天周期的第 1天给予 40mg/m2），紫杉醇（在 28天周期的第 1、8、15和 22天给予80mg/m2），拓扑替康（在 28天周期的第 1、8和 15天给予4 mg /m2），或吉西他滨（在21天周期的第 1天和第 2天给予1000 mg/m2）。主要研究终点是各组相比较的无进展生存期。次要终点包括客观响应率、总生存率、疾病控制率、响应持续时间、响应时间、癌症抗原 125响应和治疗中出现的不良事件的发生率。
符合研究条件的患者包括年龄在 18岁或以上且经组织学确认患有铂类耐药或难治性疾病，并且在铂类敏感环境中接受过至少 1种既往全身抗癌治疗的患者。患者之前接受的治疗不能超过 5线，并且还必须根据RECIST v1.1具有可测量的疾病并且愿意接受肿瘤活检。
该研究排除了以下情况的的:在一线治疗完成后不到 3个月内患有原发性铂类难治性疾病或原发性铂类耐药或疾病进展的个体。组织学证实为黏液性或癌肉瘤亚4型的上皮性卵巢癌， 非上皮性肿瘤,具有低恶性潜能的肿瘤，在研究中首次给药后 6周内需要引流 500mL或更多液体，之前接受过IL-2药物治疗，或之前接受过抗PD-1/PD- L1疗法。
FDA已授予nemvaleukinα的快速通道指定，用于与派姆单抗联合用于治疗铂类耐药卵巢癌患者癌症，此前，nemvaleukin获得了FDA的快速通道和孤儿药指定，用于治疗粘膜黑色素瘤患者。
Nemvaleukin is an engineered fusion protein consisting of a modified interleukin 2 (IL-2) and a high-affinity IL-2 α receptor chain. It is designed to preferentially amplify tumor-killing immune cells while interacting with IL-2 receptors. The complex binding avoids the activation of immunosuppressive cells.
This is a multicenter, open-label, randomized phase III clinical trial (ARTISTRY-7, NCT05092360). Approximately 376 platinum-resistant epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer patients will be enrolled, at a ratio of 3:1:1:3. 1) Nemvaleukin 6 µg/kg/day and 200 mg pembrolizumab; 2) Pembrolizumab alone; 3) Nemvaleukin alone,; 4) Combination chemotherapy at investigators’ choice. In the experimental group, nemvaleukin will be administered by intravenous infusion from day 1 to day 5 of the 21-day cycle. Pembrolizumab is administered on day 1 of a 21-day cycle. In the control group, chemotherapy options included liposomal doxorubicin (40 mg/m2 administered on day 1 of the 28-day cycle) and paclitaxel (80 mg/m2 administered on the 1, 8, 15 and 22 days of the 28-day cycle), topotecan (4 mg/m2 administered on days 1, 8 and 15 of a 28-day cycle), or gemcitabine (1000 mg/m2 administered on days 1 and 2 of a 21-day cycle). The primary study endpoint is progression-free survival within each group. Secondary endpoints include objective response rate, overall survival rate, disease control rate, response duration, response duration, response of CA 125, and the incidence of adverse events during treatment.
Eligible patients include those who are 18 years of age or older and have histologically confirmed platinum-resistant or refractory diseases, and have received at least one previous systemic anti-cancer treatment in a platinum-sensitive environment. The patient’s previous treatment cannot exceed 5 lines, and must also have a measurable disease according to RECIST v1.1 and be willing to undergo tumor biopsy.
The study excludes the following situations: Individuals with primary platinum refractory disease or primary platinum resistance or disease progression less than 3 months after the completion of the first-line treatment. Histologically confirmed epithelial ovarian cancer with mucinous or carcinosarcoma subtype, non-epithelial tumor, tumor with low malignant potential, need fluid drainage of 500 mL or more within 6 weeks after the first dose in the study, received prior treatment of IL-2 agent, or received anti-PD-1/PD-L1 therapy before.
FDA has granted fast track designation for nemvaleukin α for the treatment of platinum-resistant ovarian cancer in combination with pembrolizumab. Previously, nemvaleukin was granted fast track and orphan drug designation by FDA for the treatment of mucosal melanoma.
参考文献 Reference https://investor.alkermes.com/news-releases/news-release-details/alkermes-receives-fda-fast-track-designation-nemvaleukin-alfa-0https://clinicaltrials.gov/ct2/show/NCT05092360?term=ARTISTRY-7
FDA 批准asciminib用于治疗费城染色体阳性慢性粒细胞白血病 (11/13/2021)
FDA granted approval to asciminib for patients with Ph+ CML in chronic phase
FDA加速批准 asciminib用于治疗费城染色体阳性慢性粒细胞白血病慢性期患者，他们之前接受过两种或两种以上酪氨酸治疗激酶抑制剂 (TKI)，并批准 asciminib用于患有T315I突变的成人患者。
ASCEMBL (NCT03106779)是一项多中心,随机,开放标签的临床试验，评估asciminib在慢性期的费城染色体阳性慢性粒细胞白血病患者中的疗效，这些患者以前接受过两种或多种TKI治疗。共有 233名患者被随机化 (2:1)并根据主要细胞遗传学反应状态进行分层，每天两次接受asciminib40mg或每天一次bosutinib 500mg。患者继续治疗直至出现不可接受的毒性或治疗失败。主要疗效结果指标是 24周时的主要分子反应率。接受asciminib治疗患者的主要分子反应率为 25%（95%CI：19, 33），而接受bosutinib治疗的患者为 13%（95%CI：6.5, 23；p=0.029）。中位随访时间为 20个月，尚未达到主要分子反应率的中位持续时间。
CABL001X2101 (NCT02081378)是一项多中心、开放标签的临床试验，评估 asciminib在患有T315I突变的慢性期的费城染色体阳性患者中的疗效。疗效基于 45名T315I突变患者，他们每天两次接受asciminib 200mg。患者继续治疗直至出现不可接受的毒性或治疗失败。主要疗效结果测量是主要分子反应率。 42% (19/45, 95%CI: 28% to 58%)的患者在 24周时达到主要分子反应率。 49% (22/45, 95%CI: 34% to 64%)的患者在 96周时达到主要分子反应率。中位治疗持续时间为 108周（范围，2至 215周）。
最常见的不良反应 (≥20%)是上呼吸道感染、肌肉骨骼疼痛,疲劳,恶心,皮疹和腹泻。最常见的实验室异常是血小板计数减少,甘油三酯增加,中性粒细胞计数和血红蛋白减少以及肌酸激酶,丙氨酸氨基转移酶,脂肪酶和淀粉酶增加。
对先前接受过两种或多种TKI治疗的患者,推荐的asciminib剂量为每天一次 80mg，每天大约在同一时间口服，或每天两次 40mg，间隔大约 12小时。对于患有T315I突变的患者，推荐的asciminib剂量为每天口服两次 200mg，间隔约 12小时。
FDA granted accelerated approval of asciminib for the treatment of patients with Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML)in the chronic phase, who have previously received two or more tyrosine therapy kinase inhibitors (TKI). FDA also approved asciminib for adult patients with T315I mutations.
ASCEMBL (NCT03106779) is a multicenter, randomized, open-label clinical trial evaluating the efficacy of asciminib in patients withPh+ CMLin the chronic phase who have previously received two or more TKI treatments. A total of 233 patients were randomized (2:1) and stratified according to their major cytogenetic response, to receive asciminib 40 mg twice daily or bosutinib 500 mg once daily. The patient continues treatment until unacceptable toxicity or treatment failure. The main efficacy outcome measure is the major molecular response at 24 weeks. The major molecular response rate for patients treated with asciminib was 25% (95% CI: 19, 33), while that for patients treated with bosutinib was 13% (95% CI: 6.5, 23; p = 0.029). The median follow-up time was 20 months, and the median duration of the major molecular response has not yet been reached.
CABL001X2101 (NCT02081378) is a multicenter, open-label clinical trial evaluating the efficacy of asciminib inPh+ CMLpatientsin chronic phase with the T315I mutation. Efficacy is based on 45 T315I mutation patients who received asciminib 200 mg twice daily. They continue treatment until unacceptable toxicity or treatment failure. The primary efficacy outcome measure is the major molecular response.
Major molecular response was achieved in 42% (19/45, 95% CI: 28% to 58%) patients at 24 weeks and 49% (22/45, 95% CI: 34% to 64%) patients reached the major molecular response rate at 96 weeks. The median duration of treatment was 108 weeks (range, 2 to 215 weeks). The most common adverse reactions (≥20%) are upper respiratory tract infection, musculoskeletal pain, fatigue, nausea, rash and diarrhea. The most common laboratory abnormalities are decreased platelet counts, increased triglycerides, decreased neutrophil counts and hemoglobin, and increased creatine kinase, alanine aminotransferase, lipase, and amylase.
For patients who have previously received two or more TKI treatments, the recommended dose of asciminib is 80 mg once daily, taken orally at approximately the same time or 40 mg twice a day, approximately 12 hours apart. For patients with T315I mutations, the recommended dose is 200 mg orally twice a day, approximately 12 hours apart.
参考文献 Reference https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-asciminib-philadelphia-chromosome-positive-chronic-myeloid-leukemia
派姆单抗用于高风险II期黑色素瘤切除后的疗效 (11/6/2021)
Pembrolizumab in high-risk stage II melanoma following resection
一项III期双盲临床试验（KEYNOTE-716）评估了派姆单抗 (pembrolizumab)与安慰剂在期IIB或 IIC*期（AJCC-8）黑色素中的疗效,派姆单抗可将疾病复发或死亡的风险降低 35%。在此前,对高危II期黑色素瘤切除术后患者的护理标准是观察。
年龄≥12岁的976名患者,IIB或IIC期黑色素瘤完全切除皮肤且前哨淋巴结活检阴性的患者,按 1:1随机分配（487名派姆单抗；489名安慰剂）:派姆单抗组（200mg,儿童患者为 2mg/kg）或安慰剂, 每3星期一次，共 17个周期（最多 1年）。治疗一直持续到疾病复发或出现不可接受的毒性。主要终点是每个研究者评估的无复发生存期。还评估了安全性。
总体而言，976名患者（64%为IIB期；34.8%为IIC期）,在中位随访 14.4个月时，派姆单抗组与安慰剂组相比,无复发生存期显著延长（HR 0.65，95% CI 0.46-0.92；P=0.00658；两者均未达到中位数）。在派姆单抗 (23)与安慰剂 (38)组中，54 (11.1%)对 82 (16.8%)患者出现复发，远处复发事件几乎减半（23相对于安慰剂组的38)。12个月的无复发生存率为 90.5%相对于 83.1%。
在派姆单抗组和安慰剂组中，≥3级的任何原因副作用分别发生在 125 (25.9%)和 83 (17.1%)位患者中。 因药物相关副作用停药分别74 (15.3%)比 12 (2.5%)。 派姆单抗组未发生因任何原因药物相关副作用导致的死亡。免疫介导的副作用发生率为 36.2%对 8.4%，最常见的是甲状腺功能减退症（15.7%对 3.5%）和甲状腺功能亢进（10.4%对 0.6%）。大多数严重程度为1-2级。
结论 与安慰剂相比，派姆单抗用于已切除的 IIB和 IIC期黑色素瘤可将疾病复发或死亡的风险降低35%。
*IIB:>2.0 -4.0mm有溃疡,但无淋巴结转移; > 4.0mm无溃疡,无淋巴结转移
IIC: >4.0mm有溃疡,但无淋巴结转移
A phase III double-blind clinical trial (KEYNOTE-716) evaluated the efficacy of pembrolizumab vs. placebo in patients with stage IIB or IIC* (AJCC-8). Pembrolizumab reduced relapse and risk of death by 35%. Prior to that, the standard of care for patients with high-risk stage II melanoma after resection was observation.
A total of 976 patients aged ≥12 years with stage IIB or IIC* melanoma whose tumor was completely resected and had a negative sentinel lymph node biopsy, were randomly assigned 1:1 (487 pembrolizumab; 489 placebo): pembrolizumab (200 mg for adults, 2 mg/kg for children) or placebo, once every 3 weeks, for a total of 17 cycles (up to 1 year). Treatment continued until disease progression or unacceptable toxicity. The primary endpoint is recurrence-free survival assessed by investigators. Safety was also evaluated.
Overall, in 976 patients (64% in stage IIB; 34.8% in stage IIC), at a median follow-up of 14.4 months, the pembrolizumab group had significantly longer recurrence-free survival than the placebo group (HR 0.65, 95% CI 0.46-0.92; P=0.00658; neither of them reached median). In pembrolizumab (23) and placebo (38) groups, 54 (11.1%) versus 82 (16.8%) patients had relapses, and distant recurrence events were almost halved (23 vs. 38 in the placebo group). The 12-month relapse-free survival rate was 90.5% versus 83.1%.
In pembrolizumab group and placebo group, > grade side-effects of any cause occurred in 125 (25.9%) and 83 (17.1%) patients, respectively. Discontinuations due to drug-related side effects were 74 (15.3%) vs. 12 (2.5%). There were no deaths in the pembrolizumab group due to drug-related side effects. The incidence of immune-mediated side effects was 36.2% vs. 8.4%, the most common being hypothyroidism (15.7% vs. 3.5%) and hyperthyroidism (10.4% vs. 0.6%). Most of the severity was grade 1-2.
Conclusion Compared with placebo, pembrolizumab used in resected stage IIB and IIC melanoma reduced the risk of recurrence or death by 35%.
IIB: > 2.0 -4.0 mm with ulceration, no lymph node metastases; > 4.0 mm with no ulceration, no lymph node metastases
IIC: > 4.0 mm with ulceration, no lymph node metastases
参考文献 Reference Luke JJ et al. Ann Onc 2021; 32 (suppl_5): S1283-S1346
抗体-药物偶联物 trastuzumab deruxtecan (T-DXd) 作为二线药物用于晚期HER2 阳性乳腺癌 (11/6/2021)
Trastuzumab deruxtecan as second line therapy for advanced stage HER-2-positive breast cancer
Trastuzumab deruxtecan 是一种抗体-药物偶联物，具有三种成分：与曲妥珠单抗 （trastuzumab） 具有相同氨基酸序列的人源化抗 HER2 IgG1 单克隆抗体；拓扑异构酶 I 抑制剂有效载荷；和基于四肽的可切割接头。
这是一项多中心、开放标签、随机的 3 期研究（DESTINY-Breast03），比较 T-DXd 与与曲妥珠单抗 emtansine (T-DM1) 在先前接受曲妥珠单抗和紫杉烷治疗的 晚期HER2 阳性乳腺癌患者中的疗效和安全性。 共524 名患者被随机分组。中位年龄为 54 岁（范围 20-83）。患者按 1:1 随机分配接受T-DXd（5.4 mg/kg）或T-DM1（3.6 mg/kg）。主要终点是盲法独立中央审查的无进展生存期。次要终点包括总生存期, 客观响应率, 响应持续时间, 研究人员观察的无进展生存期和安全性。
结果 : 在中位随访约 16 个月时， T-DXd 未达到中位无进展生存期，而 T-DM1 为 6.8 个月, 无进展生存期 的风险比 (HR) 为 0.2840 (P = 7.8 x 10-22)。 T-DXd 的估计 12 个月总生存期事件发生率为 94.1%（95% CI，90.3-96.4），T-DM1 为 85.9%（95% CI，80.9-89.7）； HR：0.5546（95% CI，0.3587-0.8576；P = 0.007172, 没有跨越预先指定的显着性边界）。 T-DXd 的中位治疗持续时间为 14.3 个月（范围，0.7-29.8），而 T-DM1 为 6.9 个月（范围，0.7-25.1）。
两组治疗出现的不良事件发生率相似。两组均未发生与药物相关的死亡。 10.5% 的 T-DXd 组发生了经裁定的药物相关间质性肺病, 其中大部分 (9.7%) 为 1 级或 2 级，没有一个为 4 或 5 级。在 1.9% 的 T-DM1 组中观察到这种毒性，所有均为 1 级或 2 级。与剂量减少相关的药物相关不良事件在 T-DXd 中更为常见（21.4% 对 12.6%），与治疗中断相关的不良事件（12.8% 对 5.0%）也是如此。
Trastuzumab deruxtecan有望作为紫杉烷和曲妥珠单抗治疗失败的晚期 HER2 阳性乳腺癌患者的二线治疗。
Trastuzumab deruxtecan is an antibody-drug conjugate with three components: a humanized anti-HER2 IgG1 monoclonal antibody with the same amino acid sequence as trastuzumab; a topoisomerase I inhibitor payload ; and a cleavable tetrapeptide-based linker.
This is a multi-center, open-label, randomized phase 3 study (DESTINY-Breast03). The trial evaluated safety and efficacy between T-DXd and trastuzumab emtansine (T-DM1) in advanced HER2-positive breast cancer patients who previously received trastuzumab and taxane A total of 524 patients were randomized. The median age was 54 years (range 20-83). Patients were randomly assigned 1:1 to receive T-DXd (5.4 mg/kg) or T-DM1 (3.6 mg/kg) . The primary endpoint was progression-free survival as evaluated by blinded independent central review. Secondary endpoints included overall survival, objective response rate, response duration, researcher-observed progression-free survival, and safety.
Results: At a median follow-up of about 16 months, T-DXd did not reach median progression-free survival, while T-DM1 was 6.8 months, and the hazard ratio (HR) for progression-free survival was 0.2840 (P = 7.8 x 10-22). The estimated 12-month overall survival for T-DXd was 94.1% (95% CI, 90.3-96.4), and T-DM1 was 85.9% (95% CI, 80.9-89.7); HR: 0.5546 (95% CI , 0.3587-0.8576; P = 0.007172, not crossing the pre-specified significance boundary). Median duration of treatment for T-DXd was 14.3 months (range, 0.7-29.8), while T-DM1 was 6.9 months (range, 0.7-25.1).
The incidence of adverse events in the two treatment groups was similar. There were no drug-related deaths in either group. In T-DXd group 10.5% had drug-related interstitial lung disease, most of which (9.7%) were grade 1 or 2, and none were grade 4 or 5. This toxicity was observed in 1.9% of the T-DM1 group, all of which were grade 1 or 2. Drug-associated adverse events related to dose reduction were more common in T-DXd (21.4% vs. 12.6%), as were adverse events related to treatment discontinuation (12.8% vs. 5.0%).
Trastuzumab deruxtecan is a promising second line therapy for advanced HER2-positive breast cancer patients who failed taxane and trastuzumab.
参考文献 Reference Cortés J et al. Ann Oncol 2021; 32 (suppl_5): S1283-S1346.
联合伊匹单抗和纳武单抗治疗软脑膜癌病 (10/31/2021)
Treating leptomeningeal carcinomatosis with combination of ipilimumab and nivolumab
软脑膜癌病预后差且治疗选择有限。一项单臂II期临床试验（NCT02939300）评估了联合伊匹单抗（ipilimumab）和纳武单抗（nivolumab）治疗对软脑膜癌病的疗效和安全性。一共18 名患者接受联合伊匹单抗和纳武单抗直至出现进展或不可接受的毒性。试验主要终点是 3 个月的总生存期 (OS3)。次要终点包括毒性、3 个月的累积进展时间和无进展生存期。基于患者仍然活着的中位随访时间为 8.0 个月（范围：0.5 至 15.9 个月）。该研究已达到其主要终点，因为 18 名患者中有 8 名（OS3 0.44；90% CI：0.24 至 0.66）在三个月时存活。
另一组研究人员分析了接受联合免疫治疗的软脑膜癌病患者的脑脊液样本，发现脑脊液中的 CD8 + T 细胞在用免疫治疗的样本中比未治疗的样本更丰富和增殖更多; 脑脊液中的炎症特征比血液中的要多。
三分之一的患者经历过一次（或更多）3 级或更高级别的不良事件。两名患者由于不可接受的毒性（分别为肝炎和结肠炎）而停止了方案治疗。最常见的不良事件包括疲劳（n= 7）、恶心（n = 6）、发烧（n = 6）、厌食（n = 6）和皮疹（n = 6）。
结论: 伊匹单抗和纳武单抗联合使用具有可接受的安全性，并在软脑膜癌病患者中显示出有希望的活性。需要更大规模的临床试验来验证这些结果。
Leptomeningeal carcinomatosis carries a poor prognosis and there are limited treatment options. A single-arm phase II clinical trial (NCT02939300) evaluated the efficacy and safety of combined treatment with ipilimumab and nivolumab for leptomeningeal carcinomatosis.
A total of 18 patients received the combination of ipilimumab and nivolumab until disease progression or unacceptable toxicity. The primary endpoint of the trial was overall survival at 3 months (OS3). Secondary endpoints included toxicity, cumulative time to progression at 3 months, and progression-free survival. Median follow-up time based on the patients still alive was 8.0 months (range: 0.5 to 15.9 months). The study has reached its primary endpoint because 8 of 18 patients (OS3 0.44; 90% CI: 0.24 to 0.66) survived at three months.
Another group of researchers analyzed the cerebrospinal fluid samples of those with leptomeningeal carcinomatosis who received combination immunotherapy and they found that the CD8 + T cells in the CSF fluid were more abundant and proliferative in the treated samples than the untreated ones. Besides, there were more inflammatory features in the blood than in the blood.
One-third of patients experienced one (or more) adverse events of grade 3 or higher. Two patients discontinued the regimen due to unacceptable toxicity (hepatitis and colitis, respectively). The most common adverse events included fatigue (n = 7), nausea (n = 6), fever (n = 6), anorexia (n = 6), and skin rash (n = 6).
Conclusion: The combined use of ipilimumab and nivolumab has acceptable safety and shows promising activity in patients with leptomeningeal carcinomatosis. Larger clinical trials are needed to verify these results.
参考文献 Reference Brastianos PK et al. Nature Communications 2021; Oct. 12. Prakadan SM et al. Nature Communications 2021; Oct. 12.
卡博替尼显示对肾癌脑转移的活性 (10/30/2021)
Activity of cabozantinib in renal cell carcinoma with brain metastases
一项回顾性队列研究评估了卡博替尼（cabozantinib）治疗转移性肾细胞癌患者脑转移的临床活性和毒性作用。
这项研究包括 2014 年 1 月至 2020 年 10 月期间在 15 个国际机构（美国、比利时、法国和西班牙）接受治疗的转移性肾癌和脑转移患者。队列 A 包括没有接受过脑定向局部治疗的疾病进展性脑转移患者，队列 B 包括接受过脑定向局部治疗治疗的疾病稳定或进展性脑转移患者。 他们都在治疗过程中接受过卡博替尼单药治疗。
结果: 纳入研究的 88 例肾癌脑转移患者中，33 例（38%）在队列 A 中，55 例（62%）在队列 B 中。大多数患者为男性（n = 69；78%），卡博替尼开始治疗时的中位年龄为 61 岁（范围，34-81 岁）。中位随访时间为 17 个月（范围，2-74 个月）。在队列 A 和 B 中，颅内响应率分别为 55%（95% CI，36%-73%）和 47%（95% CI，33%-61%）。在队列 A 中，颅外响应率为 48%（95% CI，31%-66%），至治疗失败的中位时间为 8.9 个月（95% CI，5.9-12.3 个月），中位总生存期为 15 个月（ 95% CI，9.0-30.0 个月）。在队列 B 中，颅外响应率为 38%（95% CI，25%-52%），治疗失败时间为 9.7 个月（95% CI，6.0-13.2 个月），中位总生存期为 16 个月（95 % CI，12.0-21.9 个月）。
卡博替尼耐受性良好，没有报告意外的毒性作用或神经系统不良事件。没有观察到与治疗相关的死亡。
结论: 卡博替尼在肾癌和脑转移患者中显示出相当大的颅内活性和可接受的安全性。卡博替尼对肾癌患者脑转移疗效的前瞻性研究至关重要。
A retrospective cohort study evaluated the clinical activity and toxicity of cabozantinib in the treatment of renal cell carcinoma (RCC) with brain metastases.
The study included patients with RCC and brain metastases who were treated in 15 international institutions (the United States, Belgium, France, and Spain) between January 2014 and October 2020. Cohort A included patients with progressive brain metastases who did not received brain-directed local therapy, and cohort B included patients with stable or progressive brain metastases who received brain-directed local therapy. They all received cabozantinib monotherapy at any line during treatment.
Results: Of the 88 patients with brain metastases from RCC included in the study, 33 (38%) were in cohort A, and 55 (62%) were in cohort B. The majority of patients were male (n = 69; 78%), and the median age at the start of cabozantinib was 61 years (range, 34-81 years). Median follow-up time was 17 months (range, 2-74 months). In cohorts A and B, the intracranial response rates were 55% (95% CI, 36%-73%) and 47% (95% CI, 33%-61%), respectively. In cohort A, the extracranial response rate was 48% (95% CI, 31%-66%), median time to treatment failure was 8.9 months (95% CI, 5.9-12.3 months), and the median overall survival was 15 months (95% CI, 9.0-30.0 months). In cohort B, the extracranial response rate was 38% (95% CI, 25%-52%), the treatment failure time was 9.7 months (95% CI, 6.0-13.2 months), and median overall survival was 16 Months (95% CI, 12.0-21.9 months)
Cabozantinib was well tolerated, and no unexpected toxic effects or neurological adverse events were reported. No treatment-related deaths were observed.
Conclusion: Cabozantinib showed considerable intracranial activity and acceptable safety in patients with RCC and brain metastases. Prospective studies of the effect of cabozantinib on brain metastases in RCC patients will be important.
参考文献 Reference Hirsch L et al. JAMA Onc 2021; Oct 21. doi:10.1001/jamaoncol.2021.4544
Mosunetuzumab 治疗多次复发滤泡性淋巴瘤 (10/24/2021)
Mosunetuzumab treating recurrent/refractory follicular lymphoma
尽管滤泡性淋巴瘤有多种治疗方法选择，但该疾病反复复发并且仍然无法治愈。对于接受过 2 种或更多全身治疗的患者，选择有限，并且预后较差。Mosunetuzumab是一种人源化抗体，可与恶性 B 细胞表面的 CD20 和细胞毒性 T 细胞的 CD3 结合, 旨在重定向 T 细胞以参与和消除恶性 B 细胞。
正在进行的 1/2b 期试验（GO29781, NCT02500407）招募了预计会表达 CD20 的 1 至 3a 级复发/难治性滤泡性淋巴瘤患者。要符合入选条件，既往接受过 2 次或更多全身治疗。患者在第 1 天和第 8 天（21 天为1个周期）的第 1 个周期中按阶梯剂量给予静脉mosunetuzumab，然后在每个后续周期的第 15 天和第 1 天给予目标剂量。在第 8 周期达到完全响应的患者停止治疗。经历部分响应或疾病稳定的患者能够继续治疗长达 17 个周期，直到疾病进展或出现无法耐受的毒性。 试验的主要目标包括药物的疗效、确定推荐的 2 期剂量，以及检查治疗达到的最佳客观反应。此外，研究人员检查了该药物的安全性和耐受性，特别关注剂量限制性毒性和确定最大耐受剂量。
截至 2020 年 8 月 7 日的数据截止日期，共有 62 名患者参加了该试验。患者的中位年龄为 59 岁（范围，27-85）。大多数（64.5%） 的患者为男性，先前接受治疗的中位数为 3（范围，2-11）。所有患者之前都接受过抗 CD20 药物和烷化剂治疗，21.0% 之前接受过 PI3K 抑制剂，19.4% 之前接受过自体干细胞移植，8.1% 之前接受过免疫调节药物，6.5% 之前接受过 CAR T 细胞治疗。此外，87.1% 对之前的抗 CD20 治疗无效。
在所有 62 名滤泡性淋巴瘤患者中，全人源化免疫球蛋白 G1双特异性抗体引发了 67.7% (n = 42) 的客观响应率，完全响应率为 51.6% (n = 32)。在之前接受过 CAR T 细胞治疗的 4 名患者中客观响应率为 100%，完全响应率为 50.0%。对 PI3K 抑制剂难治的患者 (n = 13), 24 个月内疾病进展的患者 (n = 29), 双重难治的患者 (n = 38) 和患者最后一次治疗难治的 (n = 46)，客观响应率分别为 92.3%、75.9%、71.1% 和 65.2%。完全响应率分别为 84.6%、55.2%、50.0% 和 47.8%。
此外，对治疗作出首次响应后的中位随访时间为 18.4 个月（范围，2-34 个月）。中位缓解持续时间为 20.4 个月（95% CI，9.4-22.7）；在使用mosunetuzumab达到完全响应的患者中，中位缓解持续时间为 21.0 个月（95% CI，16.0-22.7）。
Mosunetuzumab具有可接受的毒性特征。 96.8% 的患者经历了不良反应，67.7% 的患者出现 3 级或更高的毒性，1.6% 的患者出现严重程度为 5 级的后果。超过 10% 的参与者报告的最常见的 3 级或更高的毒性是低磷血症和中性粒细胞减少症。 五名患者 (8%) 经历了导致治疗中断的不良反应，其中 4 个与研究药物有关。 62 名患者中有 17.7% 报告了任何级别的细胞因子释放综合征。在这些事件中，6.5% 是严重的。所有这些事件都在没有使用托珠单抗 (Actemra), 重症监护病房或血管加压药的情况下得到解决。
在一项 3 期临床试验 (NCT04712097) 中，正在研究 mosunetuzumab 联合来那度胺 (Revlimid) 相对于Rituxan加来那度胺，用于至少接受过 1 线全身治疗后的滤泡性淋巴瘤患者。
Although there are many treatment options for follicular lymphoma, the disease recurs frequently and there is still no cure. For patients who have received 2 or more systemic treatments, options are limited and the prognosis is poor. Mosunetuzumab is a humanized antibody that binds to CD20 on the surface of malignant B cells and CD3 on cytotoxic T cells. It is hoped to use this bispecific antibody to redirect T cells to participate and eliminate malignant B cells.
The ongoing phase 1/2b trial (GO29781, NCT02500407) recruits patients with grade 1 to 3a relapsed/refractory follicular lymphoma who are expected to express CD20. To meet the selection criteria, patients must have received 2 or more systemic treatments in the past. Patients were given intravenous mosunetuzumab in step-up doses during the first cycle on days one and eight (21 days as a cycle), and then the target dose was given on the 15th and first day of each subsequent cycle. Patients who achieved complete response in the 8th cycle stopped treatment. Patients who experienced a partial response or had stable disease can continue treatment for up to 17 cycles until disease progresses or intolerable toxicity. The main objectives of the trial included efficacy of the drug, determining recommended dose for phase 2 trial, and best objective response, as well as safety and tolerability of the drug. Attention was directed particularly to dose-limiting toxicity and maximum tolerated dose.
As of the data cutoff of August 7, 2020, a total of 62 patients had participated in the trial. Median age of the patients was 59 years (range, 27-85). The majority (64.5%) of the patients were male, and the median number of previous treatments was 3 (range, 2-11). All patients had received anti-CD20 drugs and alkylating agents before, 21.0% had received PI3K inhibitors, 19.4% had received autologous stem cell transplantation, 8.1% had received immunomodulatory drugs, and 6.5% had received CAR T cells treatment. In addition, 87.1% did not respond to previous anti-CD20 treatments.
In all 62 patients with follicular lymphoma, the fully humanized immunoglobulin G1 bispecific antibody resulted in an objective response rate of 67.7% (n = 42) and a complete response rate of 51.6% (n = 32). Among the 4 patients who had previously received CAR T cell therapy, objective response rate was 100%, and the complete response rate was 50.0%. Patients refractory to PI3K inhibitors (n = 13), patients with disease progression within 24 months (n = 29), double refractory patients (n = 38), and patients refractory to the last treatment (n = 46), the objective response rates were 92.3%, 75.9%, 71.1% and 65.2% respectively. The complete response rates were 84.6%, 55.2%, 50.0%, and 47.8%, respectively.
In addition, median follow-up time after the first response to treatment was 18.4 months (range, 2-34 months). Median duration of response was 20.4 months (95% CI, 9.4-22.7). Among patients who achieved complete response with mosunetuzumab, median duration of response was 21.0 months (95% CI, 16.0-22.7).
Mosunetuzumab has acceptable toxicity profile. A total of 96.8% patients experienced adverse reactions, 67.7% patients had grade 3 or higher toxicity, and 1.6% patients had grade 5 consequences. The most common grade 3 or higher toxicities reported by more than 10% of participants were hypophosphatemia and neutropenia. Five patients (8%) experienced adverse reactions that led to treatment discontinuation, 4 of which were related to the study drug. 17.7% of 62 patients reported any grade of cytokine release syndrome. of which 6.5% were serious. All these events were resolved without the use of tocilizumab, intensive care unit or vasopressors.
In a phase 3 clinical trial (NCT04712097), the combination of mosunetuzumab and lenalidomide versus Rituximab plus lenalidomide is being compared for patients with follicular lymphoma who have received at least 1 line of prior systemic therapy.
参考文献 Reference Assouline S et al. Pan Pacific Lymphoma Conference 2021; https://bit.ly/3DfhFLN
Adavosertib用于对 PARP 抑制剂耐药的卵巢癌 (10/23/2021)
Adavosertib for ovarian cancer refractory to PARP inhibitor
WEE1激酶是G2 / M和S期细胞周期检查点的关键调节剂。Wee1 抑制剂 adavosertib 已在 PARP 抑制剂耐药的临床前模型中单独和与 奥拉帕利（olaparib） 联合显示出活性。这是一项II期临床试验（EFFORT）, 评估 adavosertib联合或不联合奥拉帕利在复发性 PARP抑制剂耐药的卵巢癌的比较。
患有复发性卵巢癌、输卵管癌或原发性腹膜癌且在 PARP抑制剂上疾病进展的女性。所有患者都有可测量的疾病和足够的器官功能。在 adavosertib组中，患者在 21 天周期的第 1-5 天和第 8-12 天接受 300毫克/天口服。在adavosertib联合奥拉帕利组，患者在第 1-3 天和第 8-10 天接受 adavosertib 150毫克/天两次口服，在 21 天周期的第 1-21 天接受奥拉帕利 200毫克/天两次口服。主要终点是客观响应，每 2 个周期评估一次。临床受益率定义为客观缓解或疾病稳定 > 16 周的患者比例。无进展生存期使用 Kaplan Meier 方法进行评估，并从治疗开始日期到进展,死亡或最后一次就诊的最早日期计算。 这项试验筛选了 116 名患者，其中 80 名患者入组并随机分组（adavosertib组：n = 39，联合组：n = 41）。中位年龄为 60 岁（范围 36-76），大多数患者患有铂耐药性疾病（64%）和高级别浆液性组织学（98%）。患者接受了中位数为 4 次的先前治疗（范围 1-11）的，48% 具有种系或体细胞 BRCA 突变。每组有 35 名患者的响应可评估。
单独使用 adavosertib 治疗导致 23% 的患者有响应；与奥拉帕利联合使用时，响应率为 29%。中位反应持续时间分别为 5.5 个月和 6.4 个月。 单独使用 adavosertib 时，临床获益率为 63%，无论 BRCA 突变状态如何，该获益都会发生。
在 adavosertib 组中，51% 的患者出现 3/4 级毒性，最常见的是中性粒细胞减少症 (13%)、血小板减少症 (10%) 和腹泻 (8%)。 28 (72%) 名患者需要至少一次剂量中断，20 (51%) 名患者需要减少剂量。在联合组，76% 的患者出现 3/4 级毒性，最常见的是血小板减少症 (20%)、中性粒细胞减少症 (15%)、腹泻 (12%)、疲劳 (12%) 和贫血 (10%）。 36 (88%) 名患者需要至少一次剂量中断，29 (71%) 名患者需要减少剂量，4 (10%) 名患者因毒性未重新开始给药。
结论：adavosertib单独使用或与奥拉帕利联合给药在 PARP抑制剂耐药的卵巢癌患者中显示出疗效。尽管在两组中都观察到了 3 级和 4 级毒性，但这些通常可以通过支持性护理、中断剂量和根据需要减少剂量来控制。
WEE1 kinase is a key regulator of cell cycle checkpoint in G2/M and S phases. The Wee1 inhibitor adavosertib has been shown active alone or in combination with olaparib in preclinical models of PARP inhibitor resistance. This phase II clinical trial (EFFORT) was intended to evaluate adavosertib with or without olaparib in recurrent PARP inhibitor-resistant ovarian cancer.
Women who had recurrent ovarian cancer, fallopian tube cancer, or primary peritoneal cancer and had disease progression on PARP inhibitors were eligible. All patients had measurable disease and adequate organ function. In the adavosertib group, patients received 300 mg/day orally on days 1-5 and 8-12 of a 21-day cycle. In the adavosertib combined with olaparib group, patients received adavosertib 150 mg twice a day orally on days 1-3 and 8-10, and olaparib 200 mg Bid, orally on days 1-21 of the 21-day cycle. The primary endpoint was objective response, rate which was evaluated every 2 cycles. The clinical benefit rate was defined as the proportion of patients with objective response or stable disease > 16 weeks. Progression-free survival was evaluated using the Kaplan Meier method and calculated from the starting date of treatment to the earliest date of progression, death, or last visit. The trial screened 116 patients, of which 80 patients were enrolled and randomized (adavosertib group: n = 39, combination group: n = 41). Median age was 60 years (range 36-76), and most patients had platinum-resistant disease (64%) and high-grade serous histology (98%). Those patients received a median of 4 previous treatments (range 1-11), 48% had germline or somatic BRCA mutations. Response of 35 patients in each group could be assessed.
Response in adavosertib alone group was 23%, vs. 29% in the combination group. Median duration of response was 5.5 months vs. 6.4 months, respectively. When adavosertib was used alone, the clinical benefit rate was 63%, and this benefit occurred regardless of BRCA mutation status.
In the adavosertib group, 51% of patients had grade 3/4 toxicity, the most common being neutropenia (13%), thrombocytopenia (10%), and diarrhea (8%). 28 (72%) patients required at least one dose interruption, and 20 (51%) patients required dose reduction. In the combination group, 76% of patients had grade 3/4 toxicity, the most common being thrombocytopenia (20%), neutropenia (15%), diarrhea (12%), fatigue (12%) and anemia (10%). 36 (88%) patients required at least one dose interruption, 29 (71%) patients required a dose reduction, and 4 (10%) patients did not restart due to toxicity.
Conclusion: Adavosertib alone or in combination with olaparib has efficacy in patients with ovarian cancer resistant to PARP inhibitors. Although grade 3 and 4 toxicities were observed in both groups, these could usually be controlled by supportive care, dose interruption, and dose reduction as needed.
参考文献 Reference Westin SN et al: J Clinical Onc 2021; DOI: 10.1200/JCO.2021.39.15_suppl.5505
阿比特龙在雄激素受体阳性唾液腺肿瘤中具有活性 (10/17/2021)
Abiraterone showed activity in andorgn-receptor positive salivary gland cancer
雄激素受体表达发生在超过 90%的唾液腺导管癌和 20-30%的非特异性的腺癌中。雄激素剥夺疗法在唾液腺导管癌中的活性已被认可多年，但去势抵抗（castration-resistant）患者的最佳二线治疗仍然未知。
在一项 II期试验中评估了阿比特龙(Abiraterone)的潜力，该试验涉及 24名表达雄激素受体的唾液腺肿瘤患者，这些患者在雄激素剥夺疗法后进展。患者的中位年龄为 65.8岁，除一名患者外，其余均为男性。 19例组织学为唾液腺导管癌，其余 5例为腺癌。 治疗包括1毫克阿比特龙, 10毫克泼尼松 和和促黄体激素释放激素（LHRH）激动剂，一直持续到疾病进展或出现不可接受的毒性。主要终点是客观响应，次要终点包括疾病控制率和安全性。
结果显示客观响应率为 21%，41.6%的患者病情稳定。中位响应持续时间为 5.82个月, 3名患者仍在接受治疗，其余 21名患者因疾病进展而停止治疗。中位治疗持续时间为 3.93个月。 该队列的 12个月总生存率为 66.59%，其中唾液腺导管癌患者为 74.48%。诊断后的中位生存期为 94.31个月。 先前接受雄激素剥夺疗法与对阿比特龙的反应无关。这是首次证明阿比特龙联合 LHRH类似物对去势抵抗性,雄激素受体阳性唾液腺癌患者具有活性。
除了两名患者外，所有患者都至少发生了一次不良事件。最常见的任何级别治疗相关不良事件是疲劳 (38%),潮红 (29%)和低钾血症 (17%)。发生了 4次与药物相关的 3级不良事件：2例疲劳，潮红和室上性心动过速各 1例。
这些病例报告显示阿比特龙对雄激素剥夺疗法进展后的唾液腺导管癌有活性，和作为二线激素治疗的潜力。
Androgen receptor expression occurs in more than 90% of salivary duct carcinomas and 20-30% adenocarcinomas not otherwise specified.The activity of androgen deprivation therapy in salivary duct carcinoma has been recognized for many years, but the best second-line treatment for castration-resistant patients is still unknown.
The potential of abiraterone was evaluated in a phase II trial involving 24 patients with androgen receptor-expressing salivary gland tumors who progressed after androgen deprivation therapy. The median age of the patients was 65.8 years. Except for one patient, the rest were men. The histology of 19 cases was salivary gland duct carcinoma, and the remaining 5 cases were adenocarcinoma. Treatment consisted of 1 mg of abiraterone, 10 mg of prednisone, and luteinizing hormone releasing hormone (LHRH) agonists. They continued treatment until disease progresses or unacceptable toxicity. The primary endpoint was objective response, and secondary endpoints include disease control rate and safety.
The results showed that the objective response rate was 21%, and 41.6% of patients were in stable condition. Median duration of response was 5.82 months, 3 patients were still receiving treatment, and the remaining 21 patients stopped treatment due to disease progression. Median duration of treatment was 3.93 months. The 12-month overall survival rate of this cohort was 66.59%, of which 74.48% were patients with salivary duct carcinoma. Median survival time after diagnosis was 94.31 months. Previous androgen deprivation therapy was not related to response to abiraterone. This is the first demonstration that abiraterone combined with LHRH agonists were active in patients with castration resistance and androgen receptor positive salivary gland cancer.
Except for two patients, all patients had at least one adverse event. The most common treatment-related adverse events of any grade were fatigue (38%), flushing (29%) and hypokalemia (17%). There were 4 drug-related grade 3 adverse events: 2 cases of fatigue, 1 case each of flushing and supraventricular tachycardia.
The case reports show that abiraterone was active against salivary duct carcinoma after progression on androgen deprivation therapy, and it has potential as a second-line hormone therapy.
参考文献 Reference Locati LD et al. J Clin Onc 2021; Oct. 1. DOI: 10.1200/JCO.21.00468
Durvalumab与化疗联用提高广泛期小细胞肺癌的生存率 (10/16/2021) Durvalumab and chemotherapy combination prolonged overall survival in extensive-stage small cell lung cancer
这是一项III期临床试验（CASPIAN）, 包括 805名第一次接受治疗的广泛期小细胞肺癌患者，他们按 1:1:1随机分组: 1)每3周（为一个周期）接受 1,500毫克durvalumab和EP，2)每 3周接受 1,500毫克durvalumab和 75毫克tremelimumab和EP，或3)每 3周接受单独EP。Durvalumab组的患者接受了四个周期的治疗，然后是维持性durvalumab，单独EP组的患者接受了六个周期的EP。
来自试验的主要结果数据显示，durvalumab和EP与单独使用EP相比具有显着的总体生存获益（风险比，0.73）;中位随访 25.1个月后的后续分析也是如此（HR，0.75）。Durvalumab/tremelimumab与EP和单独EP相比，在数值上提高了总生存率（HR，0.82），但未达到统计学显著性。 在中位随访 39.4个月时，durvalumab和 EP组合与单独EP相比显示总生存期持续改善（HR，0.71）。 中位总生存期分别为 12.9个月和 10.5个月。Durvalumab/EP和EP在 24个月时的总生存率分别为 22.9%和 13.9%，在 36个月时分别为 17.6%和 5.8%。
Durvalumab/EP、durvalumab/tremelimumab/EP和EP组的严重不良事件发生率分别为 32.5%、47.4%和 36.5%;导致死亡的不良事件发生率分别为 5.3%、10.9%和 6.0%。
This is a phase III clinical trial (CASPIAN), that enrolled 805 patients with extensive-stage small cell lung cancer who had never received treatment. They were randomly divided into three groups at a ratio of 1:1:1: 1) receiving 1,500 mg of durvalumab and EP every 3 weeks (one cycle), 2) 1,500 mg durvalumab and 75 mg tremelimumab and EP every 3 weeks, or 3) EP only every 3 weeks. Patients in the Durvalumab groups received four cycles of chemo-immunotherapy followed by maintenance durvalumab, and patients in the EP alone group received six cycles of EP.
The main outcome data from the trial showed that durvalumab and EP had a significant overall survival benefit compared with EP alone (hazard ratio, 0.73). Follow-up analysis after a median follow-up of 25.1 months continued to show such benefit (HR, 0.75). Compared with EP alone, Durvalumab/tremelimumab/EP also increased overall survival rate (HR, 0.82), although it did not reach statistical significance. At a median follow-up of 39.4 months, the combination of durvalumab and EP showed continuous improvement in overall survival compared with EP alone (HR, 0.71). Median overall survival was 12.9 months and 10.5 months, respectively. Overall survival rates for durvalumab/EP and EP were 22.9% and 13.9% at 24 months, and 17.6% and 5.8% at 36 months, respectively.
The incidence of serious adverse events in the Durvalumab/EP, durvalumab/tremelimumab/EP, and EP groups was 32.5%, 47.4%, and 36.5%, respectively; the incidence of adverse events leading to death was 5.3%, 10.9%, and 6.0%, respectively
参考文献 Reference Paz-Ares L et al. Eur Soc Med Onc Congress 2021; abstr LBA61
早期乳腺癌腋窝淋巴结的处理（II, 接受术前化疗患者) (10/10/2021)
Management of the axilla in early-stage breast cancer (II, following neoadjuvant chemotherapy)
1) 最初淋巴结阴性的患者:即最初体格检查临床淋巴结阴性，以及针刺活检临床可疑淋巴结病理学阴性并接受术前化疗的患者,应在手术时接受前哨淋巴结活检。
2) 最初淋巴结阳性的患者:即最初活检证实淋巴结阳性的患者:
a) 术前化疗后临床淋巴结阳性的患者，推荐腋窝淋巴结清扫。
b) 术前化疗后变为淋巴结阴性的患者，建议前哨淋巴结活检。对在诊断时活检夹已放入活检阳性淋巴结的患者, 在手术时将其与前哨淋巴结活检一起定位，若没有放活检夹进行淋巴结活检的患者，建议使用双示踪剂（蓝色染料和同位素）进行前哨淋巴结活检,并切除至少三个前哨淋巴结以最大限度减少假阴性。
c) 推荐对这些患者进行淋巴结局部放疗，无论前哨淋巴结的病理状态如何。 术前化疗后手术病理为淋巴结阳性的乳房切除术后患者可在完成腋窝淋巴结清扫后接受放疗,包括淋巴结局部放疗;对于术前化疗后手术病理为淋巴结阳性的保乳手术的患者，推荐腋窝淋巴结清扫后进行淋巴结局部放疗。
3) 前哨淋巴结活检时间：建议不要在术前化疗之前和之后进行两次淋巴结取样。对于将接受术前化疗的临床淋巴结阴性患者，建议在术前化疗之后而不是之前进行前哨淋巴结活检。
1) Initially lymph nodes-negative: either negative on physical examination, or negative needle biopsy of clinically-suspected lymph node and received neoadjuvant chemotherapy. They should undergo sentinel lymph node biopsy.
2) Initially lymph node positive as proven by biopsy:
a) Patients remained lymph nodes -positive after neoadjuvant chemotherapy, ALND is recommended.
b) For patients whose lymph nodes become negative after neoadjuvant chemotherapy, SLNB is recommended. A biopsy clip needs to be placed into the biopsy-positive lymph nodes at the time of diagnosis, and be located at surgery and SLNB. If biopsy clip is not placed at initial lymph node biopsy, it is recommended to use dual tracers (blue dye and isotope). At least three sentinel lymph nodes need to be exercised to minimize false negativity.
c) Local lymph node radiotherapy is recommended regardless of the pathological status of the sentinel lymph node(s). Patients who underwent total mastectomy and who have positive lymph node(s) can be offered post-mastectomy radiotherapy, including local lymph node radiation after completion of ALND. For patients who underwent breast-conserving surgery and who are lymph node-positive after neoadjuvant chemotherapy, it is recommended to perform local lymph node radiotherapy after ALND.
4) Timing of sentinel lymph node biopsy: It is recommended against taking twice lymph node sampling before and after neoadjuvant chemotherapy. It is recommended SLNB be performed after neoadjuvant chemotherapy for clinically node-negative patients who will receive neoadjuvant chemotherapy.
参考文献 Reference Brackstone M et al. Management of the Axilla in Early-Stage Breast Cancer: Ontario Health (Cancer Care Ontario) and ASCO Guideline. J Clin Onc 2021:39: 3056-82.
早期乳腺癌腋窝淋巴结的处理: 安大略健康和ASCO指南部分摘要 (10/9/2021) (I, 未接受术前化疗患者)
Management of the axilla in early-stage breast cancer: Ontario health and ASCO guideline (I, without neoadjuvant chemotherapy)
早期浸润性乳腺癌: I、IIA 和 IIB 期； T1、T2、N0、N1mi、N1 和 M0, 和原发肿瘤≤ 5 cm
临床淋巴结阴性或未知:
1) 年龄 ≥ 70 岁的临床淋巴结阴性, 激素受体阳性和HER-2阴性, 早期浸润性乳腺癌患者（T1N0）,不需要前哨淋巴结活检, 如果她们将接受激素治疗。
2) 年龄 < 70 岁, 应考虑前哨淋巴结活检用于早期乳腺癌的腋窝分期, 是目前乳腺癌手术标准。
3) 没有淋巴结转移的早期乳腺癌女性不应行腋窝淋巴结清扫*1, 2。
4) 对于淋巴结阴性的三阴性乳腺癌患者, 在乳房切除术和接受化疗后, 胸壁放疗可能供供无进展和总生存期益处（相对于不放疗）。
*1对某些患者（如肿瘤位于乳腺内侧或中央, 或具有高风险特征的患者），提供局部淋巴结照射的选择是合理的，至少包括锁骨上和除乳房和/或胸壁外的同侧内乳淋巴结。
*2对于以下患者，应和临床医生讨论后做出关于腋窝淋巴结清扫的决定: 多中心乳腺癌、既往同侧乳腺癌手术或同侧腋窝手术史、年龄 < 18 岁或 > 80 岁，怀孕或哺乳期，对蓝色染料或放射性同位素过敏，有转移性疾病的证据，肿瘤直径 > 3 cm，有 T0 期肿瘤（ 原位导管癌），患有多灶性肿瘤，并且之前接受过术前化疗。
前哨淋巴结活检阳性:
1) 1-2个前哨淋巴结转移: 无需腋窝淋巴结清扫 （患者将接受保乳手术和传统的全乳放疗）。
a) 对于接受保乳手术的患者, 手术后除了乳房或胸壁照射外，还可以选择用放射疗法治疗腋窝，对患有内侧或中央肿瘤的患者以及具有高危特征的患者。需要与患者讨论利弊，并应根据具体情况做出决定。
b) 对于接受乳房切除术的患者，建议对腋窝进行术后放射，可以省略腋窝淋巴结清扫。对于拒绝接受术后放射的患者（即立即重建的患者），可以考虑对没有胸壁的腋窝进行放射或完成腋窝淋巴结清扫。
c) 肿瘤最大 < 5 cm , 单灶性或多灶性但病变局限于一个象限的患者，建议用腋窝放疗代替腋窝淋巴结清扫。
2) ≥ 3 个前哨淋巴结呈阳性，建议对腋窝进行腋窝淋巴结清扫/腋窝放疗; 对于接受乳房切除术者，可以考虑先行腋窝淋巴结清扫，然后再行腋窝放疗。
Early invasive breast cancer: stage I、IIA and IIB； T1、T2、N0、N1mi、N1 and M0, primary tumor ≤ 5 cm
Negative or unknown clinical lymph node status:
1) Age > 70: with clinical negative lymph node, hormone receptor positive and HER-2 negative, early invasive breast cancer (T1N0) , sentinel lymph node biopsy (SLNB) is not required if they will be treated with endocrine therapy.
2) Age <70: SLNB should be considered for axillary staging, which is the current standard for breast cancer surgery.
3) Women with early breast cancer without lymph node metastasis should not undergo axillary lymph node dissection (ALND)* 1, 2.
4) Postmastectomy patients with node-negative, triple-negative breast cancer may benefit from chest wall radiotherapy following chemotherapy compared with no radiotherapy in disease-free and overall survival.
* 1 For some patients (such as those with tumor medially or centrally located, or patients with high-risk features), it is reasonable to provide local lymph node irradiation, including at least the supraclavicular and ipsilateral internal mammary lymph nodes in addition to the breast and/or chest wall.
*2 For the following patients, a decision about ALND should be made after discussion with the clinician: multicentric breast cancer, previous ipsilateral breast cancer surgery or history of ipsilateral axillary surgery, age <18 years or> 80 years, pregnant or lactating, hypersensitivity to blue dyes or radioisotopes, evidence of metastatic disease, tumor diameter> 3 cm, stage T0 tumor (ductal carcinoma in situ), multifocal tumor, and prior preoperative chemotherapy .
Positive sentinel lymph node biopsy:
1) 1-2 sentinel lymph node metastasis: no need for further ALNB (patients will receive breast-conserving surgery with conventionally fractionated whole-breast radiotherapy.
a) For patients undergoing breast-conserving surgery, in addition to breast or chest wall irradiation after surgery, radiation therapy can also be used to treat the axilla, For patients with medially or centrally located tumors and patients with high-risk characteristics. The pros and cons need to be discussed, and a decision should be made based on the specific situation.
b) For patients undergoing mastectomy, postoperative radiation to the axillary is recommended, and ALND can be omitted. For patients who refuse to receive postoperative radiation (i.e., patients who will undergo immediate reconstruction), radiation on the axillary without chest wall radiation, or complete ALND can be considered.
c) For patients whose tumors are less than 5 cm in size, single or multifocal but all the lesions are confined to one quadrant, it is recommended to use axillary radiotherapy instead of ALND.
2) ≥ 3 positive sentinel lymph nodes: It is recommended to perform ALND and axillary radiotherapy; for those undergoing mastectomy, consider first ALND and then axillary radiotherapy.
参考文献 Reference Brackstone M et al. Management of the Axilla in Early-Stage Breast Cancer: Ontario Health (Cancer Care Ontario) and ASCO Guideline. J Clin Onc 2021:39: 3056-82.
Adavosertib 用于 TP53 和 RAS 突变的转移性结直肠癌 (10/3/2021)
Adavosertib for metastatic colorectal cancer with TP53 and RAS muutatons
TP53 突变导致癌细胞对 S 期和 G2 期检查点的依赖性增加。用 Wee1 抑制剂 adavosertib诱导 G2 检查点逃逸。或可通过损害 G2/M 检查点导致有丝分裂灾难。
在一项II 期随机临床试验（FOCUS4）中, 参加者为新诊断的转移性结直肠癌患者, 被测试 TP53 和 RAS 突变。那些在化疗 16 周后稳定或有客观响应的具有两种突变的患者以 2:1 的比例随机分配在 adavosertib 和主动监测组。在 每3 周为一个周期的第 1-5 天和第 8-12 天口服一次 Advosertib（250 毫克或 300 毫克）。主要结果是无进展生存期。
该临床试验于 2017 年 4 月至 2020 年 3 月期间进行，在此期间登记了 718 名患者； 247 个 (34%) 有 RAS/TP53 突变。从 25 家英国医院中随机分配了 69 名患者（adavosertib = 44；主动监测 = 25）。 Advosertib 与主动监测的中位无进展生存期改善相关（3.61 个月对 1.87 个月；HR = 0.35；95% CI，0.18 至 0.68；P = .0022）。与主动监测相比，adavosertib 的总生存期未改善（中位 14.0 个月对 12.8 个月；HR = 0.92；95% CI，0.44 至 1.94；P = .93）。在预先指定的亚组分析中，adavosertib 在左侧肿瘤中的活性更高（HR = 0.24；95% CI，0.11 至 0.51），而右侧肿瘤没有区别（HR = 1.02；95% CI，0.41 至 2.56）。
Advosertib 具有良好的耐受性。 3 级毒性为腹泻 (9%)、恶心 (5%) 和中性粒细胞减少 (7%)。
结论 adavosertib 与主动监测相比改善了无进展生存期，并证明了作为 RAS/TP53 突变转移性结直肠癌的耐受性良好的疗法的潜力。
Mutations in TP53 increase the dependence of cancer cells on S and G2 checkpoints. Wee1 inhibitor adavosertib was used to induce G2 checkpoint escape. It may cause a mitotic disaster by damaging the G2/M checkpoint.
In a phase II randomized clinical trial (FOCUS4), participants newly diagnosed with metastatic colorectal cancer were tested for TP53 and RAS mutations. Those patients who had two mutations and were stable or had an objective response after 16 weeks of chemotherapy were randomly assigned to adavosertib and active monitoring in a 2:1 ratio. Advosertib (250 mg or 300 mg) was taken orally on days 1-5 and 8-12 of a three-week cycle. The primary goal of the trial was progression-free survival. The clinical trial was conducted between April 2017 and March 2020, during which 718 patients were enrolled; 247 (34%) had RAS/TP53 mutations. 69 patients were randomly assigned from 25 UK hospitals (adavosertib = 44; active monitoring = 25). Advosertib was associated with an improvement in median progression-free survival vs. active monitoring (3.61 months vs. 1.87 months; HR = 0.35; 95% CI, 0.18 to 0.68; P = .0022). Compared with active monitoring, overall survival of adavosertib did not improve (median 14.0 months vs. 12.8 months; HR = 0.92; 95% CI, 0.44 to 1.94; P = .93). In a pre-specified subgroup analysis, adavosertib was more active in tumors on the left side of the colon (HR = 0.24; 95% CI, 0.11 to 0.51), while there was no difference for tumors on the right (HR = 1.02; 95% CI, 0.41 to 2.56) .
Advosertib was well tolerated. Grade 3 toxicities were diarrhea (9%), nausea (5%), and neutropenia (7%).
Conclusion: adavosertib improved progression-free survival compared to active monitoring and demonstrated its potential as a well-tolerated therapy for metastatic colorectal cancer with RAS/TP53 mutations.
参考文献 Reference Seligmann JE et a. J Clin Onc 2021: Sept 18. DOI: 10.1200/JCO.21.01435
在雄激素剥夺疗法中加入阿比特龙可改善高危前列腺癌的生存率 (10/2/2021)
Abiraterone added to ADT improved survival among high-risk prostate patients
这是一项III期临床试验（STAMPEDE）, 评估了单独使用雄激素剥夺疗法 (ADT) 治疗高风险非转移性前列腺癌相比于ADT 加阿比特龙 (abiraterone)和泼尼松龙(prednisolone)，无论是否有恩杂鲁胺（enzalutamide）。
该试验着眼于M0 人群（常规 CT 和骨扫描阴性）,包括新诊断的和（根治性前列腺切除术或放疗后）复发的患者（仅3%）。新诊断的高风险患者为淋巴结阳性或淋巴结阴性但须满足三项中的两项: T3-4 ，PSA > 40 ng/ml，或Gleason 8-10。复发的患者须满足以下任何一项: 淋巴结阳性, PSA > 20 ng/ml, PSA > 4 ng/ml 在上升而且翻倍 < 6 个月。新诊断的高风险患者接受放疗加 3 年的 ADT（标准护理）相对于标准护理加 两年阿比特龙和泼尼松龙（无论是否有恩杂鲁胺） 。
这项试验在英国和瑞士的 113 个地点招募了1.974 名男性。随机分配约 900 名患者接受标准护理，或标准护理加阿比特龙和泼尼松龙，1,000 多名患者接受标准护理，或标准护理加阿比特龙和恩杂鲁胺。两组中39%为淋巴结阳性，中位 PSA 为 34，中位年龄为 68 岁。对淋巴结阴性患者强制进行放射治疗，对 N1 疾病患者建议进行放射治疗。因此，99% 和 71% 的新诊断 N0 和 N1 患者分别接受了局部放疗。该试验的主要终点是无转移生存期。研究人群的中位随访时间为 72 个月。
在分析结果后，对照组的无转移生存事件发生率相对于阿比特龙治疗组明显更高: 306 比 180。 阿比特龙治疗提高了无转移生存率和总生存率，6 年无转移生存率从 69% 提高到 82%，6 年总生存率从 77% 提高到 86%。这在统计上有显著差别。
This is a phase III clinical trial (STAMPEDE) that evaluated the use of androgen deprivation therapy (ADT) alone in the treatment of high-risk non-metastatic prostate cancer compared to ADT plus abiraterone and prednisolone, whether or not enzalutamide was included.
The trial looked at M0 population (by negative conventional CT and bone scans), including newly diagnosed and relapsed patients (after radical prostatectomy or radiotherapy) (only 3% in the trial). Newly diagnosed high-risk patients were those who had positive lymph node or negative lymph node but met two of the three: T3-4, PSA > 40 ng/ml, or Gleason 8-10. Relapsed patients must meet any of the following: positive lymph nodes, PSA > 20 ng/ml, PSA > 4 ng/ml, rising and doubling < 6 months. Newly diagnosed high-risk patients received radiotherapy plus 3 years of ADT (standard care) as opposed to standard care plus two years of abiraterone and prednisolone (with or without enzalutamide).
The trial recruited 1.974 men from 113 locations in the United Kingdom and Switzerland. Approximately 900 patients were randomly assigned to standard care, or standard care plus abiraterone and prednisolone, and more than 1,000 patients received standard care, or standard care plus abiraterone and enzalutamide. A total of 39% of the two groups were lymph node positive, median PSA was 34 ng/ml, and median age was 68 years. Radiation was mandatory for patients with negative lymph nodes, and was recommended for patients with N1 disease. Therefore, 99% and 71% of newly diagnosed N0 and N1 patients received local radiation, respectively. The primary endpoint of this trial was metastasis-free survival. Median follow-up time for the study was 72 months.
The results showed the incidence of metastasis-free survival events in the control group were significantly higher than that in the abiraterone group: 306 vs. 180. Abiraterone treatment improved metastasis-free survival and overall survival. For example, the 6-year metastasis-free survival rate increased from 69% to 82%, and the 6-year overall survival rate increased from 77% to 86%. The differences were statistically significant.
参考文献 Reference Attard G et al. Annals of Oncol 2021; 32: Suppl 5
口服地西他滨（decitabine）和cedazuridine治疗骨髓增生异常综合征和慢性粒单核细胞白血病 (9/26/2021)
Oral decitabine and cedazuridine in treating MDS and CMML
一家制药公司（Astex Pharmaceuticals）在国际骨髓增生异常综合征大会上公布了一项III期随机交叉临床试验（ASCERTAIN）的中位生存期数据，患者为中高危骨髓增生异常综合征 (MDS)，包括慢性粒单核细胞白血病 (CMML)。比较口服 地西他滨（decitabine, 35 毫克）和cedazuridine（100 毫克）固定剂量复方片剂，每天一次，连续 5 天, 以 28 天为周期, 与单剂量静脉地西他滨（20 毫克/平方米）, 在 28 天周期中每天静脉输注, 共 5 天， 共2 个周期。从第 3 周期开始，患者继续接受口服地西他滨和 cedazuridine。
研究报告总响应率为 62%，22% 的患者达到完全响应, 中位总生存期 为 31.7 个月。
地西他滨和cedazuridine安全性结果与静脉注射地西他滨的预期结果相似，与静脉注射地西他滨相比，在第 1 周期使用口服地西他滨和cedazuridine的血细胞减少发生率略高。血小板减少症、中性粒细胞减少症和贫血最常见的不良事件 与胃肠外低甲基化剂治疗的预期不良事件一致。
A pharmaceutical company (Astex Pharmaceuticals) announced the median overall survival data in a phase III randomized crossover clinical trial (ASCERTAIN) at the International Myelodysplastic Syndrome Conference. Patients with moderate to high-risk myelodysplastic syndromes (MDS), including Chronic Myelomonocytic Leukemia (CMML). The study compared oral decitabine (35 mg) and cedazuridine (100 mg) fixed-dose compound tablets, once a day, for 5 consecutive days, in a 28-day cycle, with single-dose intravenous decitabine (20 mg/m2), intravenous infusion every day for 5 days in a 28-day cycle, for a total of 2 cycles. Starting from cycle 3, patients continued to receive oral decitabine and cedazuridine. The study reported an overall response rate of 62%, with 22% of patients achieving a complete response. Median overall survival was 31.7 months.
The safety profile of the oral decitabine and cedazuridine was similar to the expected results of intravenous decitabine. Compared with intravenous decitabine, there was a slightly higher incidence of the oral complex of blood cell reduction in the first cycle with oral treatment. The most common adverse events of thrombocytopenia, neutropenia, and anemia were consistent with expected adverse events of parenteral hypomethylating agents.
参考文献 Reference https://www.obroncology.com/news/astex-pharmaceuticals-presents-overall-survival-data-from-ascertain-phase-3
转移性膀胱尿路上皮癌的第一线免疫疗法相比于化疗 (9/25/2021)
First line immunotherapy versus chemotherapy in metastatic urothelial cancer of the bladder
一项研究使用国家癌症数据库确定了 2,796 名从 2014 年到 2017 年的转移性膀胱尿路上皮癌患者, 他们接受了第一线免疫治疗或化疗。从该组中，研究人员匹配了 960 名患者（每组 480 名）。免疫治疗组和化疗组的中位随访时间分别为 9.6 个月和 9.8 个月。研究结果报导, 从诊断到开始治疗的中位时间为 43 天，两组相似（免疫治疗组和化疗组分别为 42 天和 44 天）。免疫治疗组的中位总生存期为 12.9 个月，化疗组为 12.3 个月，差异无统计学意义。这项比较有效性分析的结果验证了最近报告的临床试验结果，表明在实际遇到的患者队列中，接受第一线免疫疗法（单药治疗）与第一线多药化疗的患者的总生存期没有显著差异。
国家癌症数据库的优势在于它有更大癌症人群的普遍性，因为它捕获了美国 70% 以上的新诊断癌症病例。 但该研究有其结果的局限性，包括生存分析的短期随访, 和回顾性比较有效性研究中选择偏倚的风险。此外，国家癌症数据库对一线全身治疗进行了广泛的分类，因此，无法区分化疗组中哪些患者接受了顺铂与卡铂和治疗周期数。也缺乏关于第一线治疗的后续治疗的具体信息。
A study using the National Cancer Database to identify 2,796 patients with metastatic bladder urothelial cancer from 2014 to 2017. They received first-line immunotherapy or chemotherapy. From this group, the researchers matched 960 patients (480 in each group). The median follow-up time of the immunotherapy group and the chemotherapy group was 9.6 months and 9.8 months, respectively. Median time from diagnosis to start of treatment was 43 days, which was similar between the two groups (42 days and 44 days for the immunotherapy group and the chemotherapy group, respectively). Median overall survival of the immunotherapy group was 12.9 months and that of the chemotherapy group was 12.3 months. The difference was not statistically significant. The results of this comparative effectiveness analysis validate the results of the recently reported clinical trials, demonstrating that there is no difference in overall survival in patients receiving first-line immunotherapy (monotherapy) or first-line multi-drug chemotherapy in the real-world clinical practice.
The advantage of the National Cancer Database is that it has a larger cancer population, and it captures more than 70% of newly diagnosed cancer cases in the United States. However, the study has its limitations including short-term follow-up for survival analysis, and the inherent risk of selection bias in retrospective comparative effectiveness studies. In addition, the National Cancer Database has a broad classification of first-line systemic treatments, so it is impossible to distinguish which patients in the chemotherapy group received cisplatin or carboplatin and the number of treatment cycles. There is also a lack of specific information about subsequent treatment following first-line therapy.
参考文献 Reference Chakiryan NH et al. Urol Onc 2021; doi:10.1016/j.urolonc.2021.07.030
比较两种手术前后化疗方案在肌肉浸润性膀胱癌患中的疗效 (9/19/2021)
Comparison of two neoadjuvant and adjuvant chemotherapy regimes in muscle-invasive bladder cancer
对肌肉浸润性膀胱癌患者的最佳手术前后化疗方案。一直没有真正定义。
一项法国癌症中心的随机 III 期对照研究（GETUG/AFU VESPER V05），报导了比较吉西他滨和顺铂 (GC) 相对于剂量密集型甲氨蝶呤, 长春碱, 多柔比星和顺铂 （dd- MVAC）对手术前后已决定化疗的患者的疗效。
从2013年2月至 2018 年 2 月期间，研究小组将 28 个法国癌症中心的 500 名患者随机分组，每 3 周接受 4 个周期的GC 或 6 个周期的 dd- MVAC新辅助组（术前）或辅助组（术后）每 2 周一次。研究的主要终点是 3 年的无进展生存期 。 总共有 437 名患者（88%）接受了新辅助化疗；其中，60% 的患者在 dd-MVAC 组接受了计划的 6 个周期，84% 在 GC 组接受了 4 个周期。随后，91% 和 90% 的患者接受了手术。 器官局限反应，定义为 < ypT3N0，在 dd-MVAC 组中观察到的频率比GC组更高，分别为 77% 相对于 63% (p = 0.001)。
在辅助治疗组中，40% 的患者在 dd-MVAC 组接受了 6 个周期，81% 在 GC 组接受了 4 个周期。在新辅助治疗组中，dd-MVAC 组的 3 年无进展生存期显着更高，分别为 66% 相对于 56%（HR 0.70，95% CI 0.51 0.96；p = 0.025）。在本研究的围手术期设置中，dd-MVAC 组的 3 年无进展生存期 提高了 64% 相对于 56%（风险比 [HR] 0.77，95% 置信区间 [CI] 0.57 1.02；p = 0.066）。 dd-MVAC 组的进展时间也有所改善，3年分别为 69% 相对于 58%（HR 0.68，95% CI 0.50 0.93；p = 0.014）。 在辅助组中，由于样本量有限，结果尚无定论。
研究者认为, dd-MVAC方案应该成为肌肉浸润性膀胱癌新辅助化疗的标准。
本站作者认为，两组实际接受化疗者的人数存在较大差异（术前为24%，术后为41%），这种差异是否可能影响到观察结果, 还有待将来分析发表的数据。
There has been no consensus about standard pre- and post-operative chemotherapy regime for patients with muscle-invasive bladder cancer. A randomized phase III study (GETUG/AFU VESPER V05) from French Cancer Centers reported the data from comparison of gemcitabine and cisplatin (GC) with dose-dense methotrexate, vinblastine, doxorubicin and cisplatin (dd-MVAC) for patients who decided to have chemotherapy before and after surgery.
From February 2013 to February 2018, the research team randomly assigned 500 patients from 28 French cancer centers to receive either 4 cycles of GC every 3 weeks or 6 cycles of dd-MVAC neoadjuvant chemotherapy every 2 weeks, and then adjuvant chemotherapy. The primary endpoint of the study was 3-year progression-free survival. A total of 437 patients (88%) received neoadjuvant chemotherapy; of those, 60% received the planned 6 cycles in the dd-MVAC group and 84% received 4 cycles in the GC group. Subsequently, 91% and 90% of the patients underwent surgery. Organ-confined response, defined as <ypT3N0, was more frequently observed in the dd-MVAC group than in the GC group, at 77% vs. 63% (p = 0.001). In the neoadjuvant treatment group, the 3-year progression-free survival of the dd-MVAC group was significantly higher, 66% versus 56% (HR 0.70, 95% CI 0.51 0.96; p = 0.025).
In the adjuvant group, 40% of patients received 6 cycles in the dd-MVAC group, and 81% received 4 cycles in the GC group. In the perioperative setting of this study, 3-year progression-free survival of the dd-MVAC group was improved by 64% compared to 56% (hazard ratio [HR] 0.77, 95% confidence interval [CI] 0.57 1.02; p = 0.066 ). Time to progression also improved in the dd-MVAC group, 69% versus 58% at 3 years (HR 0.68, 95% CI 0.50 0.93; p = 0.014). In the adjuvant group, the results were inconclusive due to the limited sample size.
Researchers believe that dd-MVAC regimen should become the standard of neoadjuvant chemotherapy for muscle-invasive bladder cancer.
The author of this website was of the opinion that there was quite a difference in the number of chemotherapy-recipients between the two groups (24% before surgery and 41% after surgery). Whether this difference might affect the reported outcome may need to wait for data in future publication..
参考文献 Reference Pfister C et al. ESMO Congress 2021; September 16-21
Oleclumab 或 monalizumab 与度伐单抗联用有益于不可切除的非小细胞肺癌 (9/18/2021)
Oleclumab or monalizumab in combination with Durvalumab showed clinical benefit in unresectable NSCLC
一项II期随机临床试验（COAST）结果显示，在同步放化疗后未进展的不可切除的 III 期非小细胞肺癌患者中, oleclumab（一种抗 CD73 单克隆抗体）或 monalizumab（一种抗 NKG2A 单克隆抗体）与度伐单抗durvalumab）联合使用, 与单独度伐单抗相比, 可提高无进展生存期和客观响应率。
度伐单抗加 oleclumab 的客观响应率相比单独使用度伐单抗为30%对18%, 度伐单抗加 monalizumab相比单独使用度伐单抗为36%对 18%。 在中位随访 11.5 个月后，中期分析结果显示度伐单抗 与 oleclumab 联用可将疾病进展或死亡风险降低 56%（风险比 [HR] 为 0.44；95% 置信区间 [CI] 0.26 -0.75); 而与 monalizumab 联合使用的风险为 35%（HR 为 0.65；95% CI 0.49-0.85）。 度伐单抗加 oleclumab 组合的 10 个月无进展生存率为64.8%，度伐单抗加monalizumab为 72.7%，而单独使用度伐单抗为39.2%。
各治疗组的安全性相似，两种度伐单抗 组合均未发现新的安全性信号。 度伐单抗治疗出现的全部不良事件的发生率为39.4%，度伐单抗加 oleclumab 的发生率为40.7%，度伐单抗加 monalizumab 的发生率为27.9%。 最常见的 3/4 级不良事件是呼吸困难（分别在 3.0%,1.7% 和 1.6% 的患者中报告）。仅报告了 1 名接受度伐单抗加monalizumab治疗的患者 (1.6%) 出现 3/4 级肺炎。
The results of a phase II randomized clinical trial (COAST) showed that the combination of oleclumab (an anti-CD73 monoclonal antibody) or monalizumab (an anti-NKG2A) can improve progression-free survival and objective response rate compared with durvalumab alone, in patients with stage III non-small cell lung cancer who did not progress after concurrent chemo-radiation.
The objective response rate of durvalumab plus oleclumab was 30% vs. 18% in durvalumab alone group, and the response rate of durvalumab plus monalizumab was 36% vs. 18%. After a median follow-up of 11.5 months, an interim analysis showed that the combination of durvalumab and oleclumab reduced the risk of disease progression or death by 56% (hazard ratio [HR] 0.44; 95% confidence interval [CI] 0.26 -0.75 ); The risk in combination with monalizumab was 35% (HR 0.65; 95% CI 0.49-0.85). The 10-month progression-free survival rate for the combination of durvalumab and oleclumab was 64.8%, that of durvalumab plus monalizumab was 72.7%, while that of durvalumab alone was 39.2%.
The safety of each treatment group was similar, and no new safety signals were found for the two ddurvalumab combinations. The incidence of all adverse events with durvalumab alone was 39.4%, the incidence of durvalumab plus oleclumab was 40.7%, and the incidence of durvalumab plus monalizumab was 27.9%. The most common grade 3/4 adverse event was dyspnea (reported in 3.0%, 1.7%, and 1.6% of patients, respectively). Only one patient (1.6%) treated with durvalumab plus monalizumab was reported to have grade 3/4 pneumonitis.
参考文献 Reference European Society for Medical Oncology 2021; Sept 17. https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2021/imfinzi-combined-with-novel-immunotherapies-improved-clinical-outcomes-for-patients-with-unresectable-stage-iii-non-small-cell-lung-cancer.html
PARP 抑制剂治疗与继发性恶性肿瘤风险 (9/12/2021)
PARP inhibitor use and risk of secondary malignancy
由于 PARP（聚 (ADP-核糖) 聚合酶） 抑制剂会干扰 DNA 修复过程，人们自然关注第二原发恶性肿瘤的风险。最近发表的一项分析结果表明，发生第二原发恶性肿瘤的风险没有增加。 研究人员系统地审查了涉及在成人患者中使用 PARP 抑制剂和安慰剂随机的临床研究。他们选择了 23 项安慰剂对照随机研究，涉及 8,857 名患者，其中 5,492 名患者 (62%) 被随机分配到 PARP 抑制剂组，3,365 名患者 (38%) 被分配到安慰剂组。PARP 抑制剂组的患者报告了 51 例第二原发恶性肿瘤 (0.9%), 安慰剂组报告了 24 例第二原发恶性肿瘤 (0.7%)。与安慰剂相比，暴露于 PARP 抑制剂与发生第二原发恶性肿瘤的风险增加无关，中位随访时间为 3.8 至 78 个月（Peto 优势比 = 1.13，95% 置信区间 [CI] = 0.70-1.83， P = .62)，研究之间没有异质性。
对PARP 抑制剂与血液系统恶性肿瘤的风险, 一组研究人员报告了一系列 20 名经过回顾性鉴定的骨髓增生异常综合征或急性髓系白血病患者的研究结果，这些患者在 PARP 抑制剂给药期间或之后发生。 他们的数据支持这样一种假设，即 PARP 抑制剂可能通过施加选择性压力来促进克隆扩增，尤其是 TP53 和 PPM1D 突变。 该团队旨在描述卵巢癌患者接受 PARP 抑制剂治疗后克隆性造血和治疗相关髓系肿瘤的流行和演变，以更好地了解血液疾病发展的分子机制。作者认为，PARP 抑制剂维持治疗卵巢癌具有临床益处，但些患者有发生与PARP 抑制剂治疗相关的血液系统恶性肿瘤的高风险。
早些时候发表的世界卫生组织药物警戒数据库的回顾性研究，表明给予 PARP 抑制剂后相关的血液系统恶性肿瘤风险增加。在这项荟萃分析，PARP 抑制剂组有 5,693 名患者，对照组有 3,406 名患者。PARP 抑制剂显着增加了骨髓增生异常综合征和急性髓系白血病的风险（Peto OR 2.63 [95% CI 1.13-6.14]，p = 0.026)，没有研究间异质性（I2=0%，χ2 p = 0.91）。 PARP 抑制剂组中骨髓增生异常综合征和急性髓系白血病的发生率为 0.73%（95% CI 0.50-1.07；I2 = 0%，χ2 p = 0.87；4,533 名患者中有 21 起事件）和安慰剂组的发生率为 0.47%（0.26-0.85；I2 = 0%，χ2 p = 1.00；2,774 名患者中有 3 起事件）。在有可用数据的情况下，中位治疗持续时间为 9.8 个月（IQR 3.6-17.4；n = 96），自首次接触 PARP 抑制剂以来的中位潜伏期为 17.8 个月（8.4-29 .2；n = 58)。在报告结果的 104 例病例中，47 例 (45%) 导致死亡。
Since PARP (poly(ADP-ribose) polymerase) inhibitors can interfere with the DNA repair process, people are naturally concerned about the risk of second primary malignancies. A recently published analysis showed that the risk of developing a second primary malignant tumor did not increase. Researchers systematically reviewed randomized clinical studies involving the use of PARP inhibitors and placebo in adult patients. They selected 23 placebo-controlled randomized studies involving 8,857 patients, of which 5,492 patients (62%) were randomly assigned to the PARP inhibitor group and 3,365 patients (38%) were assigned to the placebo group. Patients in the PARP inhibitor group reported 51 second primary malignancies (0.9%), and the placebo group reported 24 second primary malignancies (0.7%). Compared with placebo, exposure to PARP inhibitors was not associated with an increased risk of developing a second primary malignancy, with a median follow-up time of 3.8 to 78 months (Peto odds ratio = 1.13, 95% confidence interval [CI] = 0.70 -1.83, P = .62). There is no heterogeneity between studies.
Regarding the risk of PARP inhibitors and hematological malignancies, a group of researchers reported the results of a series of 20 retrospectively identified patients with myelodysplastic syndrome or acute myeloid leukemia that occurred during or after PARP inhibitor. Their data supported the hypothesis that PARP inhibitors may promote clonal expansion by exerting selective pressure, especially TP53 and PPM1D mutations. The team aimed to describe the prevalence and evolution of clonal hematopoiesis and treatment-related myeloid tumors after ovarian cancer patients were treated with PARP inhibitors, in order to better understand the molecular mechanisms of blood disease development. The authors believed that PARP inhibitor maintenance therapy in ovarian cancer has clinical benefits, but some patients had a high risk of hematological malignancies related to PARP inhibitor treatment.
A retrospective study of the World Health Organization’s Pharmacovigilance Database published earlier showed that the risk of hematological malignancies related to the administration of PARP inhibitors was increased. In this meta-analysis, there were 5,693 patients in the PARP inhibitor group and 3,406 patients in the control group. PARP inhibitors significantly increased the risk of myelodysplastic syndrome and acute myeloid leukemia (Peto OR 2.63 [95% CI 1.13-6.14], p = 0.026), and there was no inter-study heterogeneity (I2=0%, χ2 p = 0.91). The incidence of myelodysplastic syndrome and acute myeloid leukemia in the PARP inhibitor group was 0.73% (95% CI 0.50-1.07; I2 = 0%, χ2 p = 0.87; 21 events in 4,533 patients) and across placebo groups was 0.47% (0.26-0.85; I2 = 0%, χ2 p = 1.00; 3 events in 2,774 patients). With available data, the median duration of treatment was 9.8 months (IQR 3.6-17.4; n = 96), and the median incubation period since the first exposure to PARP inhibitors was 17.8 months (8.4-29 .2; n = 58). Of the 104 cases reported results, 47 (45%) resulted in death.
参考文献 Reference Morice PM et al Ann Onc 2021; 32: 1048 Martin JE et al. Ann Onc 2021; June 5. doi.org/10.1016/j.annonc.2021.04.05). Morice PM et al. Lancet Haematol 2021; 8: e122.
TROP2 抗体-药物偶联物治疗非小细胞肺癌 (9/11/2021)
TROP2 antibody-drug conjugate in treating non-small cell lung cancer
一项 I 期剂量探索研究的最新结果显示，一种针对 TROP2 的新型抗体药物偶联物在非小细胞肺癌中有活性。
Deruxtecan （Dato-DXd） 是一种抗体-药物偶联物，包括三个成分：靶向 TROP2 的单克隆抗体、拓扑异构酶 I 抑制剂和接头。该试剂旨在消除靶肿瘤细胞以及周围的“旁观者”细胞。
这是一项I期临床试验（TROPION）的非小细胞肺癌队列, 包括 180 名既往接受过治疗的晚期或转移性疾病患者，并测试了 Dato-DXd 的三个剂量水平：4 毫克/公斤 (n = 50)、6 毫克/公斤 (n = 50) 和8 毫克/公斤 (n = 80)。在三个队列中，患者的中位年龄为 61-64 岁。大多数患者之前接受过免疫治疗（74%-88%），几乎所有患者之前都接受过铂类化疗（96%-98%），约 20% 接受过酪氨酸激酶抑制剂治疗，54%-64% 的患者总共接受了三种或更多的先前治疗。大多数患有非鳞状肿瘤（82%-90%），一些患者有EGFR突变（14%-19%）。虽然 TROP2 在非小细胞肺癌肿瘤上高度表达并且与不良预后相关，但研究中的患者没有选择 TROP2 表达。
在该队列中，28% 的患者对该药物有响应，另外 40% 的患者病情稳定。 在6 毫克/公斤剂量组患者中，中位响应持续时间 为 10.5 个月, 其中绝大多数患者在接受铂类化疗和检查点抑制剂治疗后均失败。 大多数响应是持久的，在数据截止时每个队列中都有几个患者的响应继续进行。
在该队列中，54% 有 3 级或更高级别的治疗出现的不良事件，14% 因毒性而停药，30% 有剂量中断，10% 需要减少剂量。 三名患者 (6%) 患有间质性肺病，被认为与 6 毫克/公斤 队列中的研究药物有关。 高剂量 (8 毫克/公斤) 队列中因间质性肺病 导致的三例治疗相关死亡。 最常见的不良事件（15% 或更高）包括恶心和呕吐、口腔炎、脱发、疲劳、食欲下降、便秘、输液相关反应、皮疹、贫血、干眼症、粘膜炎症、咳嗽、腹泻和呼吸困难。 在因间质性肺病风险增加而不再进行评估的最高剂量队列中，24% 的患者有响应（包括 1 例完全响应），53% 的患者病情稳定，中位响应持续时间为 9.4 个月。
Dato-DXd 正在 III 期 TROPION-LUNG01 研究。
The latest results of a phase I dose expansion study showed that a new antibody-drug conjugate against TROP2 was active in non-small cell lung cancer. Deruxtecan (Dato-DXd) is an antibody-drug conjugate consisting of three components: a monoclonal antibody targeting TROP2, a topoisomerase I inhibitor, and a linker. The reagent was designed to eliminate target tumor cells and surrounding “bystander” cells.
This is a phase I clinical trial (TROPION) non-small cell lung cancer cohort, including 180 patients with advanced or metastatic disease who had previously received treatment, and they were tested at three dose levels of Dato-DXd: 4 mg/kg ( n = 50), 6 mg/kg (n = 50) and 8 mg/kg (n = 80). In the three cohorts, the median age of patients was 61-64 years. Most patients had previously received immunotherapy (74%-88%), almost all patients had previously received platinum-based chemotherapy (96%-98%), about 20% had received tyrosine kinase inhibitor, 54%- 64% of patients received a total of three or more previous treatments. Most had non-squamous tumors (82%-90%), and some patients had EGFR mutations (14%-19%). Although TROP2 is highly expressed on non-small cell lung cancer tumors and is associated with poor prognosis, the patients in the study were not chosen based on TROP2 expression.
In this cohort, 28% of patients responded to the drug, and 40% of patients were clinically stable. Among patients in the 6 mg/kg dose group, the median duration of response was 10.5 months, and most of them progressed on platinum-based chemotherapy and checkpoint inhibitor. Most responses were persistent, and several patients in each cohort continued to respond at the time of data cut-off.
In this cohort, 54% had adverse events with grade 3 or higher treatment-related side-effects, 14% had drug discontinuation due to toxicity, 30% had dose interruption, and 10% required dose reduction. Three patients (6%) had interstitial lung disease, which was considered to be related to the study drug in the 6 mg/kg cohort. There were three treatment-related deaths in the high-dose (8 mg/kg) cohort due to interstitial lung disease. The most common adverse events (15% or higher) included nausea, vomiting, stomatitis, hair loss, fatigue, decreased appetite, constipation, infusion-related reactions, skin rash, anemia, dry eye, mucosal inflammation, cough, diarrhea, and dyspnea . In the highest-dose cohort that was no longer evaluated due to an increased risk of interstitial lung disease, 24% of patients responded (including 1 complete response), 53% of patients were in stable condition, and the median duration of response was 9.4 months.
Dato-DXd is in phase III TROPION-LUNG01 trial.
参考文献 Reference Garon EB et al. World Conference on Lung Cancer 2021; abstr MA03.02
Alrizomadlin 用于对PD-1 阻断剂耐药的肿瘤 (9/5/2021)
Alrizomadlin used in tumors that were resistant to PD-1 inhibitor
根据 一项II 期研究结果，alrizomadlin 与 派姆单抗（pembrolizumab） 的使用似乎可以恢复抗 PD-1 抗体在对免疫疗法有抵抗力或不耐受的黑色素瘤（也包括少数恶性周围神经鞘瘤和脂肪肉瘤）患者中的抗肿瘤作用。
MDM2 是一些恶性肿瘤的常见分子改变，Alrizomadlin 是一种小分子 MDM2-p53 拮抗剂，可恢复 TP53 功能，是宿主免疫调节剂和肿瘤免疫逃逸机制的调节剂，可增强 T 细胞介导的抗肿瘤免疫。当与 PD-1 阻断剂一起使用时，临床前模型显示出协同作用。 在大型回顾性数据库搜索中，PD-1 抑制剂的超进展（hyperprogression）与 MDM2 扩增有关，这表明 MDM2 可能以某种方式表达对免疫疗法的抵抗力或产生有害影响。
这是一项II期临床试验, 研究者报导了102 名成年人（中位年龄，64 岁；范围，23-89；61.8% 男性）的数据，这些人之前接受过中位数为 2 次（范围，1-22）次的治疗。 分析包括以下剂量扩展队列：34 名免疫疗法耐药黑色素瘤患者； 15例免疫治疗耐药的非小细胞肺癌患者和10例STK11突变的肺腺癌患者; 20 例 ATM 和野生型 p53 突变的实体瘤患者； 15 名 MDM2 扩增型和 p53 野生型脂肪肉瘤患者； 15例免疫治疗耐药的尿路上皮癌患者；恶性周围神经鞘瘤10例。
患者每隔一天接受 150 毫克alrizomadlin 以及在21天周期的第 1 天 200 毫克静脉注射派姆单抗。 安全性和总体响应率是该研究的主要终点。 总体而言，该组合具有良好的耐受性。大多数不良事件是胃肠道反应，包括恶心、呕吐和腹泻。大多数 3 至 4 级不良事件是血液学的，包括血小板减少症、贫血和中性粒细胞减少症。
研究人员观察到黑色素瘤患者的总体响应率最高，为 24.1%，其中包括一项完全反应和六项部分反应。黑色素瘤队列的疾病控制率达到 55.2%。 当研究人员仔细评估黑色素瘤队列时，他们发现葡萄膜黑色素瘤患者的总体响应率为 14.3%，粘膜黑色素瘤患者的为 40%，皮肤黑色素瘤患者的为 26.7%。黑色素瘤队列的总体响应率接近 25%，接近那些以前从未见过派姆单抗的人的总体响应率。尽管其他队列的响应率较低（每一个队列都 一个部分响应）: 非小细胞肺癌 (6.7%), 脂肪肉瘤 (6.2%), 尿路上皮癌 (12.5%) 和恶性周围神经鞘瘤 (16.7%) 。
According to the results of a phase II study, adding alrizomadlin to pembrolizumab seemed to restore the anti-tumor activity of anti-PD-1 antibodies in melanomas that are resistant or intolerant to immunotherapy (including a small number of malignant peripheral nerve sheath tumors). and liposarcoma) in patients with anti-tumor effects. MDM2 is a common molecular change of some malignant tumors. Alrizomadlin is a small molecule MDM2-p53 antagonist, which can restore the function of TP53. It is a host immune modulator and a modulator of tumor immune escape mechanism. It can enhance T cell-mediated anti-tumor immunity. When used with PD-1 inhibitor, the preclinical model showed a synergy. In a large retrospective database search, the hyperprogression of PD-1 inhibitors was related to the expansion of MDM2, which suggests that MDM2 may somehow express resistance to immunotherapy or produce harmful effects.
This is a phase II clinical trial. The investigators reported data on 102 adults (median age, 64 years; range, 23-89; 61.8% males) who had received a median of 2 lines of prior treatments (range, 1-22). The trial included the following dose expansion cohort: 34 patients immunotherapy-resistant melanoma; 15 patients with immunotherapy-resistant non-small cell lung cancer and 10 patients with STK11 mutant lung adenocarcinoma; 20 solid tumor patients with ATM and wild-type p53; 15 patients with MDM2 amplified and p53 wild-type liposarcoma; 15 patients with immunotherapy-resistant urothelial carcinoma; 10 patients with malignant peripheral nerve sheath tumors.
Patients received 150 mg of alrizomadlin every other day and 200 mg of intravenous pembrolizumab on day 1 of the 21-day cycle. Safety and overall response rate were the major endpoints of the study. Overall, the combination was well tolerated. Most adverse events were gastrointestinal reactions, including nausea, vomiting and diarrhea. Most adverse events of grade 3 and 4 were hematological, including thrombocytopenia, anemia, and neutropenia.
Overall response rate of melanoma was he highest (24.1%), including one complete response and six partial responses. Disease control rate in the melanoma cohort reached 55.2%. When the researchers carefully evaluated the melanoma cohort, they found that the overall response rate was 14.3% for patients with uveal melanoma, 40% for mucosal melanoma, and 26.7% for cutaneous melanoma. The overall response rate of the melanoma cohort was close to 25%, which was close to the overall response rate of those who had never seen pembrolizumab before. Although the response rate of other tumor cohorts was low (each cohort had a partial response): non-small cell lung cancer (6.7%), liposarcoma (6.2%), urothelial carcinoma (12.5%) and malignant peripheral nerve sheath tumor (16.7) %).
参考文献 Reference Tolcher AW et al. J Clin Onc 2021;39 (suppl 15): 2506
前列腺癌根治术后辅助放疗与早期挽救性放疗对高危复发性患者死亡风险的影响 (9/4/2021)
Impact of adjuvant versus early salvage radiation following radical prostatectomy on risk of death among patients with high risk of recurrence
在以往随机对照试验中，根治性前列腺切除手术后辅助治疗与早期挽救性放疗相比，并未显示可降低无进展生存期。然而，鉴于这些试验中具有不良病理特性的患者的代表性可能不足, 因此这些患者错过了术后辅助治疗助益处，并且可能存在由于过长时间生存期引起的偏差, 这项报导调查了这种可能性。 方法是评估的对像是阳性盆腔淋巴结 (pN1) 或 pGleason 评分 8-10 前列腺癌和疾病扩展到前列腺以外（pT3/4）。在估计辅助治疗与早期挽救性放疗对全因死亡率（all-cause mortality）风险的因果影响时，研究者使用了治疗倾向评分来缩小治疗选择偏差，并使用敏感性分析来评估不良病理的不同定义对全因死亡率风险的影响，考虑到手术时的年龄, 前列腺的预后因素, 肿瘤部位和时间依赖性使用雄激素剥夺治疗。该研究队列包括 26,118 名患有 pT2-4N0 或 N1M0 前列腺癌的男性，他们在 1989 年 6 月至 2016 年 7 月期间接受了根治性前列腺切除术和盆腔淋巴结评估，然后接受了辅助或早期挽救性放疗, 随访始于根治性前列腺切除术之日，数据库最后更新于 2020 年 10 月。 主要结局指标是具有不良病理的男性的全因死亡风险。
结果: 在中位随访 8.16 (6.00-12.10) 年后，研究队列中的 26,118 名男性中有 2,104 名（8.06%）死亡，其中 539 名（25.62%）来自前列腺癌。在排除具有持续性前列腺特异性抗原的男性后，与早期挽救性放疗相比，在具有根治性前列腺切除术不良病理的男性中，辅助治疗与全因死亡率风险显着降低相关（0.33 [0.13-0.85]；P = .02 ) （排除 pN1患者）, 或 (0.66 [0.44-0.99]; P = .04) （包括 pN1患者）。
结论: 对于 pN1 或 pGleason 评分为 8 至 10 和 pT3/4 前列腺癌的男性，应考虑辅助放射治疗。
In previous randomized controlled trials, adjuvant therapy after radical prostatectomy has not been shown to reduce progression-free survival compared with early salvage radiotherapy. However, given those patients with adverse pathological characteristics in these trials were underrepresented, and possible immortal time bias, the trial might have missed a benefit of adjuvant radiation. This report investigated this possibility. The method was to evaluate patients with positive pelvic lymph nodes (pN1) or pGleason score 8-10 and disease extending beyond prostate (pT3/4). When estimating the causal impact of adjuvant versus early salvage radiotherapy on the risk of all-cause mortality, the researchers used treatment propensity scores to minimize treatment selection bias, and used sensitivity analysis to assess the impact of varying definition of adverse pathology on the risk of all-cause mortality, adjusting for age at the time of surgery, prognostic factors of prostate cancer, tumor site and time-dependent use of androgen deprivation therapy. The study cohort included 26,118 men with pT2-4N0 or N1M0 prostate cancer who underwent radical prostatectomy and pelvic lymph node assessment between June 1989 and July 2016, and then received adjuvant radiation or early salvage radiotherapy. Follow-up started on the day of radical prostatectomy, and the database was last updated in October 2020. The main outcome measure was risk of all-cause death in men with adverse pathologic features.
Results: After a median follow-up of 8.16 (6.00-12.10) years, 2,104 (8.06%) of the 26,118 men in the study cohort, of which 539 (25.62%) died from prostate cancer. After excluding men with persistent prostate-specific antigen, adjuvant compared with early salvage radiotherapy was associated with a significantly lower risk of all-cause mortality in men with adverse pathology after radical prostatectomy (0.33 [0.13] -0.85]; P = .02) when men with pN1 were excluded, or included (0.66 [0.44-0.99]; P = .04).
Conclusion: For men with pN1 or pGleason scores of 8 to 10 and pT3/4 prostate cancer, adjuvant radiotherapy should be considered.
参考文献 Reference Tilki D et al. J Clin Oncol 2021: 39:2284
比较Cabaztaxel与紫杉醇化疗作为 HER2 阴性转移性乳腺癌的 一线治疗 (8/29/21)
Comparison of cabazitaxel and paclitaxel as first line therapy for HER-2-negative metastatic breast cancer
紫杉醇通常用作 HER2 阴性转移性乳腺癌的一线化疗药物。然而，它有显著的周围神经病变风险，因此需要有效和耐受性更好的化疗 。
这是一项开放标签, 随机分布的III期临床试验, 比较了每 3 周一次 共6 个周期的cabaztaxel (25 毫克/平方米)，18 周内每周一次共18周的的紫杉醇 (80毫克/平方米) 作为一线化疗药物。 HER2 阴性且体能状态 < 1 名患者符合条件。使用cabaztaxel的患者接受 GCSF 预防。主要终点是无进展生存期 。次要终点包括客观响应率, 反应时间, 总生存期, 安全性和耐受性以及生活质量。
结果：从 14 家英国医院（每组 79 人）招募了 158 名患者。Cabaztaxel组的中位年龄为 56（34-81）岁，紫杉醇组为 61（34-79）岁。 61% 的患者体能状态为 0。两组的中位治疗时间为 15 周，但更多的紫杉醇患者出现治疗延迟（61% 对 39%）或剂量减少（37% 对 24%）。在 146 次无进展生存期事件后比较cabaztaxel与紫杉醇，中位无进展生存期分别为 6.7 和 5.8 个月（HR 0.84；95%CI 0.60–1.18，P = 0.3）。 中位总生存期 19.3 个月和 20.0 个月（HR 0.94；95%CI 0.63-1.40，P = 0.7）, 客观响应率（42% 对 37%）或反应时间（HR 1.09；95%CI 0.68-1.74，P）没有差异 = 0.7。
共42% 的cabaztaxel患者和 48% 的紫杉醇患者发生≥ 3 级不良事件。腹泻、发热性中性粒细胞减少和恶心是卡巴他赛组最常见的 ≥ 3 级事件，发生率分别为 11%、11% 和 10%，而紫杉醇组为 1%、1% 和 0%。在紫杉醇组中，最严重的≥3 事件是肺部感染和周围神经病变，分别为 6% 和 5%，而卡巴他赛组为 2.5% 和 0%。 55% 接受紫杉醇治疗的患者报告了任何级别的周围神经病变，而接受cabaztaxel治疗的患者为 17%。 41% 的紫杉醇患者出现脱发，而 cabazitaxel 为 27%。紫杉醇（22%）导致停药的不良事件比卡巴他赛（14%）更常见。在治疗过程中，平均 EQ5D 单项指标效用评分（+0.05；95%CI 0.004-0.09，P = 0.03）和视觉模拟量表评分, cabazitaxel 臂与紫杉醇相比，表明 cabazitaxel 具有更好的生活质量。
结论：与每周紫杉醇相比，每3 周cabaztaxel作为 HER2 阴性转移性乳腺癌的一线化疗并未显着改善无进展生存期，但它具有较低的周围神经病变风险，并且患者报告的整体健康结果更好。
Paclitaxel is commonly used as first-line chemotherapy for HER2-negative metastatic breast cancer. However, it has a significant risk of peripheral neuropathy. Effective and better tolerated chemotherapy is therefore needed.
This is an open-label, randomized phase III clinical trial that compared cabaztaxel (25 mg/m²) every 3 weeks for 6 cycles and paclitaxel (80 mg/m²) once a week for 18 weeks as first-line chemotherapy for her-2-negative metastatic breast cancer.. Patients KPS was < 1. Patients taking cabaztaxel received prophylactic GCSF. Primary endpoint was progression-free survival. Secondary endpoints included objective response rate, time to response, overall survival, safety and tolerability, and quality of life.
Results: 158 patients were recruited from 14 British hospitals (79 patients in each group). Median age was 56 (34-81) years in the cabaztaxel group and 61 (34-79) years in the paclitaxel group. Among them, 61% of patients had a performance status of 0. Median treatment time in the two groups was 15 weeks, but more paclitaxel patients experienced treatment delays (61% vs. 39%) or dose reductions (37% vs. 24%). Comparing cabaztaxel and paclitaxel after 146 progression-free survival events, median progression-free survival was 6.7 and 5.8 months, respectively (HR 0.84; 95% CI 0.60–1.18, P = 0.3). Median overall survival was 19.3 months and 20.0 months (HR 0.94; 95%CI 0.63-1.40, P = 0.7). There was no significant difference in objective response rate (42% vs. 37%) , or time to response (HR 1.09; 95%CI 0.68- 1.74, P = 0.7).
A total of 42% in the cabaztaxel patients and 48% in the paclitaxel patients had grade ≥3 adverse events. Diarrhea, febrile neutropenia, and nausea were the most common grade ≥ 3 events in the cabazitaxel group, with incidences of 11%, 11%, and 10%, respectively, compared with 1%, 1%, and 0% in the paclitaxel group. In the paclitaxel group, the most severe ≥3 events were lung infection and peripheral neuropathy, which were 6% and 5%, respectively, while the cabazitaxel group was 2.5% and 0%. Fifty-five% of patients treated with paclitaxel reported any grade of peripheral neuropathy, compared with 17% of patients treated with cabaztaxel. Hair loss occurred in 41% in the paclitaxel patients, compared to 27% with cabazitaxel. Paclitaxel (22%) led to discontinuation due to adverse events that were more common than cabazitaxel (14%). During treatment, the average EQ5D single index utility score (+0.05; 95%CI 0.004-0.09, P = 0.03) and visual analog scale score, cabazitaxel arm compared with paclitaxel, showed that cabazitaxel had a better quality of life.
Conclusion: Compared with weekly paclitaxel, every 3 weeks, cabaztaxel as first-line chemotherapy for HER2-negative metastatic breast cancer did not significantly improve progression-free survival. However, it had a lower risk of peripheral neuropathy and the overall reported overall health outcomes was better.
参考文献 Reference Bahl A. et al. J Clin Onc 2021; 39 (15) supp 1008.
Leronlimab 治疗转移性三阴性乳腺癌 (8/28/2021)
Leronlimab for triple-negative beast cancer
Leronlimab 是一种研究性人源化 IgG4 mAb，可与 CCR5 结合，是 CCR5 拮抗剂，已发表的研究表明，在侵袭性乳腺癌和前列腺癌的实验室和动物模型中，阻断 CCR5 可以减少肿瘤转移。
一项 Ib/II 期临床试验的初步结果， 显示30 名转移性三阴性乳腺癌患者。 使用leronlimab 诱导后, 修改的无进展生存/12 个月无进展生存期增加 400%-660% ; 修改的总体生存/12 个月总体生存增加 570%-980%。
LifeTracDx™ 可测试循环肿瘤细胞的减少, 作为一种平行诊断工具来识别对 leronlimab 有响应的患者。 来自这 30 名患者的数据符合这样一个前提，即如果在接受一次 leronlimab 剂量后观察到循环肿瘤细胞 降低，则大多数三阴性乳腺癌患者对 leronlimab 有响应。可能预测哪些患者对 leronlimab 反应良好。 该研究中的 30 名患者73% 的人观察到在 leronlimab 诱导后环肿瘤细胞降低。
Leronlimab 在小鼠异种移植模型中将人类乳腺癌转移减少了 97% 以上。该制药公司正在进行两项临床试验，一项是三阴性乳腺癌的第二阶段，该试验于 2019 年被 FDA 授予快速通道指定，第二项是包含 22 种不同实体瘤癌症的第二阶段篮式试验。在多种疾病中使用 leronlimab 的患者中，没有发现强烈的安全信号。
Leronlimab is an investigative humanized IgG4 monoclonal antibody that binds to CCR5 and is a CCR5 antagonist. Published data has demonstrated that blocking CCR5 can reduce the spread of breast and prostate tumors in laboratory and animal models.
Preliminary results in a phase Ib/II clinical trial showed encouraging results in 30 patients with metastatic triple-negative breast cancer. After induction with leronlimab, modified progression-free survival/12-month progression-free survival increased by 400%-660%; modified overall survival/12-month overall survival increased by 570%-980%.
LifeTracDx™ can test the reduction of circulating tumor cells as a parallel diagnostic tool to identify patients who are responding to leronlimab. Data from these 30 patients showed that if there was a decrease in circulating tumor cells after receiving a dose of leronlimab, most of such patients with triple-negative breast cancer responded to leronlimab. It is possible to predict which patients would respond well to leronlimab. In this study, 73% of the 30 patients were found to have a decrease in circulating tumor cells after leronlimab induction.
In mouse xenograft model leronlimab reduced human breast cancer metastasis by more than 97. The pharmaceutical company is conducting two clinical trials: one is a phase II in triple-negative breast cancer. Leronlimab was granted Fast Track designation by FDA in 2019, and the second is a phase II basket trial containing 22 different solid tumors. In patients receiving leronlimab in a variety of diseases, no strong safety signals were observed.
参考文献 Reference https://www.obroncology.com/news/cytodyns-final-mtnbc-report-indicates-as-much-as-980-increase-in-12-month?ap=334&vhid=VHBR2383394
在吉西他滨（gemcitabine）中加入 Adavosertib 治疗耐铂的浆液性卵巢癌 (8/22/2021)
Adavosertib plus gemcitabine for platinum-refractory high-grade serous ovarian cancer
TP53 突变在高级别（high-grade）浆液性卵巢癌中普遍存在，导致对 S 期和 G2 期检查点的依赖性增加。用 Wee1 抑制剂 adavosertib诱导 G2 检查点逃逸。将吉西他滨与 Wee1 抑制相结合可通过损害 G2/M 检查点导致有丝分裂灾难。
这是一项双盲II期临床试验，美国加拿大 11 个地点的 94 名铂耐药的、高级别、浆液性卵巢癌患者被随机分配到adavosertib 加吉西他滨（n = 61）或安慰剂加吉西他滨（n = 33）。另外 25 名患有非高级别浆液性卵巢癌的女性被纳入一个探索性队列并接受了联合治疗。治疗包括在第 1、8 和 15 天服用 1,000 毫克/平方米的吉西他滨，在第 1、2、8、9、15 和 16 天每天一次口服175 毫克adavosertib或安慰剂，以 28 天为周期直至疾病进展或不可接受的毒性。主要终点是无进展生存期。 患者的中位年龄为 62 岁 。
试验组和对照组原发肿瘤为上皮卵巢的，分别为 92% 和 88%。在已知状态的患者中，17% 与 12% 有种系或体细胞 BRCA1/2 突变。在有可用数据的 56 相对于 32 名患者中，93% 对 94% 的免疫组织化学有 TP53 突变的肿瘤，56 人中有 86% 相对于 33 人的 67% 有 Sanger 测序上的 TP53 突变。
在最终分析时（2019 年 3 月），adavosertib 加吉西他滨组的中位无进展生存期为 4.6 个月（95% 置信区间 [CI] = 3.6-6.4 个月）相对于 3.0 个月（95% CI = 1.8 –3.8 个月）（风险比 [HR] = 0.55，95% CI = 0.35–0.90，P = .015）。Adavosertib 加吉西他滨组的中位总生存期为 11.4 个月（95% CI = 8.2-16.5 个月），而对照组为 7.2 个月（95% CI = 5.2-13.2 个月）（HR = 0.56，95% CI = 0.35–0.91，P = .017）。 联合组 14 名患者 (23%) 与对照组 2 名 (6%) 患者发生客观响应（部分响应）（P = .038）。联合组中另外 35 名患者 (57%) 与对照组中的 24 名 (73%) 患者观察到病情稳定。在探索性队列中，4 名患者 (16%) 观察到部分响应，另外 9 名患者 (36%) 病情稳定。
最常见的≥ 3 级不良事件是血液学，包括联合组 62% 的患者中性粒细胞减少和对照组的 30%、贫血 31% 相对于 21%、血小板减少症 31% 相对于 6% 和发热性中性粒细胞减少 11% 相对于 0%。联合组中最常见的 ≥ 3 级非血液学不良事件是疲劳、高血压、腹痛、血栓栓塞事件、腹泻、呼吸困难和斑丘疹。 不良事件导致 21% 相对于 0% 的患者停止治疗。 没有报告与治疗相关的死亡。
研究人员的结论：在吉西他滨中加入口服 Wee1 抑制剂 adavosertib 可改善铂类耐药患者的无进展生存期和总生存期。
TP53 mutation is prevalent in high-grade serous ovarian cancer, leading to increased dependence on S and G2 checkpoints. Wee1 inhibitor adavosertib was used to induce G2 checkpoint escape. Combining gemcitabine with Wee1 inhibition can lead to mitotic catastrophe by damaging the G2/M checkpoint.
This is a double-blind, phase II clinical trial. Ninety-four platinum-resistant, high-grade, serous ovarian cancer patients in 11 locations in the United States and Canada were randomly assigned to adavosertib plus gemcitabine (n = 61) or placebo plus gemcitabine ( n = 33). Another 25 women with non-high-grade serous ovarian cancer were included in an exploratory cohort and received combination therapy. Treatment includes 1,000 mg/m² of gemcitabine on days 1, 8, and 15, and 175 mg of adavosertib or placebo orally once a day on days 1, 2, 8, 9, 15 and 16, in a 28-day cycle until disease progression or unacceptable toxicity. The primary endpoint is progression-free survival. The median age of the patients was 62 years. Primary tumor location was epithelial ovary in 92% vs 88%. Among those with a known status, 17% vs 12% had germline or somatic BRCA1/2 mutation. Among 56 vs 32 patients with available data, 93% vs 94% had TP53-mutated tumors on immunohistochemistry and 86% of 56 vs 67% of 33 had TP53 mutation on Sanger sequencing.
At the time of the final analysis (March 2019), median progression-free survival in the adavosertib plus gemcitabine group was 4.6 months (95% confidence interval [CI] = 3.6-6.4 months) versus 3.0 months (95%[ CI]= 1.8 – 3.8 months) (hazard ratio [HR] = 0.55, 95% CI = 0.35–0.90, P = .015). Median overall survival of the adavosertib plus gemcitabine group was 11.4 months (95% CI = 8.2-16.5 months), while the control group was 7.2 months (95% CI = 5.2-13.2 months) (HR = 0.56, 95 % CI = 0.35–0.91, P = .017). Objective responses occurred in 14 patients (23%) in the combination group and 2 (6%) patients in the control group (all were partial response) (P = .038). Stable disease was observed in another 35 patients (57%) in the combination group and 24 (73%) in the control group. In the exploratory cohort, 4 patients (16%) observed a partial response, and 9 patients (36%) were in stable condition.
The most common ≥ grade 3 adverse events were hematological, including neutropenia in 62% of patients in the combination group and 30% in the control group, anemia 31% vs. 21%, thrombocytopenia 31% vs. 6%, and febrile neutropenia 11% compared to 0%. The most common nonhematological adverse events of grade ≥3 in the combination group were fatigue, hypertension, abdominal pain, thromboembolic events, diarrhea, dyspnea, and maculopapular rash. Adverse events caused 21% of patients to discontinue treatment compared to 0%. No deaths related to treatment were reported.
Conclusions from the researchers: adding the oral Wee1 inhibitor adavosertib to gemcitabine may improve progression-free survival and overall survival of platinum-resistant patients.
参考文献 Reference Lheureux S et al. Lancet 2021; 397:281
Tivozanib用于复发或难治性晚期肾细胞癌 (8/21/2021)
Tivozanib for refractory or relapsed renal cell cancer
这是一项随机、开放标签、多中心试验（TIVO-3, NCT02627963），Tivozanib 是一种血管内皮生长因子受体 (VEGFR) 酪氨酸激酶抑制剂。该试验旨在评价tivozanib与索拉非尼（sorafenib）相比在复发或难治性晚期肾细胞癌患者中的疗效。这些患者曾接受过两种或三种先前的全身治疗，包括在索拉非尼或tivozanib以外的至少一种 VEGFR 激酶抑制剂。患者被随机分配接受每天一次口服 1.34 毫克 tivozanib , 每 28 天连续 服21 天, 或每天两次口服索拉非尼 400 毫克，直至疾病进展或出现不可接受的毒性。 主要疗效结果指标是无进展生存期，由不知情的独立放射学审查委员会评估。其他疗效终点是总生存期和客观反应率。
Tivozanib 组的中位无进展生存期为 5.6 个月（95% 置信区间 [CI] = 4.8-7.3），而索拉非尼治疗组的中位无进展生存期为 3.9 个月（95% CI = 3.7-5.6）（风险比 [HR] = 0.73，95% CI = 0.56–0.95，P = .016）。 Tivozanib 和索拉非尼组的中位总生存期分别为 16.4（95% CI = 13.4-21.9）和 19.2 个月（95% CI = 14.9-24.2）（HR = 0.97，95% CI = 0.75-1.24）。 Tivozanib 组的客观响应率为 18%（95% CI = 12%–24%），索拉非尼组的客观响应率为 8%（95% CI = 4%–13%）。
最常报告的不良反应是疲劳、高血压、腹泻、食欲下降、恶心、发声困难、甲状腺功能减退、咳嗽和口腔炎。最常报告的 3 级或 4 级实验室异常是钠减少、脂肪酶增加和磷酸盐减少。
FDA 已批准 Tivozanib 用于治疗复发性或难治性晚期肾细胞癌，推荐的 tivozanib 剂量为 1.34 毫克，每天一次，连续 21 天，每 28 天为一个周期。
This is a randomized, open-label, multicenter trial (TIVO-3, NCT02627963). Tivozanib is a differentiated vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor. The trial aimed to evaluate the efficacy of tivozanib in comparison with sorafenib in patients with relapsed or refractory advanced renal cell carcinoma. These patients had received two or three previous systemic treatments, including at least one VEGFR kinase inhibitor other than sorafenib or tivozanib. Patients were randomly assigned to receive either daily 1.34 mg of tivozanib orally for 21 consecutive days every 28 days, or sorafenib 400 mg orally twice a day, until disease progression or unacceptable toxicity. The main efficacy measure was progression-free survival, which was assessed by a blinded independent radiology review committee. Other efficacy endpoints were overall survival and objective response rate.
Median progression-free survival in the Tivozanib group was 5.6 months (95% confidence interval [CI] = 4.8-7.3), while that in the sorafenib group was 3.9 months (95% CI = 3.7-5.6) (hazard ratio [HR] = 0.73, 95% CI = 0.56–0.95, P = .016). Median overall survival in the Tivozanib and Sorafenib groups was 16.4 (95% CI = 13.4-21.9) and 19.2 months (95% CI = 14.9-24.2) (HR = 0.97, 95% CI = 0.75-1.24), respectively. The objective response rate in the Tivozanib group was 18% (95% CI = 12%–24%), and that in the sorafenib group was 8% (95% CI = 4%–13%).
The most commonly reported adverse reactions were fatigue, high blood pressure, diarrhea, loss of appetite, nausea, dysphonia, hypothyroidism, cough and stomatitis. The most commonly reported grade 3 or 4 laboratory abnormalities were decreased sodium, increased lipase, and decreased phosphate.
FDA has approved Tivozanib for the treatment of relapsed or refractory advanced renal cell carcinoma. The recommended dose of tivozanib is 1.34 mg once a day for 21 consecutive days in a 28-day cycle.
参考文献 Reference https://ascopost.com/issues/april-25-2021/fda-approves-tivozanib-for-relapsed-or-refractory-advanced-renal-cell-carcinoma
免疫抑制剂派姆单抗（pembrolizumab）联合化疗作为新辅助治疗高危早期三阴性乳腺癌 (8/15/2021)
Pembrolizumab in combination with chemotherapy for high-risk early-stage triple-negative breast cancer
FDA 批准派姆单抗联合化疗用于新辅助治疗高危早期三阴性乳腺癌, 然后继续单药作为手术后的辅助治疗。
KEYNOTE-522 (NCT03036488) 是一项随机、多中心、双盲、安慰剂对照试验，在 1,174 名患有新诊断的未经治疗的高危早期三阴性乳腺癌（肿瘤 > 1 厘米 但直径 ≤ 2 厘米 且淋巴结受累, 或肿瘤 > 2 cm，无论淋巴结受累情况如何）。无论肿瘤 PD-L1 表达如何，患者都被纳入研究。 患者随机 (2:1) 接受派姆单抗联合化疗或安慰剂联合化疗。派姆单抗（每 3 周 200 毫克）加紫杉醇（每周）和卡铂（每周或每三周）共四个周期，然后是派姆单抗加环磷酰胺和阿霉素（每 3 周）共四个周期作为手术前的新辅助治疗。手术后再接受九个周期的 派姆单抗（每三周）作为辅助治疗。派姆单抗与化疗联合给药用于新辅助治疗 24 周，然后作为单药用于辅助治疗长达 27 周。主要疗效结果指标是病理完全响应率和无事件生存率。
派姆单抗联合化疗患者的病理完全响应率为 63%（95% CI：59.5、66.4），而单独接受化疗的患者病理完全响应率率为 56%（95% CI：50.6、60.6）。经历无事件生存率事件的患者人数分别为 123 (16%) 和 93 (24%)（HR 0.63；95% CI：0.48, 0.82；p = 0.00031）。 在派姆单抗联合化疗的试验中，≥20% 的患者报告的最常见不良反应是疲劳/乏力、恶心、便秘、腹泻、食欲下降、皮疹、呕吐、咳嗽、呼吸困难、发热、脱发、周围神经病变、粘膜炎症、口腔炎、头痛、体重减轻、腹痛、关节痛、肌痛和失眠。
这种联合疗法改变了治疗高危早期三阴性乳腺癌的实践。
FDA approved, on July 26, 2021, pembrolizumab in combination with chemotherapy for neoadjuvant treatment of high-risk early-stage triple-negative breast cancer, and then as a single drug for adjuvant therapy.
KEYNOTE-522 (NCT03036488) is a randomized, multicenter, double-blind, placebo-controlled trial of 1,174 newly diagnosed untreated high-risk early-stage triple-negative breast cancer (tumor diameter > 1 cm but ≤ 2 cm with lymph node involvement, or tumor diameter > 2 cm, no matter whether lymph node is involved). Regardless tumor PD-L1 expression, patients were included in the study. The patients were randomized (2:1) to receive pembrolizumab plus chemotherapy or placebo plus chemotherapy. As neoadjuvant treatment before surgery, pembrolizumab (200 mg every 3 weeks) plus paclitaxel (weekly) and carboplatin (weekly or every three weeks) for four cycles, followed by pembrolizumab plus cyclophosphamide and doxorubicin (every 3 weeks) for four cycles. After surgery, patients received nine cycles of pembrolizumab (every three weeks) as adjuvant therapy. In total, pembrolizumab was administered in combination with chemotherapy for neoadjuvant therapy for 24 weeks, and then as a single agent for adjuvant therapy for up to 27 weeks. The main efficacy outcome indicators were pathological complete response rate and event-free survival rate.
The pathological complete response rate of patients with pembrolizumab combined with chemotherapy was 63% (95% CI: 59.5, 66.4), while the pathological complete response rate of patients receiving chemotherapy alone was 56% (95% CI: 50.6, 60.6). The number of patients who experienced event-free survival events were 123 (16%) and 93 (24%) (HR 0.63; 95% CI: 0.48, 0.82; p = 0.00031) respectively.
The most common adverse reactions (>20%) reported in the combination arm, were fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, fever, hair loss, peripheral Neuropathy, mucosal inflammation, stomatitis, headache, weight loss, abdominal pain, arthralgia, myalgia, and insomnia.
This combination therapy is practice-changing in managing high-risk early-stage triple-negative breast cancer.
参考文献 Reference https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-high-risk-early-stage-triple-negative-breast-cancer July 26, 2021 Schmid P et al. N Engl J Med 2020; 382: 810
Amivantamab 与 lazertinib 联用可能治疗奥希替尼（Osimertinib）而复发的非小细胞肺癌 (8/14/2021)
Combination of Amivantamab and lazertinib may overcome osimertinib-resistance in non-small cell lung cancer patients
在初治和奥希替尼复发的非小细胞肺癌患者 中，观察到了 amivantamab（一种 EGFR-MET 双特异性抗体）和 lazertinib（一种第三代酪氨酸激酶抑制剂）的组合的初步疗效。
正在进行的一项II期临床试验（ CHRYSALIS, NCT02609776) 的联合队列中招募了具有表皮生长因子受体 （EGFR） 外显子 19 缺失或 L858R 突变的非小细胞肺癌患者，这些患者没有接受过化疗, 在奥希替尼治疗上进展。通过前瞻性收集治疗前肿瘤活检和 ctDNA。患者接受 1050或1400 毫克 amivantamab 与 240 毫克 lazertinib 的组合剂量，以评估对奥希替尼复发人群的安全性和有效性。研究人员根据 RECIST v1.1 标准评估反应。通过下一代测序 (NGS) 在 ctDNA 或肿瘤活检中鉴定的 EGFR/MET 中的奥希替尼抗性突变或扩增，评估了富集反应。 EGFR 和 MET 表达的免疫组织化学染色也被探索为潜在的响应生物标志物。
结果：在 45 名奥希替尼复发患者中，36%（95% CI，22-51）有确认的响应（1 个完全响应和 15 个部分响应）。中位随访时间为 8.2 个月（1.0-11.8），20/45 患者（44%）仍在接受治疗。 11/16 患者 (69%) 持续缓解（2.6-9.6+ 个月），尚未达到中位响应持续时间。中位无进展生存期为 4.9 个月（95% CI，3.7-8.3）。
总共有 44/45 患者可通过 ctDNA 进行评估。生物标志物和下一代序列确定了一个更可能对这种组合产生响应的患者亚组：那些具有基于 EGFR/MET 的耐药性的患者。 免疫组织化学染色表明 EGFR 和 MET 的高表达可能是识别这种组合响应者的另一种方法。
结论：amivantamab 和 lazertinib 的组合治疗在 36% 的奥希替尼进展的未接受化疗的患者中产生了响应。在这些患者中，基于基因 EGFR 和 MET 的耐药生物标志物确定了一个更可能对 amivantamab 和 lazertinib 产生反应的患者亚组。
Preliminary results suggested clinical benefit of a combination of amivantamab (an EGFR-MET bispecific antibody) and lazertinib (a third-generation tyrosine kinase inhibitor) in non-small cell lung cancer patients who relapsed following osimertinib treatment.
An ongoing phase II clinical trial (CHRYSALIS, NCT02609776) recruited non-small cell lung cancer patients with epidermal growth factor receptor (EGFR) exon 19 deletion or L858R mutation in a combination cohort These patients had never received chemotherapy and they progressed in the treatment of osimertinib. Through prospective collection, tumor biopsy and ctDNA before treatment were obtained. Patients received a combined dose of 1050 or 1400 mg of amivantamab and 240 mg of lazertinib. The aim was to evaluate the safety and effectiveness of osimertinib-refractory population. The researchers assessed response according to the RECIST v1.1 criteria. The enrichment response was evaluated by next-generation sequencing (NGS) in ctDNA or tumor biopsy to identify osimertinib resistance mutations or amplifications in EGFR/MET. Immunohistochemical (IHC) staining of EGFR and MET expression has also been explored as potential response biomarkers.
Results: Of the 45 osimertinib-relapsed patients, 36% (95% CI, 22-51) had a confirmed response (1 complete response and 15 partial responses). The median follow-up was 8.2 months (1.0-11.8), and 20/45 patients (44%) were still receiving treatment. 11/16 patients (69%) had sustained remission (2.6-9.6+ months) and had not yet reached median duration of response. The median progression-free survival was 4.9 months (95% CI, 3.7-8.3).
A total of 44/45 patients could be evaluated by ctDNA. Biomarkers and next-generation sequences identified a subset of patients who were more likely to respond to this combination: those with EGFR/MET-based resistance. IHC staining indicated that high expression of EGFR and MET may be another way to identify responders with this combination.
Conclusion: The combination therapy of amivantamab and lazertinib responded in 36% of osimertinib-refractory patients who did not receive prior chemotherapy. Among these patients, resistance biomarkers based on EGFR and MET identified a subgroup of patients who were more likely to respond to amivantamab and lazertinib combination.
参考文献 Reference Bauml J. J Clin Onc 2021; 39 (5) supp. DOI: 10.1200/JCO.2021.39.15_suppl.9006
数据库研究显示他汀类药物可能有利于三阴性乳腺癌患者 (8/8/2021)
Retrospective data analyses suggested possible benefit of Statin in triple-negative breast cancer
以往对他汀类药物治疗和乳腺癌结果之间的关联的研究结果不一。这是一项调查他汀类药物对三阴性乳腺癌的临床影响。 该回顾性调查使用的数据来自”监测、流行病学和最终结果 – 医疗保险和德克萨斯癌症登记” 数据库的数据，对像患为有 I、II 和 III 期乳腺癌的 66 岁以上女性。多变量 Cox 比例风险回归模型用于检查乳腺癌诊断后 12 个月内新使用他汀类药物与总生存率和乳腺癌特异性生存率的关联。 在整个组中，1,534 名患者患有三阴性乳腺癌, 1,376 名非使用者和 158 名他汀类药物使用者。 总生存率的中位随访时间为 4.4 年，乳腺癌特异性生存率的中位随访时间为 3.3 年。 研究人群中共有 5,327 人死亡，其中 1,038 人死于乳腺癌。
结果: 在检查意外使用他汀类药物使用（定义为在乳腺癌诊断后 12 个月内开始他汀类药物治疗）时，他汀类药物使用与三阴性乳腺癌的乳腺癌特异性生存率改善之间存在显著关联（标准风险比，0.42；95% 置信区间 [CI]，0.20- 0.88；P = .022）; 也包括总生存率（风险比，0.70；95% CI，0.50-0.99；P = .046）。在非三阴性乳腺癌中（n = 15,979）, 未观察到与乳腺癌特异性生存率（标准风险比，0.99；95% CI，0.71-1.39；P = .97）或总生存率（风险比，1.04；95% CI，0.92-1.17；P = .55）之间的关联。 在将他汀类药物暴露作为时变变量（time-varying variable）进行检查时，结果是一致的。
结论 在 I、II 和 III 期三阴性乳腺癌 女性中，在乳腺癌诊断后 12 个月内开始他汀类药物治疗与总生存率和乳腺癌特异性生存率获益相关。研究者指出，由于他们的研究队列仅限于诊断时年龄在 66 岁或以上的女性，并且他们排除了在之后的 12 个月内没有连续加入医疗保险D 部分的患者，因此他们的结果的普遍性可能会受到限制。 还有其他一些限制，没有包括医疗保险前他汀类药物的使用，以及乳腺癌特异性生存结果的随访时间相对较短，特别对早期乳腺癌亚型。他汀类药物是否可能在特定的乳腺癌患者中起作用，需要进一步研究。
Previous studies on the association between statin use and breast cancer outcomes led to mixed results. The current study investigated clinical impact of statins on triple-negative breast cancer. This retrospective survey used data from the “Surveillance, Epidemiology, and End Results-Medicare and Texas Cancer Registry” Medicare database, and women over 66 years of age with stage I, II, and III breast cancer. Multivariable Cox proportional hazarsd regression model was used to examine the association of new statin use in the 12 months after a breast cancer diagnosis with overall survival and breast cancer-specific survival. In the entire group, 1,534 patients had triple-negative breast cancer, 1,376 non-users and 158 statin users. Median follow-up time for overall survival was 4.4 years, and the median follow-up time for breast cancer-specific survival was 3.3 years. There were 5,327 deaths in the study population, of which 1,038 died of breast cancer.
Results: When examining incidental use of statins (defined as starting statin treatment in the 12 months of breast cancer diagnosis), there was a significant association between statin use and improved breast cancer-specific survival for triple-negative breast cancer (standardized hazard ratio, 0.42; 95% confidence interval [CI], 0.20-0.88; P = .022), and overall survival (hazard ratio, 0.70; 95% CI, 0.50-0.99; P = .046 ). In non-triple-negative breast cancer (n = 15,979), no breast cancer-specific survival (standardized hazard ratio, 0.99; 95% CI, 0.71-1.39; P = .97) or overall survival (hazard ratio , 1.04; 95% CI, 0.92-1.17; P = .55). When examining statin exposure as a time-varying variable, the results were consistent.
Conclusion In women with stage I, II, and III triple-negative breast cancer, starting statin therapy within 12 months after breast cancer diagnosis was associated with overall survival and breast cancer-specific survival benefits. The investigators pointed out that because their study cohort was limited to women who were 66 years of age or older at the time of diagnosis, and that they excluded patients who did not have continuous Part D enrollment in the 12 months after diagnosis, the generalizability of their results might be limited. Other limitations included the use of statins before Medicare enrollment, and the relatively short follow-up time for breast cancer-specific survival, especially for early breast cancer subtypes. Whether statins may work in a specific breast cancer subtype needs further research.
参考文献 Reference Malgorzata K et al. Cancer First published: 03 August 2021 https://doi.org/10.1002/cncr.33797
双特异性抗体Amivantamab治疗非小细胞肺癌 (8/7/2021)
Bispecific antibody Amivantamab in treating non-small cell lung cancer
Amivantamab 是一种具有免疫细胞定向活性的双特异性抗体，旨在参与非小细胞肺癌的两种不同驱动途径：EGFR 和 MET。当 EGFR 发生突变时，细胞生长不受控制，使异常细胞有机会生长和繁殖。在不到 10% 的患者中有一种 EGFR 外显子 20 插入 (EGFR Ex20Ins)突变, 对 酪氨酸激酶抑制剂没有反应, 这种特定 EGFR 突变的患者预后较差。 一个下一代测序平台STAR（Solid Tumor Actionable Result），可精确识别可能受益于 EGFR Ex20Ins 靶向治疗的 EGFR Ex20Ins 突变患者。
CHRYSALIS 是一项评估 amivantamab 的 1 期、开放标签、剂量递增和剂量扩展试验，该研究的新数据包括 81 名患者。总响应率为 40%， 3 名患者完全缓解，29 名患者出现部分响应。中位响应持续时间为 11.1 个月，其中 20 名患者的响应至少为 6 个月或更长。这种新型疗法已获得FDA的突破性疗法命名。
Amivantamab is a bispecific antibody with immune cell directing activity, designed to engage in two different driver pathways of non-small cell lung cancer: EGFR and MET. When EGFR is mutated, cell growth is not normally regulated, giving abnormal cells a chance to grow and reproduce. In less than 10% of patients, there is an EGFR exon 20 insertion (EGFR Ex20Ins) mutation that does not respond to tyrosine kinase inhibitors approved by FDA. Patients with this specific EGFR mutation have a poor prognosis. A next-generation sequencing platform, STAR (Solid Tumor Actionable Result), can accurately identify patients with EGFR Ex20Ins mutations who may benefit from EGFR Ex20Ins targeted therapy.
CHRYSALIS is a phase 1, open-label, dose escalation, and dose extension trial evaluating amivantamab. The new expanded data for the study included 81 patients. Overall response rate was 40%, 3 patients had a complete response, and 29 patients had a partial response. The median duration of response was 11.1 months, of which 20 patients had a response of at least 6 months or longer. This new type of therapy has been granted breakthrough therapy by the FDA.
参考文献 Reference https://moffitt.org/newsroom/press-release-archive/novel-therapy-shows-promise-for-lung-cancer-patients-with-rare-egfr-mutation/
临床试验BBP-398与nivolumab联合治疗具有 KRAS 突变的晚期实体瘤 (8/1/2021)
Clinical trial to study the combination of BBP-398 with nivolumab in advanced solid tumors with KRAS mutation
BBP-398是一种SHP2 抑制剂,。 SHP2 是一种蛋白质酪氨酸磷酸酶，可将生长因子、细胞因子和整合素信号与下游 RAS/ERK MAPK 通路联系起来，以调节细胞增殖和存活。 SHP2 通路的过度活跃通常由不同的基因突变驱动，是导致多种癌症的关键因素，并且是对多种靶向疗法产生抗性的一种机制。 过度活跃的 MAPK 信号驱动的癌症，包括某些 RAS 突变，如 KRASG12C，可能对 SHP2 抑制敏感。KRAS 突变发生在大约 27% 的非小细胞肺癌病例和大约 17% 的恶性实体瘤中, 到目前为止，很少有药物可以成功靶向这种突变。将抗 PD-1 治疗与 BBP-398 以及其他靶向治疗相结合，希望可能对 KRAS 突变患者有效。
这项临床I/II 期试验将研究BBP-398与纳武单抗组合治疗具有 KRAS 突变的晚期实体瘤患者，还将评估 BBP-398 联合纳武单抗作为双联疗法, 和此双联加上 KRASG12C 抑制剂的三联疗法作为具有 KRAS 突变的非小细胞肺癌的安全性和初步疗效。
BP-398 is a SHP2 inhibitor. SHP2 is a protein-tyrosine phosphatase that links growth factor, cytokine and integrin signals with downstream RAS/ERK MAPK pathways to regulate cell proliferation and survival. Overactivity of the SHP2 pathway. often driven by different gene mutations, is a key factor leading to a variety of cancers, and a mechanism for resistance to a variety of targeted therapies. Cancers driven by overactive MAPK signaling, including certain RAS mutations, such as KRASG12C, may be sensitive to SHP2 inhibition. KRAS mutations occur in approximately 27% of non-small cell lung cancer and approximately 17% of malignant solid tumors. So far, few drugs can successfully target this mutation. Combining anti-PD-1 therapy with BBP-398 and other targeted therapies, it is hoped that this combination may be effective for patients with KRAS mutations.
This phase I/II clinical trial will study the combination of BBP-398 and nivolumab in the treatment of patients with advanced solid tumors with KRAS mutations. It will also evaluate the combination of BBP-398 and nivolumab as a dual therapy, as well as this dual therapy plus KRASG12C inhibitors as a triple therapy to evaluate the safety and preliminary efficacy in non-small cell lung cancer with KRAS mutations.
参考文献 Reference https://bridgebio.com/news/bridgebio-announces-clinical-collaboration-with-bristol-myers-squibb-to-study-bbp-398-a-potentially-best-in-class-shp2-inhibitor-in-combination-with-opdivo-nivolumab-in-advanced-solid-tumors
Eganelisib 联合纳武单抗 (Nivolumab) 治疗铂类难治性尿路上皮癌 (7/31/21)
Eganelisib in combination with Nivolumab in treating cisplatin-refractory urothelial cancer
MARIO-275 是一项II期临床试验, 评估 eganelisib 联合纳武单抗在铂类难治性 尿路上皮癌患者中的疗效和安全性。 在多项临床研究中，eganelisib 是第一种口服免疫肿瘤候选药物，可选择性抑制 PI3K-γ。一共49 名患者参加了试验。 在意向治疗人群中，eganelisib 加纳武单抗联合治疗组的中位总生存期为 15.4 个月，而单独使用纳武单抗的对照组为 7.9 个月，死亡风险为0.62 (0.28, 1.36) 。 在随访一年中，接受 eganelisib 加纳武单抗联合治疗的意向治疗人群中有 59% 的患者仍然存活，而纳武单抗对照组中这一比例为 32%。
在 PD-L1阴性肿瘤患者中, 中位总生存期获益与意向治疗人群相同，eganelisib 加纳武单抗联合组的中位总生存期为 15.4 个月，而单独使用纳武单抗的为 7.9 个月，风险比为 0.60 (0.21, 1.71)。 在随访一年中, PD-L1阴性的联合组肿瘤患者中有 54% 仍然活着，而纳武单抗对照组中这一比例为 17%。
最常见的≥3 级不良事件 是贫血 (12.1%) 和肝脏不良事件，包括肝毒性 (15.2%)、ALT 升高 (12.1%) 和 AST 升高 (12.1) %) 。未报告 5 级肝脏不良事件。 来自外周血的基因表达研究表明，在将治疗第 15 天与基线进行比较时，促炎性干扰素 γ 和干扰素 α 通路是联合组中最显著增加的通路，无论PD-L1 状态如何，与对照组相比具有更高的富集分数和更低的 p 值。这些数据与 eganelisib 的作用机制一致，即减少免疫抑制并增加免疫激活。
MARIO-275 is a phase II clinical trial to evaluate the efficacy and safety of eganelisib in combination with nivolumab in patients with platinum- refractory urothelial cancer. In a number of clinical studies, eganelisib has been shown to be the first oral immuno-oncology drug development candidate that can selectively inhibit PI3K-γ. A total of 49 patients participated in the trial. Among the intent-to-treat population, median overall survival of the eganelisib and nivolumab combination treatment group was 15.4 months, while that of the nivolumab alone control group was 7.9 months, and the risk of death was 0.62 (0.28, 1.36). At the one-year landmark, 59% of the intent-to-treat population receiving the combination of eganelisib and nivolumab were still alive, compared with 32% in the control group.
In patients with PD-L1 negative tumors, median overall survival benefit was the same as that of the intent-to-treat population. Median overall survival of the eganelisib and nivolumab combination group was 15.4 months, while that of the control group was 7.9 Month, with a hazard ratio of 0.60 (0.21, 1.71). At the one-year landmark, 54% of tumor patients in the PD-L1-negative combination group were still alive, compared with 17% in the control group.
The most common adverse events of > grade 3 treatment-related side-effects were anemia (12.1%) and liver adverse events, including liver toxicity (15.2%), elevated ALT (12.1%), and elevated AST (12.1)%). No grade 5 liver adverse events were reported. Gene expression studies from peripheral blood showed that when comparing the 15th day with baseline, the pro-inflammatory interferon gamma and interferon alpha pathways were the most significantly enriched pathways in the combination group, regardless of PD-L1 status. Compared with the control group, it had a significantly higher enrichment score and a lower p-value. These data are consistent with eganelisib’s mechanism of action, which is to reduce immunosuppression and increase immune activation.
参考文献 Reference Infinity Pharmaceuticals Data: Published online July 27, 2021. Accessed July 28, 2021. https://bwnews.pr/3y6gEmt.
首例研究性磁性装置在人体试验中缩小胶质母细胞瘤 (7/25/2021)
Oncomagnetic device treatment in a first case of recurrent glioblastoma
胶质母细胞瘤是成人中最致命的脑癌，预期寿命为几个月到两年。 一位 53 岁的胶质母细胞瘤患者, 他的病在手术、放疗和基因治疗后复发。 美国休斯顿卫理公会神经病学研究所神经外科系的研究人员使用头盔产生的无创振荡磁场给他治疗, 首先在诊所的监督下进行两个小时的治疗，随后在家中进行治疗，治疗时间增加到每天最多只有 6 小时。附有 3 个 oncoscillators 的设备头盔。它们连接到由可充电电池供电的控制器盒。 在五周治疗期间，磁疗耐受性良好。在接受治疗大约一个月后死于无关的伤害，但在这短短的时间内，31% 的肿瘤块消失了。他的大脑尸检证实了对治疗的快速反应。 缩小似乎与治疗剂量相关。
Glioblastoma is the deadliest brain cancer in adults, with a life expectancy of several months to two years. A 53-year-old patient with glioblastoma relapsed after surgery, radiation and gene therapy. Researchers from the Department of Neurosurgery at the Methodist Institute of Neurology, Houston, USA used a non-invasive oscillating magnetic field to treat him. First, he was treated for two hours under the supervision at the clinic, and then he was treated at home. The treatment time was every day to a maximum of 6 hours. The magnetic device comes with 3 oncoscillators’ equipment in a helmet. They are connected to a controller box powered by a rechargeable battery. During the five-week treatment period, magnetic therapy was well tolerated. He died of unrelated injuries about a month after receiving treatment, but within this short period of time, 31% of the tumor mass disappeared. An autopsy of his brain confirmed a rapid response to treatment. The reduction seems to be related to the therapeutic dose.
参考文献 Reference David S et al. Frontiers in Oncology, 2021; 11
术后pembrolizumab延长高危肾细胞癌的无病生存期 (7/24/2021)
Adjuvant pembrolizumab extends disease-free survival in high-risk renal cell carcinoma
高达 40%肾细胞癌 会在手术后发展为转移性疾病, 手术后没有标准的治疗方案来预防复发。KEYNOTE-564 是肾细胞癌辅助免疫疗法的第一个 III 期研究，也是许多在 III 期试验中呈阳性的辅助方法中的第一个。
这是一项随机、双盲, 国际 III期临床试验。 招募了 994 名经组织学证实的高危透明细胞肾细胞癌患者，这些患者在随机分布前至少 12 周接受了肾切除术。患者既往未接受全身治疗。他们以 1:1 的比例随机分配接受每 3 周 200 毫克的辅助（术后）帕pembrolizumab治疗，最多 17 个周期（约 1 年）或安慰剂。主要终点是根据研究者评估的无病生存率; 总生存期和安全性是次要终点。
主要发现 在中位随访 24 个月时，达到了主要终点。与安慰剂相比，pembrolizumab将复发或死亡风险降低了 32%，这种差异具有统计学意义（P = .0010）。Pembrolizumab组的 12 个月无病生存率为 85.7%，而安慰剂组为 76.2%。在第 24 个月时，无病生存率分别为 77.3% 和 68.1%。 在 12 个月和 24 个月时，两组之间无病生存率的绝对差异大约为 10%。生存数据还为时过早，但在第 24 个月，96.6% 的 pembrolizumab 组存活，而安慰剂组为 93.5% 。派姆单抗组有 18 人死亡，安慰剂组有 33 人死亡。
安全性结果符合预期，pembrolizumab没有新的安全性信号，96.3% 的 pembrolizumab 组和 91.1% 的安慰剂组报告了不良事件。 3 至 5 级不良事件的发生率分别为 32.4% 和 17.7%。 由于不良事件，pembrolizumab组有 2 人死亡，安慰剂组有 1 人死亡。
Up to 40% of renal cell carcinoma will develop metastatic disease after surgery, and there is no standard treatment plan to prevent recurrence after surgery. KEYNOTE-564 is the first phase III study of adjuvant immunotherapy for renal cell carcinoma and the first of many adjuvant therapies that have been positive results in phase III trials.
This is a randomized, double-blind, international phase III clinical trial. It enrolled 994 patients with histologically confirmed high-risk clear cell renal cell carcinoma who underwent nephrectomy at least 12 weeks before randomization. The patient did not receive systemic treatment in the past. They were randomly assigned to receive 200 mg of adjuvant (postoperative) pembrolizumab every 3 weeks at a 1:1 ratio for up to 17 cycles (approximately 1 year) or placebo. The primary endpoint was disease-free survival per investigator’s assessment. Overall survival and safety were secondary endpoints.
At a median follow-up of 24 months, the primary endpoint was reached. Compared with placebo, pembrolizumab reduced the risk of recurrence or death by 32%. This difference was statistically significant (P = .0010). The 12-month disease-free survival rate in the Pembrolizumab group was 85.7%, compared with 76.2% in the placebo group. At 24th month, disease-free survival rates were 77.3% and 68.1%, respectively. At 12 months and 24 months, the absolute difference in disease-free survival between the two groups was approximately 10%. Survival data was too early, but at month 24, 96.6% of the pembrolizumab group survived, compared to 93.5% of the placebo group. There were 18 deaths in the pembrolizumab group and 33 deaths in the placebo group.
The safety results were in line with expectations. There were no new safety signals for pembrolizumab. Adverse events were reported in 96.3% of the pembrolizumab group and 91.1% of the placebo group. The incidence of grade 3 to 5 adverse events was 32.4% and 17.7%, respectively. Due to adverse events, there were 2 deaths in the pembrolizumab group and 1 death in the placebo group.
参考文献 Reference Choueiri TK et al. 2021 ASCO Annual Meeting. Abstract LBA5.
Olaparib 用于 BRCA1 或 BRCA2 突变的乳腺癌患者的辅助治疗 (7/18/2021)
Olaparib for adjuvant use in BRCA1/2-mutated breast cancer
这是一项 III 期、双盲、随机试验（OlympiA），共有1.836名患有 BRCA1 或 BRCA2 种系致病性或可能致病性变异和高危临床病理因素患者参加, 她们为HER2 阴性的早期乳腺癌患者（三阴性或雌/孕激素受体阳性）, 并且接受过局部治疗和新辅助或辅助化疗。患者被随机分配（以 1:1 的比例）接受 1 年的口服Olaparib或安慰剂。主要终点是无侵袭性疾病生存期。
在中位随访 2.5 年的预先指定的中期分析中，Olaparib组的 3 年无侵袭性疾病生存率为 85.9%，安慰剂组为 77.1%（差异，8.8 个百分点；95%置信区间 [CI]，4.5 至 13.0；侵袭性疾病或死亡的风险比，0.58；99.5% CI，0.41 至 0.82；P < 0.001）。Olaparib组的 3 年无远处疾病生存率为 87.5%，安慰剂组为 80.4%（差异，7.1 个百分点；95% CI，3.0 至 11.1；远处疾病或死亡的风险比，0.57；99.5% CI，0.39 至 0.83；P < 0.001)。与安慰剂相比，Olaparib与更少的死亡相关（分别为 59 和 86）（风险比，0.68；99% CI，0.44 至 1.05；P = 0.02）；然而，在中期分析时，两组间无P 值小于 0.01的显著差别。
安全性数据与Olaparib的已知副作用一致，没有过多的严重不良事件或特别关注的不良事件。Olaparib对患者报告的生活质量只具有限的影响。
This is a phase III, double-blind, randomized trial (OlympiA). A total of 1.836 patients with BRCA1 or BRCA2 germline pathogenic or likely pathogenic variants and high-risk clinicopathological factors participated. They were HER2-negative early breast cancer patients (triple-negative or ER/PR-positive). They received local treatment and neoadjuvant or adjuvant chemotherapy. Patients were randomly assigned (in a 1:1 ratio) to receive oral Olaparib or placebo for 1 year. The primary end point was invasive disease-free survival.
In a prespecified interim analysis with a median follow-up of 2.5 years, the 3-year invasive disease-free survival rate was 85.9% in the Olaparib group and 77.1% in the placebo group (difference, 8.8 percentage points; 95% confidence interval [CI], 4.5 to 13.0; risk ratio for invasive disease or death, 0.58; 99.5% CI, 0.41 to 0.82; P <0.001). The 3-year distant disease -free survival was 87.5% in the Olaparib group and 80.4% in the placebo group (difference, 7.1 percentage points; 95% CI, 3.0 to 11.1; risk ratio of distant disease or death, 0.57; 99.5% CI , 0.39 to 0.83; P <0.001). Compared with placebo, Olaparib was associated with fewer deaths (59 and 86, respectively) (hazard ratio, 0.68; 99% CI, 0.44 to 1.05; P = 0.02). However, the between-group difference was not significant at an interim-analysis boundary of a P value of less than 0.01.
Safety data are consistent with the known side effects of Olaparib, with no excess serious adverse events or adverse events of special interest. Olaparib has limited effect on global patient-reported quality of life.
参考文献 Reference Andrew NJ et al. N Engl J Med 2021; 384:2343
Lifileucel用于疾病进展后的转移性黑色素瘤 (7/17/2021)
Lifileucel used in metastatic melanoma after disease progression
多数转移性黑色素瘤患者,在使用免疫检查点抑制剂治疗后,疾病会进展并且没有获得批准的治疗方法。Lifileucel 是一种利用自体肿瘤浸润淋巴细胞 (TIL) 的过继细胞疗法。它使用能够识别肿瘤抗原的肿瘤组织 T 细胞，在简化的 22 天集中制造过程中从收获的肿瘤中生产出来的，在体外扩增, 然后在非骨髓抑制性淋巴耗竭后注入（连同高剂量白细胞介素 2 [IL-2]）到患者体内。
这是一项全球II 期开放试验（ C-144-01 ）,该研究包括 165 名不可切除或转移性黑色素瘤患者, 他们既往接受过至少一种全身治疗, 包括 PD-1 阻断抗体，如果患者患有 BRAF V600 突变疾病，则接受过 BRAF 抑制剂，有或没有 MEK 抑制剂。 研究者报导了队列 2 的结果，其中包括 66 名患者，这些患者之前接受过平均 3.3 次的治疗，并且在基线时肿瘤负荷很高。 研究者评估的客观响应率为 36.4%，其中完全响应率为 4.5%（三名患者）。在 33 个月时，尚未达到中位缓解持续时间（范围，3-38 个月）。在响应者中，79% 的患者曾接受过伊匹单抗治疗，46% 的患者此前接受过抗 PD-1 和抗 CTLA-4 联合治疗。大多数响应是在第一次扫描时看到的。用 lifileucel 治疗 24 个月后，一些部分响应转变为完全响应。70% 的响应者在 12 个月时仍保持无复发此外，大多数反应者患有 PD-L1 阴性疾病，而且，他们对检查点抑制具有原发性难治性。
研究者发现，先前抗 PD-1/L1 治疗的累积持续时间与响应率无关，但与响应持续时间相关。对于治疗持续时间≤ 中位数（5.06 个月）vs > 5.06 个月，风险比为 0.218（置信区间 = 0.056–0.854），表明有统计学意义。根据多变量模型，先前抗PD-1/L1 的暴露量每减少 6 个月，对lifileucel 的中位响应持续时间几乎翻倍。
In most patients with metastatic melanoma who received treatment with immune checkpoint inhibitors, their disease will progress and there is no standard therapy. Lifileucel is an adoptive cell therapy using autologous tumor infiltrating lymphocytes (TIL). Tumor tissue T cells that can recognize tumor antigens are produced from harvested tumors in a simplified 22-day intensive manufacturing process. They are expanded in vitro, and then injected back into patients after non-myeloablative lymphatic depletion (along with high-dose white blood cells interleukin 2 [IL-2.
This is a global phase II open label clinical trial (C-144-01). The study included 165 patients with unresectable or metastatic melanoma who had previously received at least one systemic treatment, including PD-1 blocking antibodies. If Patients had BRAF V600 mutation , they had received BRAF inhibitors, with or without MEK inhibitors. The researchers reported the results of cohort 2, which included 66 patients who had received an average of 3.3 lines of treatments before and had a high tumor burden at baseline. The objective response rate assessed by the investigator was 36.4%, of which complete response rate was 4.5% (three patients). At 33 months, the median duration of remission has not been reached (range, 3-38 months). Among the responders, 79% patients had received ipilimumab, and 46% of patients had previously received a combination of anti-PD-1 and anti-CTLA-4. Most of the responses were found after the first scan. After 24 months of treatment with lifileucel, some partial responses coverted to complete responses. 70% of responders remained relapse-free at 12 months. In addition, most responders had PD-L1-negative disease, and they were primarily refractory to checkpoint inhibitors.
The researchers also found that the cumulative duration of previous anti-PD-1/L1 treatment was not related to response rate, while related to the duration of the response. For treatment duration ≤ median (5.06 months) vs> 5.06 months, the hazard ratio was 0.218 (confidence interval = 0.056–0.854), indicating statistical significance. According to the multivariate model, the median duration of response to lifileucel almost doubled for every 6 months of reduction in previous exposure to anti-PD-1/L1.
REFERENCES Larkin J et al. ASCO Annual Meeting. 2021 Abstr 9505 Sarnaik AM et al. J Clin Onc May 12 2021 Thomas SS et al. ASCO Annual Meeting. 2021 Abstr 9537
使用抗生素与早发性结直肠癌之间是否存在联系？ (7/11/2021)
Is there a link between antibiotics use and early-onset of colorectal cancer
一项研究结果显示，抗生素的使用可能与所有年龄组患者的结直肠癌形成有关（尽管没有显示直接的因果关系），尤其是在 50 岁以下的患者中。
结直肠癌在过去 20 年中以每年至少 3% 的速度增加, 这是第一项将抗生素使用与日益增加的早发性结肠癌风险联系起来的研究。据报导从 2000 年至 2015 年间, 全球抗生素消费量估计增长了 65% 。垃圾食品、含糖饮料、肥胖症和酒精 [消费] 可能在这种上升中发挥了作用，但这项研究强调了避免不必要的抗生素的重要性，尤其是在儿童和年轻人中。
该研究使用苏格兰初级保健数据库，对7,903 名结直肠癌患者与相匹配的30,418名健康者进行了研究。 在结直肠癌患者中，445 人（5.6%）在诊断时年龄在 50 岁以下。结果发现，45% 的患者服用了抗生素。抗生素的使用都与任何年龄组的结肠癌风险显着增加有关，但这在诊断时年龄小于 50 岁的患者中最为明显。 具体而言，任何抗生素的使用都与 50 岁以下患者的结肠癌调整比值比为 1.49 (P = .018) , 50 岁以下患者的风险增加了近 50%。 50 岁及以上患者的比值比为 1.09 (P = .029) 相关, 患者的风险增加了 9%。在年轻年龄组中，使用抗生素与右侧结肠的癌症有关。用于治疗多种感染的喹诺酮类和磺胺类/甲氧苄啶（Quinolones 和sulfonamides/trimethoprim）与这些右侧癌症有关。
结肠右侧的内容物更多是液体，生活在那里的天然细菌, 可能与远端结肠不同，即使肠道已被清除以进行内窥镜检查，微生物组也可以迅速恢复到以前的状态。目前还不知道抗生素是否会对微生物组产生直接或间接导致结肠癌发展的影响。 在结直肠癌患者中，20 至 40 岁的年轻人的预后通常比老年患者更差，因为他们经常在较晚的阶段诊断出来, 此外，这些癌症在年轻患者中的生物学行为可能与老年人不同。虽然现在说过度使用抗生素是一个致病因素还为时过早，然而，新的研究确实提示，除非确实需要，否则不应给予抗生素。
A recent study showed that the use of antibiotics may be related to the development of colorectal cancer in patients of all age groups (although no direct cause and effect has been shown), especially among patients under 50 years of age.
Colorectal cancer has increased at a rate of at least 3% per year for the past 20 years. This is the first study to link the use of antibiotics with the increased risk of early-onset colon cancer. It is reported that between 2000 and 2015, global antibiotic consumption was estimated to have increased by 65%. Junk food, sugary drinks, obesity, and alcohol consumption may have played a role in this rise, but this study emphasizes the importance of avoiding unnecessary antibiotics, especially among children and young people.
The study used a large Scottish Primary Care Database. It included 7,903 colorectal cancer patients and 30,418 matched healthy individuals. Among patients with colorectal cancer, 445 (5.6%) were under 50 years old at the time of diagnosis. It was found that 45% of patients took antibiotics. The use of any antibiotic is associated with a significant increase in the risk of colon cancer in all age groups, but this is most pronounced in patients younger than 50 years of age at the time of diagnosis. Specifically, the ratio of any antibiotic use to the adjusted ratio of colon cancer in patients under 50 years of age was 1.49 (P = .018), with an increased risk by nearly 50%. The odds ratio for patients 50 years and older was 1.09 (P = .029), and the risk increased by 9%. In the younger age group, the use of antibiotics is associated with cancer on the right-side of the colon. Quinolones and sulfonamides/trimethoprim were associated with cancer on right-side colon.
The contents on the right-side of the colon are more liquid, and the natural bacteria living there may be different from those in the distal colon. Even if the intestine is cleared out for endoscopy, the microbiome can quickly revert to its previous state. It is not yet known whether antibiotics directly or indirectly lead to the development of colon cancer. Among colorectal cancer patients, the prognosis of young people between 20 and 40 years old is usually worse than that of elderly patients because they are often diagnosed at a later stage. In addition, the biological behavior of the cancer in young patients may be different from that of elderly people. Although it is too early to say that overuse of antibiotics is a causative factor, this new research does suggest that antibiotics should not be given unless really needed.
参考文献 Reference Perrott S et al. World Congress of GI Cancer 2021; abstr SO-25
分子成像可改善胰腺导管腺癌的分期和治疗 (7/10/2021)
Molecular imaging may improve staging and treatment of pancreatic ductal cancer
胰腺导管腺癌具有强烈的促结缔组织增生反应。 癌症相关的成纤维细胞和细胞外纤维化可占总肿瘤质量的 90%，而原始肿瘤细胞仅占少数。 许多癌症相关成纤维细胞与正常成纤维细胞的不同之处在于它们的成纤维细胞活化蛋白 (FAP) 的相对特异性表达。 因此，FAP 抑制剂（FAPI）首先被开发为抗癌药物，然后连续推进到肿瘤靶向放射性药物。 这导致新型 PET 放射性示踪剂 68Ga-FAPI 成像。
胰腺导管腺癌的最佳成像对于诊断初期的准确TNM分期和治疗的选择至关重要。随访影像对于尽可能早和尽可能准确地检测局部复发或转移扩散也很重要。 目前，对比增强 CT 是分期的黄金标准，而 PET 成像通常还不是临床常规的一部分，
在一项对胰腺导管腺癌患者的回顾性研究中，使用 68Ga-FAPI 进行 PET/CT 成像导致超过一半患者的疾病再分期，尤其是局部复发患者。该研究包括 19 名胰腺导管腺癌患者，他们接受了对比增强 CT 成像，再接受 68Ga-FAPI PET/CT。然后将 68Ga-FAPI PET/CT 扫描的结果与基于对比增强 CT 的 TNM 分期进行比较。19 名患者中有 10 名基于 68Ga-FAPI PET/CT 的 TNM 分期与对比增强 CT 成像不同，导致 TNM 分期发生变化。在 12 名复发性疾病患者中，8 名分期升级，1 名分期降级，3 名保持不变。
在新诊断为胰腺导管腺癌的 7 名患者中，有 1 名患者分期升级，而其中 6 名患者的分期保持不变。 这项分析表明，68Ga-FAPI PET/CT 是一种很有前景的胰腺导管腺癌分期新成像方式，这可能避免不必要的手术，或改变术前治疗，或在复发的情况下开始早期干预。
Pancreatic ductal adenocarcinoma has a strong connective tissue hyperplasia response. Cancer-related fibroblasts and extracellular fibrosis can account for 90% of the total tumor mass, while primary tumor cells account for only a small percentage. Many cancer-related fibroblasts differ from normal fibroblasts in their relative specific expression of fibroblast activation protein (FAP). Therefore, FAP inhibitors (FAPI) were first developed as anticancer drugs, and then continuously advanced to tumor-targeted radiopharmaceuticals. This led to imaging of the new PET radiotracer 68Ga-FAPI. Optimal imaging of pancreatic ductal adenocarcinoma is essential for accurate TNM staging and treatment selection at the initial stage of diagnosis. Follow-up imaging is also important to detect local recurrence or metastasis as early as possible and as accurately as possible. At present, contrast-enhanced CT is the gold standard for staging, and PET imaging is usually not part of clinical routine.
In a retrospective study of patients with pancreatic ductal adenocarcinoma, the use of 68Ga-FAPI for PET/CT imaging resulted in more than half of the patients re-staged, especially in patients with local recurrence. The study included 19 patients with pancreatic ductal adenocarcinoma who underwent contrast-enhanced CT imaging followed by 68Ga-FAPI PET/CT. Then comparisons were made between the two in the TNM staging. In 10 of the 19 patients, TNM staging based on 68Ga-FAPI PET/CT was different from contrast-enhanced CT imaging, resulting in changes in TNM staging. Among the 12 patients with recurrent disease, 8 were upstaged, one was down-staged and 3 remained unchanged. Of the 7 newly diagnosed pancreatic ductal adenocarcinomas, one patient was upstaged, while the staging of 6 patients remained unchanged. This analysis shows that 68Ga-FAPI PET/CT is a promising new imaging method for the staging of pancreatic ductal adenocarcinoma. Accurate staging may avoid unnecessary surgery, or change the preoperative treatment to facilitate curability, or start early intervention in the setting of recurrence .
参考文献 Reference Manuel Röhrich et al, J Nuclear Med (2020). DOI: 10.2967/jnumed.120.253062
抗寄生虫药ivermectin在治疗乳腺癌中的应用 (7/4/2021)
Anti-parasitic drug Ivermectin in treating breast cancer
免疫检查点抑制剂疗法利用患者自身的免疫系统来治疗癌症。然而，它作为单一药物仅对一部分患者和癌症类型有效。它们对乳腺癌几乎没有影响。 最近的研究表明，检查点抑制剂的功效主要限于已经被 T 细胞浸润的癌症, 通常被称为“热”肿瘤。相比之下，“冷”肿瘤几乎没有 T 细胞浸润，通常对免疫检查点抑制剂治疗没有反应。因此，非常需要确定能够引发乳腺肿瘤（将“冷”肿瘤变成“热”）以与检查点封锁协同作用的药物。 有一种称为免疫原性细胞死亡 (ICD) 现象，是一种刺激宿主免疫系统的细胞死亡形式。在不抑制免疫功能的情况下诱导癌细胞 ICD 的药剂, 有可能与免疫检查点抑制剂治疗结合的理想选择。
研究者发现ivermectin是一种抗寄生虫药物，它促进了乳腺癌细胞中的 ICD。 在三阴性乳腺癌动物模型中，乳腺肿瘤是“冷的”，表明很少或没有浸润的 T 细胞。Ivermectin治疗导致强大的 T 细胞浸润，将冷肿瘤转变为热肿瘤，癌细胞在体内显示 ICD 标志物。 将三阴性乳腺癌 从冷转变为热的能力表明Ivermectin可以与免疫检查点抑制剂 （例如抗 PD-1 单克隆抗体）协同作用。
这是首次利用Ivermectin联合抗检查点抑制剂用于成功治疗乳腺癌:动物中有 40-60% 的肿瘤完全根除。在重新引入癌症后，他们能够再次对抗癌症。单独使用任何一种药物的效果几乎为零，但它们一起具有协同作用。 该组合对转移性乳腺癌有效，可能治愈 50% 的动物。
这些临床前研究结果表明，Ivermectin和抗 PD1 抗体的组合值得在乳腺癌患者中进行临床试验。
Immune checkpoint inhibitor therapy uses the patient’s own immune system to treat cancer. However, as a single drug, it is only effective for some patients and cancer types. They have little effect on breast cancer. Recent studies have shown that the efficacy of checkpoint inhibitors is mainly limited to cancers that have been infiltrated by T cells, often referred to as “hot” tumors. In contrast, “cold” tumors have almost no T cell infiltration and usually do not respond to immune checkpoint inhibitor. Therefore, there is a great need to identify drugs that can trigger breast tumors (turning “cold” tumors into “hot”) to work synergistically with checkpoint inhibitor. There is a phenomenon called immunogenic cell death (ICD), which is a form of cell death that stimulates the host’s immune system. Agents that induce ICD in cancer cells without suppressing immune function may be an ideal choice in combination with immune checkpoint inhibitor.
Researchers discovered that ivermectin is an antiparasitic drug that promotes ICD in breast cancer cells. In animal models of triple-negative breast cancer, breast tumors are “cold”, indicating little or no infiltrating T cells. Ivermectin treatment results in strong T cell infiltration, transforming cold tumors into hot tumors, and cancer cells display ICD markers in vivo. The ability to transform triple-negative breast cancer from cold to hot suggests that Ivermectin can work synergistically with immune checkpoint inhibitors such as anti-PD-1 monoclonal antibodies.
This is the first time the research team has demonstrated that ivermectin in combination with checkpoint inhibitors can be used to successfully treat breast cancer: 40-60% of the tumors in animals models treated with Ivermectin combined with anti-PD1 antibodies were completely eradicated. After reintroducing cancer cells, the combination were able to fight cancer again. The effect of using any drug alone was almost zero, but together they had a synergistic effect. This combination is effective against metastatic breast cancer and may cure 50% of animals.
The results of these preclinical studies indicate that the combination of Ivermectin and anti-PD1 antibody merits further clinical trials in breast cancer.
参考文献 Reference Lee P. Oncol Times: 2021; 43:10
FDA 批准piflufolastat F 18用于前列腺特异性膜抗原（PSMA）PET成像的药物 (7/3/2021)
Piflufolastat F 18 was approved by FDA as a PSMA targeted PET imaging agent in prostate cancer
Pylarify （piflufolastat F 18）是一种放射性诊断剂，以静脉注射的形式给药, 一旦通过注射给药，Pylarify 就会与前列腺特异性膜抗原（PSMA）结合。PSMA 是前列腺癌成像的重要药理学靶点，因为前列腺癌细胞通常含有升高水平的抗原。作为一种发射正电子的放射性药物，Pylarify 可以通过 PET 成像来指示身体组织中是否存在 PSMA 阳性前列腺癌病变。 CT扫描、磁共振扫描和骨扫描是常用于对前列腺癌患者进行成像的方法。然而，这些成像技术在检测前列腺癌病变方面存在局限性。 FDA 于 2020 年 12 月批准了第一种 PSMA PET 成像药物 Ga 68 PSMA-11，已上市的 Ga 68 PSMA-11 目前仅在加利福尼亚的两个地点提供。 Pylarify 预计将从美国的多个地点分发。
Pylarify 的安全性和有效性在两项前瞻性临床试验中进行了评估，共有 593 名患有前列腺癌的男性每人接受了一次 Pylarify 注射。在第一项试验中，一组 268 名经活检证实的前列腺癌患者接受了 Pylarify PET/CT 扫描。这些患者是手术切除前列腺和盆腔淋巴结的候选者。在手术患者中, 手术病理证实的转移癌发生率具有重要临床意义。在治疗前获得这些信息将对患者护理产生重要影响, 它可以使某些患者免于接受不必要的手术。
第二项试验招募了 208 名患者，这些患者在前列腺手术或其他根治性治疗后血清 PSA 水平升高，因此具有前列腺癌复发的生化证据。在单次 Pylarify PET/CT 扫描之前，所有这些患者都进行了基线常规成像，未显示前列腺癌的明确扩散。在这些患者中，60% 的 Pylarify PET 在至少一个身体区域（骨骼、前列腺床、盆腔淋巴结、其他淋巴结或软组织）中检测到至少一处阳性病变。在 Pylarify PET 阳性且具有相关活检组织病理学、随访成像结果或可用于比较的PSA 水平的患者中，估计有 85% 至87% 已经被证实。因此，第二项试验表明 Pylarify PET 可以发现PSA 水平升高患者的复发部位，从而提供可能影响治疗方法的重要信息。
Pylarify 最常见的不良反应是头痛、味觉改变和疲劳。对 Pylarify 存在过敏反应的风险，尤其是对其他药物和食物有过敏史的患者。因为 Pylarify 结合可能发生在其他类型的癌症以及某些可能导致图像解释错误的非恶性疾病, 可能存在误诊风险，
Pylarify (piflufolastat F 18) is a radiological diagnostic agent that is administered by intravenous injection. Once administered by injection, Pylarify binds to prostate-specific membrane antigen (PSMA). PSMA is an important pharmacological target for prostate cancer imaging because prostate cancer cells usually contain elevated levels of PSA. Pylarify can use PET imaging to indicate the presence of PSMA-positive prostate cancer lesions in the body. CT scans, magnetic resonance scans, and bone scans are methods commonly used to image prostate cancer patients. However, these imaging techniques have limitations in detecting prostate cancer lesions. FDA approved the first PSMA PET imaging drug, Ga 68 PSMA-11, in December 2020. Ga 68 PSMA-11 is currently only available in two locations in California. Pylarify is expected to be distributed from multiple locations in the United States.
The safety and effectiveness of Pylarify were evaluated in two prospective clinical trials. A total of 593 men with prostate cancer received Pylarify injection. In the first trial, a group of 268 patients with prostate cancer confirmed by biopsy underwent a Pylarify PET/CT scan. These patients were candidates for surgical resection of prostate and pelvic lymph nodes. In surgical candidates, the finding of metastatic lesions has important clinical significance. Obtaining this information before treatment will have an important impact on patient care. It can save some patients from unnecessary surgery.
The second trial enrolled 208 patients, who had elevated serum PSA levels after prostate surgery or other radical treatments had biochemical evidence of prostate cancer recurrence. Prior to the single Pylarify PET/CT scan, all the patients had baseline routine imaging and did not show clear metastases of prostate cancer. In these patients, 60% of Pylarify PET detected at least one positive lesion in at least one body area (bone, prostate bed, pelvic lymph nodes, other lymph nodes, or soft tissue). Among patients who were Pylarify PET positive and hae relevant biopsy histopathology, follow-up imaging results, or comparable PSA levels, it was estimated that 85% to 87% were confirmed. Therefore, the second trial showed that Pylarify PET can detect recurrence of patients with elevated PSA levels, thereby providing important information that may affect treatment.
The most common adverse reactions of Pylarify are headaches, changes in taste and fatigue. There is a risk of allergic reactions to Pylarify, especially in patients who have a history of allergies to other drugs and foods. Because Pylarify can combine with other types of cancers and certain non-malignant diseases that may cause interpretation errors, there may be a risk of misdiagnosis.
参考文献 Reference https://www.fda.gov/drugs/drug-safety-and-availability/fda-approves-second-psma-targeted-pet-imaging-drug-men-prostate-cancer
恩杂鲁胺（Enzalutamide）联合化疗治疗晚期或复发性子宫内膜癌 (6/27/2021)
Enzalutamide in combination with Paclitaxel and carboplatin in advanced or recurrent endometrioid endometrial cancer
这是一项II期临床试验（ENPAC, NCT02684227），参加试验的患者患有 III/IV 期疾病或复发性疾病。所有人都必须具有可测量的疾病、可活检的肿瘤。该研究排除了具有非子宫内膜样组织学的子宫内膜癌、既往接受过顺铂以外的化疗、适合放疗或手术治愈性治疗的孤立复发。在安全性导入研究中，恩杂鲁胺以 40 毫克胶囊给药（雄激素在大约 90% 的子宫内膜样子宫内膜肿瘤中过度表达），推荐的 2 期剂量为每天 160 毫克。紫杉醇以175毫克/平方米 通过静脉 输注每 3 周一次给药，卡铂以 AUC = 5 每 3 周给药一次。 客观响应率是主要终点、研究中探索的次要终点包括响应持续时间、估计的无进展生存期和总生存期，以及恩杂鲁胺和紫杉醇的药代动力学相互作用。 结果显示，在评估的 6 名患者中，恩杂鲁胺联合卡铂和紫杉醇没有剂量限制性毒性。
在安全导入期之后，进入了研究的第 2 阶段。患者接受了 4 周的恩杂鲁胺单药治疗。在导入期间进行了治疗前和治疗后活检。然后和紫杉醇/卡铂联合方案治疗.每 3 周为一周期，CT每 3 个周期。患者最多可以接受 9 个周期的治疗。49 名患者参加了研究的 2 期部分。在基线时，患者的中位年龄为 64 岁（范围 41-81）。大多数患者在基线时有复发性疾病 (86.1%) 或 IV 期疾病 (18.4%)，病理学2 级是最常见的基线等级 (53.0%)。大多数患者微卫星稳定 (59.2%)，但 28.6% 微卫星不稳定。
在中位 9 个周期（范围，0-9）后，响应率为 71%（95% CI，54%-85%）, 和83%（95% CI，66%-92%）的患者无进展至少 6 个月。对于整个队列，中位无进展生存期为 11.47 个月（95% CI，9.86-17.94）。然而，在 14.42 个月时可评估响应的患者的中位无进展生存期更高（95% CI，11.2-25.5）。
在参与研究的人中，16.3% 的人无法完成 3种药物方案的治疗。 3 名患者因疾病进展迅速停止治疗，2 名患者因与治疗无关的原因死亡，2 名患者退出研究，1 名患者因与研究治疗无关的脑血管事件而停止治疗。就恩杂鲁胺联合卡铂和紫杉醇的毒性特征而言，任何级别的最常见不良事件是中性粒细胞减少 (20.4%)、贫血 (18.4%) 和疲劳 (18.4%)。这些不良事件分别在 18.4%、14.3% 和 4.1% 的患者中为 3 级或 4 级。ENPAC 的分析正在进行中，以评估对雄激素抑制剂治疗的响应和抵抗的预测因素。
This is a phase II clinical trial (ENPAC, NCT02684227). Participating in the trial had stage III/IV disease or recurrent disease. They must have measurable disease and tumor accessible to biopsy. The study excluded non-endometrioid histology of endometrial cancer, previous chemotherapy other than cisplatin, isolated recurrences suitable for radiotherapy or surgical curative treatment. In the safety lead-in phase, enzalutamide was administered in 40 mg capsules (androgens are known to be overexpressed in approximately 90% of endometrioid endometrial tumors), and the recommended phase 2 dose was 160 mg per day. Paclitaxel was given by intravenous infusion at 175 mg/m² every 3 weeks, and carboplatin was given at AUC = 5 every 3 weeks. Objective response was the primary endpoint. Secondary endpoints explored in the study included response duration, estimated progression-free survival and overall survival, and the pharmacokinetic interaction of enzalutamide and paclitaxel. The results showed that in the 6 patients evaluated, enzalutamide combined with carboplatin and paclitaxel had no dose-limiting toxicity.
After the safety lead-in phase, it entered the second phase of the research. Patients received enzalutamide monotherapy for 4 weeks. Pre-treatment and post-treatment biopsies were performed during the induction period. Then patients were treated with 3-drug combination with paclitaxel/carboplatin given every 3 weeks as a cycle, CT was performed every 3 cycles. Patients coulc receive up to 9 cycles of treatment. Forty-nine patients participated in the phase 2 part of the study. At baseline, the median age of patients was 64 years (range 41-81). Most patients had recurrent disease (86.1%) or stage IV disease (18.4%) at baseline, and pathology grade 2 was the most common baseline grade (53.0%). Most patients had stable microsatellites (59.2%), but 28.6% had unstable microsatellites.
After a median of 9 cycles (range, 0-9), the response rate was 71% (95% CI, 54%-85%), and 83% (95% CI, 66%-92%) of patients had no progression At least 6 months. For the entire cohort, the median progression-free survival was 11.47 months (95% CI, 9.86-17.94). However, patients with an evaluable response at 14.42 months had a higher median progression-free survival (95% CI, 11.2-25.5).
Among people who participated in the study, 16.3% were unable to complete the treatment of the three drug regimens. Three patients discontinued treatment due to disease progression, two patients died of causes unrelated to treatment, two patients withdrew from the study, and one patient discontinued treatment due to cerebrovascular events unrelated to the study treatment. In terms of the toxicity characteristics of enzalutamide combined with carboplatin and paclitaxel, the most common adverse events of any grade were neutropenia (20.4%), anemia (18.4%), and fatigue (18.4%). These adverse events were grade 3 or 4 in 18.4%, 14.3%, and 4.1% of patients, respectively.
ENPAC’s analysis is ongoing to evaluate predictors of response and resistance to androgen inhibitor therapy.
参考文献 Reference Westin SN et al. Soc Gynecol Oncol (SGO) 2021 Virtual Ann Meeting on Women’s Cancer; 2021; Abstr 7
一种新型选择性雌激素受体降解剂Elacestrant对雌激素受体阳性转移性乳腺癌的 I 期研究 (6/26/2021)
Phase I study of a novel selective ER degrader in ER-positive advanced breast cancer
这是一项I期临床试验 (RAD1901-005; NCT02338349) , 目的是评估口服选择性雌激素受体降解剂 (SERD) elacestrant，在经过多线治疗的雌激素受体阳性（包括雌激素受体基因α[ESR1]突变的）、HER2阴性转移性乳腺癌患者中确定最大耐受剂量和/或推荐的 II 期剂量。
在登记的 57 名绝经后妇女中，50 名接受了推荐的 II 期剂量（400 毫克，每天一次）：中位年龄为63 岁。她们接受过中位三线的先前抗癌疗法，包括细胞周期蛋白依赖性激酶 4/6 抑制剂（52%）、SERD（52%）和 ESR1 突变（循环肿瘤 DNA；50%）。没有发生剂量限制性毒性。最常见的不良事件（400 毫克片剂；n = 24）是恶心（33.3%）、血甘油三酯升高和血磷降低（各为 25.0%）。大多数不良事件的严重程度为 1-2 级。
客观响应率为 19.4%（n = 31 ），接受过既往 SERD 患者为 15.0%，既往 CDK4/6抑制剂患者为 16.7%，ESR1 突变患者为 33.3%（n = 5/15）。总体24周临床受益率总体为 42.6%（n = 47 ）、56.5%（n = 23，ESR1 突变）和 30.4%（n = 23，既往 CDK4/6抑制剂）。 Elacestrant 临床获益与 ESR1 突变等位基因分数的下降有关。
结论每天一次口服400毫克Elacestrant具有可接受的安全性，并在经过多线治疗的的雌激素受体阳性转移性乳腺癌患者中证实了单药活性。而且，在具有 ESR1 突变的患者以及先前接受过 CDK4/6抑制剂和SERD 的患者中也观察到了反应。一项研究 Elacestrant 与标准内分泌治疗的 III 期试验正在进行中。
This phase I clinical trial (RAD1901-005; NCT02338349) was to evaluate an oral selective estrogen receptor degrading agent (SERD) elacestrant, in heavily pre-treated ER positive (including ER gene α [ESR1] mutation) and HER2-negative advanced breast cancer patients. The primary object was maximum tolerated dose and/or the recommended phase II dose.
Of the 57 registered postmenopausal women, 50 received the recommended phase II dose (400 mg once a day): the median age was 63 years. They have received a median three-line previous anti-cancer therapy, including cyclin-dependent kinase 4/6 inhibitor (52%), SERD (52%), and ESR1 mutation (circulating tumor DNA; 50%). No dose limiting toxicity was found. The most common adverse events (400 mg tablets; n = 24) were nausea (33.3%), increased blood triglycerides, and decreased blood phosphorus (25.0% each). The severity of most adverse events was grade 1-2.
The objective response rate was 19.4% (n = 31), 15.0% in patients who had received previous SERD, 16.7% in patients with previous CDK4/6 inhibitors, and 33.3% in patients with ESR1 mutations (n = 5/15). The overall 24-week clinical benefit rate was 42.6% (n = 47), 56.5% (n = 23, ESR1 mutation), and 30.4% (n = 23, with prior CDK4/6 inhibitor). The clinical benefit of Elacestrant was related to a decrease in ESR1 mutant allele fraction.
Conclusion Oral elacestrant at 400 mg once daily has acceptable safety and single-agent activity in patients who was heavily pre-treated, ER-positive metastatic breast cancer. Response was also observed in patients with ESR1 mutations and in those who had previously received CDK4/6 inhibitors and SERD. A phase III trial of Elacestrant vweaua standard endocrine therapy is ongoing.
参考文献 Reference Bardia A et al. J Clin Onc 2021; 39: 1360
纳武单抗作为肌肉浸润性尿路上皮癌的辅助治疗改善生存 (6/20/2021)
Adjuvant Nivolumab improved survival in muscle-invasive urothelial cancer
这是一项随机、双盲、多中心的III期临床试验（CheckMate 274, NCT02632409)，检查纳武单抗作为辅助（术后）治疗相对于安慰剂在指定患者人群中的疗效。纳入试验的患者 (n = 709) 以 1:1 的比例随机接受每 2 周 240 毫克的纳武单抗辅助治疗或安慰剂治疗长达 1 年。新辅助（术前）顺铂的经验是允许的，但并不是必需的。纳武单抗（n = 353）和安慰剂（n = 356）组的中位随访时间分别为 20.9 个月和 19.5 个月, 并且通过影像学随访。无病生存期是试验的主要终点。
研究人员发现，手术后纳武单抗治疗使意向治疗人群的疾病复发或死亡风险降低了 30%（HR，0.70；98.31% CI，0.54-0.89；P < .001 ）。在 PD-L1 阳性（表达至少为 1%） 的患者中，疾病复发或死亡风险降低 47%（HR，0.53；98.87% CI，0.34-0.84；P < .001）。意向治疗人群中使用纳武单抗患者的中位无病生存期在为21.0 个月，而使用安慰剂的患者则为 10.9 个月。在 PD-L1 阳性人群中，纳武单抗未达到中位无病生存期，而安慰剂组为 10.8 个月。
在纳武单抗组中，53.3% 的患者停止治疗，而安慰剂组为 56.3%，最常见的原因是疾病复发。实验方案的安全性与该药物在实体瘤患者中的已知安全性一致。
当作为肌肉浸润性尿路上皮癌患者根治性手术后的辅助治疗时，纳武单抗是第一个证明能改善生存的全身性免疫疗法。
This is a randomized, double-blind, multi-center phase III clinical trial (CheckMate 274, NCT02632409) for the purpose of examing the efficacy of nivolumab as an adjuvant (postoperative) treatment versus placebo in a designated patient population. The patients enrolled in the trial (n = 709) were randomized at a ratio of 1:1 to receive 240 mg nivolumab or placebo every 2 weeks for up to 1 year. Experience with neoadjuvant (preoperative) cisplatin was permitted, but not required. The median follow-up time for nivolumab (n = 353) and placebo (n = 356) groups were 20.9 months and 19.5 months, respectively. They were followed by regular imaging. Disease-free survival was the primary endpoint of the trial.
It has been found that nivolumab treatment reduced the risk of disease recurrence or death in the intent-to-treat population by 30% (HR, 0.70; 98.31% CI, 0.54-0.89; P < .001). In patients with PD-L1 positive (at least 1% expression), risk of disease recurrence or death was reduced by 47% (HR, 0.53; 98.87% CI, 0.34-0.84; P < .001). In the intent-to-treat population, median DFS in nivolumab group was 21.0 months, while that of placebo group was 10.9 months. In the PD-L1 positive nivolumab group, median DFS has not reached, while it was 10.8 months in the placebo group.
In the nivolumab group, 53.3% of patients discontinued treatment, compared with 56.3% in the placebo group. The most common cause was disease recurrence. The safety of the experimental group was consistent with the known safety of the drug in patients with solid tumors.
When used as an adjuvant treatment for patients with muscle-invasive urothelial carcinoma after radical surgery, nivolumab is the first systemic immunotherapy that has been proven shown to improve survival.
参考文献 Reference Bajorin DF et al. J Clin Oncol. 2021;39(suppl 6):391. doi:10.1200/JCO.2021.39.6_suppl.391
FDA 加速批准 dostarlimab-gxly 用于错配修复缺陷( dMMR) 子宫内膜癌 (6/19/2021)
Dostarlimab was granted accelerated approval for dMMR endometrial cancer.
2021年4月，FDA加速批准 dostarlimab-gxly (Jemperli) 用于治疗错配修复缺陷 (dMMR), 且在先前含铂方案后出现进展或复发性晚期子宫内膜癌患者。
这项推荐是根据 GARNET 临床试验 (NCT02715284) 中的队列评估疗效，它是一项多中心、多队列、开放标签试验。由 71 名 dMMR 复发或晚期子宫内膜癌患者组成，这些患者在含铂方案治疗中或之后进展。患者接受 dostarlimab-gxly，500 毫克 静脉注射，每 3 周一次，共 4次，然后每 6 周静脉注射 1,000毫克。 通过独立中央审查评估的主要疗效终点是总体响应率和响应持续时间。结果显示,总体响应率为 42.3%（95% CI：30.6%，54.6%）。完全响应率为 12.7%，部分响应率为 29.6%。中位响应持续时间未达到，93.3% 的患者持续时间≥6 个月（范围：2.6 至 22.4 个月，在最后一次评估时仍在进行）。
不良反应: 34% 接受 dostarlimab-gxly 的患者发生严重不良反应。 > 2% 患者的严重不良反应包括败血症、急性肾损伤、尿路感染、腹痛和发热。最常见的 3 级或 4 级不良反应 (≥ 2%) 是贫血和转氨酶升高。可能发生免疫介导的不良反应，包括肺炎、结肠炎、肝炎、内分泌疾病和肾炎。 推荐的 dostarlimab-gxly 剂量和时间表为每 3 周 500 毫克。从第 4 次给药后 3 周开始，随后的给药剂量为每 6 周 1,000 毫克，直至疾病进展或出现不可接受的毒性。 Dostarlimab-gxly 应在 30 分钟内静脉输注给药。
In April 2021, FDA granted accelerated approval of dostarlimab-gxly (Jemperli) for the treatment of patients with mismatch repair defects (dMMR), recurrent advanced endometrial cancer following previous platinum-containing regimen.
This recommendation was based on the cohort assessment in the GARNET clinical trial (NCT02715284). It is a multi-center, multi-cohort, open-label trial. It had 71 patients with recurrent dMMR advanced endometrial cancer who progressed during or after platinum-containing regimens. Participants received 500 mg of dostarlimab-gxly intravenously, once every 3 weeks for a total of 4 doses, and then 1,000 mg intravenously every 6 weeks. The primary endpoints of the trial as assessed by independent central review were overall response rate and duration of response. The results showed that overall response rate was 42.3% (95% CI: 30.6%, 54.6%). Complete response rate was 12.7%, and partial response rate was 29.6%. Median response duration was not reached, and 93.3% of patients had a duration ≥ 6 months (range: 2.6 to 22.4 months, still ongoing at the time of the last evaluation).
Adverse reactions: 34% of patients receiving dostarlimab-gxly had serious adverse reactions. Serious adverse reactions in> 2% of patients included sepsis, acute kidney injury, urinary tract infection, abdominal pain, and fever. The most common grade 3/4 adverse reactions (≥ 2%) were anemia and elevated transaminases. Immune-mediated adverse reactions ncluded pneumonia, colitis, hepatitis, endocrine diseases, and nephritis. The recommended dose and schedule of dostarlimab-gxly is 500 mg every 3 weeks. Starting 3 weeks after the fourth dose, the subsequent dose is 1,000 mg every 6 weeks until disease progresses or unacceptable toxicity. Dostarlimab-gxly should be administered intravenously within 30 minutes.
参考文献 Reference https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-dostarlimab-gxly-dmmr-endometrial-cancer
针对RET 融合性实体瘤的Selpercatinib 的益处扩展到肺癌和甲状腺癌之外 (6/13/2021)
Clinical benefit of Selpercatinib to RET-fusion-positive tumor beyond lung and thyroid cancer
RET 基因融合（一部分 RET 基因与另一个基因融合）见于大约 2% 的非小细胞肺癌和 10% 至 20% 的甲状腺乳头状癌患者，RET 的较小突变, 则见于超过一半的甲状腺髓样癌。在其他肿瘤中并不常见。这些变化导致异常 RET 激酶的产生，从而刺激癌细胞的生长。
LIBRETTO-001 试验是一项正在进行的全球多中心 I/II 期试验。该研究的总登记人数为 441 名患有 RET 融合阳性癌症的患者。如果患者年满 12 岁，已被诊断患有晚期或转移性实体瘤，并且ECOG功能状态为 0 到 2，都符合条件。大多数患者 (80.7%) 患有非小细胞肺癌，其次是甲状腺癌 (10.7%) 和其他癌症 (8.6%)。在剂量增加后，患者接受每日两次口服160毫克 Selpercatinib。 该研究的主要终点是客观反应率，次要终点包括反应持续时间、反应时间和安全性。
2021年AACR报告的结果集中在 38 名其他癌症患者，主要是胰腺癌或结肠癌（各 28.1%），乳腺癌、唾液腺癌和肉瘤各占 6.3%。其他癌症发生频率较低。安全性数据来自所有 38 名患者。疗效数据来自 32 名治疗后至少随访 6 个月的患者。 疗效队列的中位年龄为 48 岁，女性略多（53%）。大多数 (84%) 之前接受过全身治疗（中位数 2 线，范围 0-9）。一半的患者接受了手术。 与RET 融合的其它基因包括 NCOA4 (41%)、CCDC6 (16%)、KIF5B (9%) 和其他 (34%)。
由不同试验研究者评估的 32 名患者的客观缓解率为 47%（95% 置信区间为 29%–65%）。这包括 2 位完全回应和 13 位部分回应。在九种癌症类型中观察到客观响应，包括结肠癌、胰腺癌、类癌、小肠癌、唾液癌、黄色肉芽肿、乳腺癌、卵巢癌和肉瘤。还有10例病情稳定，其中5例出现疾病进展。最后 2 名患者尚未进行评估。 响应通常在治疗开始后不久发生，中位响应时间为 1.9 个月（范围 0.7-7.3）。响应是持久的，在 13 个月的中位随访期后尚未达到中位响应持续时间。
安全性与试验中的总体人群一致，不良事件通常是剂量依赖性的。 38 名患者中最常见的任何级别的不良事件（至少 20%）是口干 (38.9%)、腹泻 (36.6%)、高血压 (35.9%)、疲劳 (35.0%)、水肿 ( 34.5%）和肝毒性（天冬氨酸转氨酶增加，29.9%；丙氨酸转氨酶增加，28.6%）。 在总体人群中，6.9% 的患者在不到 12 个月后停止治疗，2.1% 的患者在 12 个月或更长时间后因治疗中出现的不良事件而停止治疗。然而，在非肺癌和非甲状腺癌患者队列中没有发生与治疗相关的停药。
LIBRETTO-001 试验将继续探索 Selpercatinib 的安全性和有效性，该试验仍在招募 RET 融合阳性的非肺癌患者。
RET gene fusion (a portion of the RET gene fused to part of another gene) is seen in approximately 2% of non-small cell lung cancer and 10% to 20% of patients with papillary thyroid cancer. Smaller mutations are found in more than half of medullary thyroid cancers. RET gene fusion is not common in other tumors. These changes lead to the production of abnormal RET kinase, which stimulates the growth of cancer cells.
The LIBRETTO-001 trial is an ongoing global multicenter phase I/II trial. The total enrollment for the study is 441 patients with RET fusion-positive cancer. If the patient is over 12 years old, has been diagnosed with advanced or metastatic solid tumors, and has an ECOG performance status of 0 to 2, they are eligible. Most patients (80.7%) have non-small cell lung cancer, followed by thyroid cancer (10.7%) and other cancers (8.6%). After dose was increased, patients received 160 mg of selpercatinib orally twice daily. The primary endpoint of the study is objective response rate, and secondary endpoints include response duration, time to response, and safety.
The results reported at the 2021 AACR were focused on the 38 patients of other cancer types, mainly pancreatic cancer or colon cancer (28.1% each), breast cancer, salivary gland cancer and sarcoma each accounted for 6.3%. Safety data were from all 38 patients. Efficacy data were from 32 patients who were followed up for at least 6 months after treatment. The median age of the efficacy cohort was 48 years, with slightly more women (53%). Most (84%) had previously received systemic therapy (median 2-line, range 0-9). Half of the patients underwent surgery. Genes fused with RET include NCOA4 (41%), CCDC6 (16%), KIF5B (9%) and others (34%).
Objective response rate of 32 patients evaluated by different trial investigators was 47% (95% confidence interval 29%–65%). This included 2 complete responses and 13 partial responses. Objective responses were observed in nine cancer types, including colon, pancreas, carcinoid, small bowel, saliva gland, xanthogranuloma, breast, ovarian, and sarcoma. There were also 10 cases of stable disease, of which 5 cases developed disease progression. The last 2 patients have not yet been evaluated. The response usually occurs shortly after the start of treatment, with a median time to response of 1.9 months (range 0.7-7.3). The response was long-lasting, and the median response duration has not been reached after a median follow-up period of 13 months.
Safety is consistent with the overall population in the trial and adverse events were usually dose-dependent. The most common adverse events (at least 20%) of any grade among 38 patients were dry mouth (38.9%), diarrhea (36.6%), hypertension (35.9%), fatigue (35.0%), edema (34.5%) and hepatotoxicity (increased aspartate aminotransferase, 29.9%; increased alanine aminotransferase, 28.6%). In overall population, 6.9% of patients discontinued treatment after less than 12 months, and 2.1% of patients discontinued treatment after 12 months or more due to adverse events during treatment. However, no treatment-related discontinuations occurred in the non-lung cancer and non-thyroid cancer patient cohorts.
The LIBRETTO-001 trial will continue to explore the safety and efficacy of selpercatinib, and the trial is still recruiting non-lung cancer patients who are RET fusion-positive.
参考文献 Reference Subbiah V. et al. Virtual AACR Ann Meeting 2021; abstr CT011
Ixabepilone加贝伐单抗对铂类耐药或复发性卵巢癌有效 (6/12/2021)
Ixabepilone plus bevacizumab active for platinum-refractory or recurrent ovarian cancer
Ixabepilone是一种具有微管稳定剂作用的epothilone，于 2007 年被批准用于治疗乳腺癌，但它在其他疾病部位也显示出活性，包括前列腺、胰腺、肺和妇科恶性肿瘤。
这是一项II期临床试验, 在美国 2 个中心随机分配了 76 名患有复发性或铂耐药性或难治性上皮性（非粘液性）卵巢癌、输卵管癌或原发性腹膜癌的患者。关键的其它标准包括可测量的疾病、肿瘤组织样本可用免于疫组织化学以及之前接受过至少三个周期的紫杉醇治疗（但对之前接受过多少线的药物没有限制，包括贝伐单抗）。 该研究的主要终点是无进展生存期。次要终点包括总生存期、安全性和客观反应率。 患者根据先前接受贝伐单抗以及研究地点进行分层，随后被随机分配接受 20 毫克/平方米Ixabepilone单药治疗（在 28 天周期的第 1、8 和 15 天）或Ixabepilone联合10 毫克/公斤贝伐单抗（第 1 天和第 15 天）。每两个周期评估患者的实体瘤反应。没有从单一疗法组到联合疗法组的交叉。 两组中大约 50% 的患者接受了三线以上的预先治疗。此外，56% 的患者之前接受过贝伐单抗治疗。
结果表明，Ixabepilone联合贝伐单抗的客观响应率提高至 33%，相对于单独使用Ixabepilone的 8%。联合治疗组的无进展生存期为 5.5 个月，相对于 2.2 个月 （风险比 [HR] = 0.33）。尽管该研究统计样本不足，但总生存期也显著提高，联合治疗组为 10 个月, 相对于单独使用Ixabepilone的6 个月。在亚组分析中，先前接受贝伐单抗治疗不会影响无进展生存期或总生存期，
安全性分析显示周围神经病变、中性粒细胞减少和疲劳是剂量限制性毒性。 联合治疗组的患者更可能出现高血压（36% 对 8%）和周围神经病变（51% 对 19%）。 然而，在两个治疗组之间没有观察到严重不良事件的差异。 在临床数据截止时，Ixabepilone组 78% 的患者死亡，而联合组为 72%。
Ixabepilone, an epothilone, is a microtubule stabilizer. It was approved for the treatment of breast cancer in 2007, but it also showed activity in other diseases, including prostate, pancreas, lung and gynecological malignancies.
This is a phase II clinical trial conducted in 2 centers in the U.S. A total of 76 patients with relapsed or platinum-resistant or refractory epithelial (non-mucinous) ovarian cancer, fallopian tube cancer or primary peritoneal cancer were randomly assigned. Other key entry criteria included measurable disease, tumor availability for immunohistochemistry, and prior receipt of at least three cycles of paclitaxel but there was no limit of previous lines, including bevacizumab). The primary endpoint of the study was progression-free survival. Secondary endpoints included overall survival, safety, and objective response rate. Patients were stratified according to their previous bevacizumab and study location, and were subsequently randomly assigned to receive 20 mg/m² Ixabepilone monotherapy (on days 1, 8 and 15 of the 28-day cycle) or Ixabepilone combined with 10 mg/kg Bevacizumab (days 1 and 15). The patient’s solid tumor response was evaluated every two cycles. There was no crossover from the monotherapy group to the combination therapy group. Participants were heavily pretreated. Approximately 50% of the patients in the two groups received more than three lines of pretreatment. In addition, 56% of patients were previously treated with bevacizumab.
The results showed that the objective response rate of Ixabepilone combined with bevacizumab was 33%, compared with 8% in Ixabepilone alone group. Progression-free survival in the combination group was 5.5 months, compared to 2.2 months (hazard ratio [HR] = 0.33). Although the study was underpowered, overall survival was also significantly improved, from 10 months in the combination group, compared to 6 months in Ixabepilone alone group. In subset analysis, prior treatment with bevacizumab did not influence progression-free survival or overall survival.
Safety analysis showed that peripheral neuropathy, neutropenia, and fatigue were dose-limiting toxicities. Patients in the combination group were more likely to have hypertension (36% vs. 8%) and peripheral neuropathy (51% vs. 19%). However, no difference in serious adverse events was observed between the two groups. At the time of clinical data cutoff, 78% of patients in the Ixabepilone alone group died, compared with 72% in the combination group.
参考文献 Reference Roque DM et a. SGO 2021 Virtual Annual Meeting on Women’s Cancer 2021 Abstr 11570
伊匹单抗/纳武单抗/帕尼单抗联用在 RAS/BRAF 野生型/微卫星稳定的转移性结直肠癌 (6/6/2021)
Combination of ipilimumab/nivolumab/panitumumab used in RAS/BRAF wild-type/microsatellite stable metastatic colorectal cancer
帕尼单抗（panitumumab）是一种靶向表皮生长因子受体 (EGFR) 的单克隆抗体，是 KRAS/NRAS/BRAF 野生型的转移性结直肠癌的标准疗法。临床前数据显示，抗 EGFR 治疗会引起肿瘤特异性适应性免疫反应和免疫原性细胞凋亡，需要功能性适应性免疫来调节疗效。然而，抗 EGFR 抗体治疗不可避免地会产生耐药性，并与 CTLA-4 和 PD-L1 的表达增加有关。研究者设想在帕尼单抗中加入易普利姆玛（抗 CTLA-4）和纳武单抗（抗 PD-1）将提高 KRAS/NRAS/BRAF野生型, 微卫星稳定患者的响应率。
这是一项多中心、单臂II期两阶段临床试验（LCCC1632）, 符合条件的患者必须接受过 1-2 线先前的治疗，并且之前没有接受过抗 EGFR 或免疫检查点抑制剂治疗。受试者接受每6星期一次静脉注射1 毫克/公斤伊匹单抗, 每2星期一次静脉注射240 毫克纳武单抗, 每2星期一次静脉注射6毫克/公斤帕尼单抗, 直至进展、毒性或患者停药。主要终点是12 周时的响应率，关键次要终点包括无进展生存期和响应持续时间。从2018 年 3 月至 2020 年 6 月共招募了 56 名受试者, 包括 6 名受试者的安全性试验，前 12 周的剂量限制性毒性为 0/6。
两阶段临床试验的第一阶段（n=32）有足够的响应率，值得招收其他参与者入组。对于 12 周响应率的主要终点，有 7 名无法评估的受试者。在 49 名可评估受试者中，12 周响应率为 35%（n = 17）（95% CI 21-48）。 20 名受试者在任何时候都至少有未经证实的响应。中位无进展生存期为 5.7 个月（95% CI 5.5-7.9）。最常见的治疗相关的 3-4 级不良事件包括脂肪酶升高 (9%)、淀粉酶升高 (7%)、ALT 升高 (5%)、AST 升高 (5%)、腹泻 (5%)、低磷血症 (5%) ) 和斑丘疹 (5%)。有1 例与治疗相关的 5 级心肌炎不良事件。
结论是, 该试验达到预先指定的 12 周响应率的主要终点，值得进一步研究。
Panitumumab is a monoclonal antibody that targets epidermal growth factor receptor (EGFR) and is the standard treatment for KRAS/NRAS/BRAF wild-type metastatic colorectal cancer. Preclinical data showed that anti-EGFR treatment can cause tumor-specific adaptive immune responses and immunogenic cell apoptosis, and functional adaptive immunity is required to regulate the efficacy. However, anti-EGFR antibody treatment inevitably leads to drug resistance, which is related to the increased expression of CTLA-4 and PD-L1. Researchers hypothesized that adding ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) to panitumumab will increase response rate of KRAS/NRAS/BRAF wild-type, microsatellite stable patients.
This is a multi-center, single-arm phase II two-stage clinical trial (LCCC1632). Eligible patients must have received 1-2 lines of previous treatment and have not received anti-EGFR or immune checkpoint inhibitor before. Participants received intravenous injection of 1 mg/kg ipilimumab once every 6 weeks, 240 mg nivolumab intravenously once every 2 weeks, and 6 mg/kg panitumumab intravenously once every 2 weeks, until progression, toxicity or patient withdrawal. The primary endpoint is response rate at 12 weeks, and the key secondary endpoints include progression-free survival and duration of response.
From March 2018 to June 2020, a total of 56 patients were recruited, including the 6 subjects safety run-in with 0/6 in the dose-limiting toxicity in first 12 weeks. The first phase of the two-stage clinical trial (n=32) had sufficient response rate to merit full enrollment. For the primary endpoint of 12-week response rate, there were 7 subjects who could not be assessed. Among 49 evaluable subjects, the 12-week response rate was 35% (n = 17) (95% CI 21-48). Twenty subjects had at least unconfirmed responses at any time. Median progression-free survival was 5.7 months (95% CI 5.5-7.9). The most common treatment-related grade 3-4 adverse events included increased lipase (9%), increased amylase (7%), increased ALT (5%), increased AST (5%), and diarrhea (5 %), hypophosphatemia (5%) and maculopapular rash (5%). There was 1 case of grade 5 treatment-related grade 5 myocarditis.
Conclusion: the trial met its prespecified primary endpoint of a 12-week response rate criteria to merit further study.
参考文献 Reference Lee MS et al. J Clin Onc 2021; 39（3） suppl 7-7.
术后Nivolumab（纳武单抗）治疗食管癌或胃食管交界处癌 (6/5/2021)
Adjuvant Nivolumab for Resected Esophageal or Gastroesophageal Junction Cancer
在术前（新辅助）放化疗后切除食管或胃食管交界处癌患者, 尚无辅助（术后）治疗减少高复发风险。
这是一项全球性、随机、双盲、安慰剂对照的 3 期试验（CheckMate 577），旨在评估检查点抑制剂作为食管癌或胃食管交界处癌患者的辅助治疗。有794位已切除 (R0) 的 II 期或 III 期食管癌或胃食管交界处癌患者参加, 他们接受了新辅助放化疗并有残留病理病变, 以 2:1 的比例随机分配接受纳武单抗（剂量为每 2 周 240 毫克，持续 16 周 ，然后每 4 周 480 毫克剂量）, 或安慰剂。试验干预期的最长持续时间为 1 年。主要终点是无病生存率。 中位随访时间为 24.4 个月。
在接受纳武单抗治疗的 532 名患者中，中位无病生存期为 22.4 个月（95% 置信区间 [CI]，16.6 至 34.0），而在接受安慰剂的 262 名患者中，中位无病生存期为 11.0 个月（95% CI，8.3 至 14.3）。疾病复发或死亡的风险比为0.69（96.4% CI，0.56 至 0.86；P < 0.001）。在多个预先指定的亚组中，无病生存率有利于纳武单抗。
与活性药物或安慰剂相关的 3 级或 4 级不良事件发生在纳武单抗组 532 名患者中的 71 名 (13%) 和安慰剂组 260 名患者中的 15 名 (6%)。由于纳武单抗组 9% 的患者和安慰剂组 3% 的患者发生与活性药物或安慰剂相关的不良事件，试验被终止。
FDA 已批准纳武单抗用于辅助治疗已接受新辅助放化疗的完全切除的食管或胃食管交界处 癌患者并有残留病理病变。
In patients with esophageal or GE-junction cancer after neoadjuvant chemoradiation, there is no adjuvant treatment to reduce high risk recurrence. This is a global, randomized, double-blind, placebo-controlled phase 3 trial (CheckMate 577), which aims to evaluate checkpoint inhibitors as an adjuvant treatment for patients with esophageal or GE-junction cancer. Participated were 794 patients with stage II or III esophageal or GE-junction cancer who had been resected (R0). They received neoadjuvant chemoradiation and had residual pathologic disease. They were randomly assigned to receive nivolumab or placebo at a 2:1 ratio. Nivolumab was given at 240 mg every 2 weeks for 16 weeks, then 480 mg every 4 weeks. The longest duration of treatment intervention was 1 year. The primary endpoint was disease-free survival. The median follow-up was 24.4 months.
Among the 532 patients who received nivolumab, median disease-free survival was 22.4 months (95% confidence interval [CI], 16.6 to 34.0), while among the 262 patients who received placebo, the median disease-free survival was 11.0 months (95% CI, 8.3 to 14.3). Hazard ration for disease recurrence or death was 0.69 (96.4% CI, 0.56 to 0.86; P <0.001). In multiple prespecified subgroups, disease-free survival rates favor nivolumab.
Grade 3 or 4 adverse events related to the active drug or placebo as judged by the investigators occurred in 71 of 532 patients (13%) in the nivolumab group and 15 (6%) of 260 patients in the placebo group. The regime was discontinued because 9% of patients in the nivolumab group and 3% of patients in the placebo group had adverse events related to the active drug or placebo.
FDA has approved nivolumab for the adjuvant treatment of patients with completely resected esophagus or GE-junction cancer who have received neoadjuvant chemoradiation and have residual pathological changes.
参考文献 Reference Kelly Rj et al. New Engl J Med 2021; 384:1191-1203
单剂量放疗用于乳腺癌治疗 (5/30/2021)
Single dose adjuvant radiation for breast cancer
一项期随机临床试验（TARGIT-A）研究乳腺癌切除术期间靶向术中放疗(TARGIT-IORT) 与全乳房外照射放疗 (EBRT) 一样有效。
该临床试验于 2000 年 3 月开始，2,298 名 45 岁或以上患有浸润性乳腺癌（≤ 3.5 厘米, cN0-N1）的女性被随机分配接受肿瘤切除术期间靶向术中放疗或术后 EBRT。该试验由伦敦大学学院设计和运行，涉及 10 个国家的 32 家医院和医疗中心：英国、法国、德国、意大利、挪威、波兰、瑞士、美国、加拿大和澳大利亚。在肿瘤切除后立即递送TARGIT-IORT，在相同的麻醉下，通过放置在乳房内的小球形装置，直接在癌症所在的位置。单次剂量治疗持续约 20-30 分钟，十个病例中有八个不需要额外的医院就诊。
该试验研究了肿瘤大小、分级、ER、PR、HER2 和淋巴结状态对局部无复发生存率的影响，以及局部复发对远处复发和死亡率的影响。使用回归模型分析了在 TARGIT-IORT 后推荐补充 EBRT 作为风险适应方法的一部分的预测因素。比较了 TARGIT-IORT 加 EBRT 与 EBRT 之间的非乳腺癌死亡率。
结果是, 在每个肿瘤亚组中，TARGIT-IORT 和 EBRT 的局部无复发生存率没有差异。与 EBRT 组不同，TARGIT-IORT 组的局部复发不是远处复发或死亡风险较高的预测因素。此外, TARGIT-IORT 组的非乳腺癌死亡率显着降低，包括患者接受补充了 EBRT（HR 0.38, 95% CI 0.17–0.88, P = 0.0091）。 研究者对在 TARGIT-IORT 后推荐再补充EBRT 的预测方法位于 https://targit.org.uk/addrt。
研究人员推断，术后立即向肿瘤所在部位进行放射治疗可以减少手术创伤的不利影响，使该部位不利于癌症生长，并可能产生“远隔”（abscopal）效应。这可能是包括在内放疗的治疗对远离手术部位的组织产生积极影响的地方，是一种有益的免疫作用。
结论 TARGIT-IORT 在所有亚组中与 EBRT 一样有效。与 EBRT 不同，TARGIT-IORT 后局部复发具有良好的预后。 TARGIT-IORT 可能具有有益的远隔效应。
A randomized clinical trial (TARGIT-A) studied targeted intraoperative radiotherapy (TARGIT-IORT) during breast cancer resection as effective as whole-breast external beam radiation therapy (EBRT).
The clinical trial started in March 2000. A total of 2,298 women (45 years of age or older) with invasive breast cancer (≤ 3.5 cm, cN0-N1) were randomly assigned to undergo TARGIT-IORT or postoperative EBRT . The trial was designed and run by University College London and involved 32 hospitals and medical centers in 10 countries: the United Kingdom, France, Germany, Italy, Norway, Poland, Switzerland, the United States, Canada, and Australia. TARGIT-IORT was delivered immediately after tumor resection, under the same anesthesia, through a small spherical device placed in the breast, directly at the location of the cancer. The single-dose treatment lasted about 20-30 minutes, and eight out of ten cases did not require additional hospital visits.
The trial studied the effects of tumor size, grade, ER, PR, HER2, and lymph node status on local recurrence-free survival, as well as the impact of local recurrence on distant recurrence and mortality. A regression model was used to analyze the predictors of recommending supplementary EBRT as part of the risk adaptation method after TARGIT-IORT. The non-breast cancer mortality rates between TARGIT-IORT plus EBRT and EBRT were compared.
Analyses of the results indicated that there was no difference in the local recurrence-free survival rate between TARGIT-IORT and EBRT in each tumor subgroup. Unlike the EBRT group, local recurrence in the TARGIT-IORT group was not a predictor of a higher risk of distant recurrence or death. In addition, the non-breast cancer mortality rate in the TARGIT-IORT group was significantly reduced, including patients receiving supplemental EBRT (HR 0.38, 95% CI 0.17–0.88, P = 0.0091). A prediction tool for recommending supplementary EBRT after TARGIT-IORT was provided and could be found at https://targit.org.uk/addrt.
Researchers hypothesized that immediate postoperative radiation therapy to the site of the tumor may reduce the adverse effects of surgical trauma, make the site not conducive to cancer growth, and may have an “abscopal” effect. This may be where the treatment including radiotherapy has a positive effect on the tissues far away from the surgical site, and has been regarded as a beneficial immune effect.
Conclusion TARGIT-IORT is as effective as EBRT in all subgroups. Unlike EBRT, local recurrence after TARGIT-IORT has a good prognosis. TARGIT-IORT may have a beneficial abscopal effect.
参考文献 Reference Vaidya JS et al. Br J Cancer2021; on line published May 25.
Nivolumab联合化疗可提高术前非小细胞肺癌患者的病理完全响应 (5/29/2021)
Pre-operative Nivolumab in combination with chemotherapy increased pathologic complete response rate among NSCLC patients
在2021年虚拟的美国癌症研究协会（AACR) 年会上报导的数据展示了 CheckMate-816 临床试验的结果，该研究评估了Nivolumab联合化疗对手术前Ib-IIIA非小细胞肺癌患者的效果。
在随机、开放标签的III期试验中，研究人员以 1:1 的比例随机分配患者接受360 毫克纳武单抗加铂双药化疗（n = 179）每 3 周一次，持续 3 个周期; 或单独化疗(n = 179) 每 3 周一次，共 3 个周期。 两种方案均在治疗后 6 周内进行手术。该研究的主要终点是病理完全响应 ，定义为手术后切除的肺标本和取样淋巴结中没有残留的活肿瘤，以及无事件生存率。
研究人员发现，在意向治疗人群中，Nivolumab联合化疗将病理完全响应率提高到 24%，而单独接受化疗的患者只有 2.2%（odds ratio [OR], 13.94; 99% CI, 3.49-55.75; P < .0001）。 而在手术切除患者中，接受Nivoluma/化疗组合的患者的病理完全响应率进一步增加至 30.5%，而单独接受化疗的患者的病理完全响应率为 3.2%。病理完全响应的改善在各亚组中是一致的，包括疾病分期、非小细胞肺癌亚型、PD-L1 状态、肿瘤突变负荷状态和性别。Nivolumab的给药也没有影响患者接受根治性手术的资格: 在Nivolumab/化疗组中为 83.2%，而在单独化疗组中为 75.4%。 此外，Nivolumab联合组的术前影像学客观反应率为 53.6%，而化疗组为 37.4%，影像学降期率分别为 30.7% 和 23.5%。
每组2名患者（每组1%）由于不良事件手术被取消; 联合12名患者 (7%)由于疾病进展手术被取消, 相对于单独化疗组17名患者 (9%) 。 3至4级治疗相关不良事件的发生率分别为 33.5% 和 36.9%，手术相关不良事件的发生率为11.4% 和14.8%。
CheckMate-816是第一个显示术前免疫疗法加化疗益处的III期试验，该研究将继续到完成另一个主要终点无事件生存率的分析。
Data presented at the 2021 virtual AACR annual meeting regarding the results of the CheckMate-816 clinical trial, which evaluated the effect of neoadjuvant Nivolumab in combination with chemotherapy on patients with IB-IIIA non-small cell lung cancer patients.
In a randomized, open-label phase III trial, researchers randomly assigned patients at 1:1 ratio to receive 360 mg nivolumab plus platinum doublet chemotherapy (n = 179) every 3 weeks for 3 cycles; or chemotherapy alone (n = 179) once every 3 weeks for a total of 3 cycles. In both groups, surgery was performed within 6 weeks after treatment. The primary endpoint of the study was pathological complete response, which is defined as the absence of residual live tumors in lung specimens and lymph nodes after surgery, and event-free survival (EFS).
Researchers have found that in the intention-to-treat population, Nivolumab combined with chemotherapy（n=179） increased the pathological complete response rate to 24%, compared with 2.2% of patients receiving chemotherapy alone（n=179）(odds ratio [OR], 13.94; 99% CI, 3.49-55.75; P < .0001). In patients who had surgical resection, the pathological complete response rate of patients receiving Nivoluma/chemotherapy combination further increased to 30.5%, while that of patients receiving chemotherapy alone was 3.2%. The improvement of pathological complete response was consistent across subgroup, including disease stage, NSCLC subtype, PD-L1 status, tumor mutation burden status, and gender. The administration of Nivolumab did not affect the eligibility of patients to receive radical surgery: 83.2% in Nivolumab/chemotherapy group and 75.4% in chemotherapy alone group. In addition, the objective response rate of preoperative imaging in the Nivolumab combination group was 53.6%, while that of the chemotherapy group was 37.4%, with resultant radiographic downgrade rate of 30.7% versus 23.5%, respectively.
Surgery was canceled in two patients in each group (1%) due to adverse events, or due to disease progression in 12 patients (7%) in combination group compared to 17 patients in chemotherapy group (9%). The incidence of grade 3 to 4 treatment-related adverse events was 33.5% and 36.9%, respectively, and the incidence of surgery-related adverse events was 11.4% and 14.8%.
CheckMate-816 is the first phase III trial to show the benefits of preoperative immunotherapy plus chemotherapy. The study will continue to mature for data from co-primary endpoint of EFS.
参考文献 Reference Forde PM et al. Virtual AACR Annual Meeting 2021; abstr CT003
Tislelizumab联合化疗作为转移性鼻咽癌的一线治疗 (5/23/2021)
Tislelizumab in combination with chemotherapy as first line therapy for metastatic nasopharyngeal cancer
Tislelizumab联合化疗在中期分析中显示该试验达到了无进展生存的主要终点: 无进展生存率有统计学意义的改善, 这是由药物公司在5月21日宣布的。
RATIONALE 309是一项随机，双盲，安慰剂对照的3期临床试验（NCT03924986），旨在评估tislelizumab联合化疗（吉西他滨和顺铂）相对于安慰剂联合化疗作为一线治疗复发或转移性鼻咽癌的疗效和安全性。研究的主要终点是无进展生存期。主要的次要终点包括总体生存期，独立审查委员会评估的客观响应率和响应持续时间。总共263名亚洲患者入组，并以1:1的方式随机分配给tislelizumab +化疗组或安慰剂+化疗组。
与单独化疗相比，tislelizumab联合化疗在意向治疗人群中无进展生存期的改善具有统计学意义。Tislelizumab的安全性与其已知风险相符，没有发现新的安全性信号伴随化疗。药物公司表示会在即将举行的医学会议上报告这些数据。
An interim analysis of Tislelizumab in combination with chemotherapy showed that the trial has reached the primary endpoint of the phase III clinical trial: a statistically significant improvement in progression-free survival. It was announced by the drug company on May 21.
RATIONALE 309 is a randomized, double-blind, placebo-controlled Phase 3 clinical trial (NCT03924986), which aims to evaluate the efficacy and safety of tislelizumab in combination with chemotherapy (gemcitabine and cisplatin) versus placebo combined with chemotherapy as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma. The primary endpoint of the study was progression-free survival. The primary secondary endpoints included overall survival, objective response rate as assessed by the independent review committee, and the duration of response. A total of 263 Asian patients were enrolled and randomly assigned to tislelizumab + chemotherapy group or placebo + chemotherapy group in a 1:1 ratio.
Compared with chemotherapy alone, tislelizumab combined with chemotherapy has statistically significant improvement in progression-free survival in the intent-to-treat population. The safety of tislelizumab was consistent with its known risks, and no new safety signals have been found. The drug company announced it would report the data at an upcoming medical conference.
参考文献 Reference https://ir.beigene.com/news-releases/news-release-details/beigene-announces-positive-topline-results-phase-3-trial?loc=us
一项新的药物敏感测试确定卵巢透明细胞癌的新治疗方法 (5/22/2021)
A new drug sensitivity assay identifies therapeutic options for clear cell carcinoma of the ovary
卵巢透明细胞癌是卵巢癌一种相对罕见的亚型，通常对化疗反应较差，而导致总生存期降低。
一项新的测试方法称为PARIS®（一种使用患者来源的肿瘤类器官的高通量药物敏感性测定方法）用于鉴定新型对抗卵巢透明细胞癌的药物靶标和组合。 研究人员将BET蛋白BRD2和BRD3确定为针对卵巢透明细胞癌的新型靶标，这可能导致针对该亚型的更有效的靶向治疗。进一步的药物敏感性筛选确定了BET蛋白和PI3K-AKT途径抑制剂的组合是进一步研究的有希望的治疗途径。
在一个包含44个可评估患者样本的卵巢癌队列中，研究者发现, 卵巢癌患者衍生的3D培养物保留了原始肿瘤样品的组织病理学和分子特征。 对于82％的患者样本，PARIS®测试确定了至少一种（FDA批准或临床试验证明有效的）药物具有良好反应。 在22/24的患者测试中（91％），测试结果表明对至少一种药物有耐药性使患者的病情进展。 PARIS®测试显示出良好的临床反应，与为临床预测进行评估的10/12例患者（83％）的结果相符。
这项研究还提供了一个基于PARIS®测试结果对接受个性化治疗进行临床治疗的实例。一个患者被诊断为IV期低度上皮浆液性癌，在多轮化疗后病情进展。根据PARIS®测试结果, 患者的肿瘤对Ibrutinib产生了响应，该药物是FDA批准用于治疗套细胞淋巴瘤和慢性淋巴细胞性白血病。以前从未用于卵巢癌。
Clear cell carcinoma is a relatively rare subtype of ovarian cancer. It usually responds poorly to chemotherapy, leading to a low overall survival. A new test method called PARIS® Test (a high-throughput drug sensitivity assay using patient-derived tumor organoids) is used to identify novel drug targets and combinations against ovarian clear cell carcinoma. The researchers identified the BET proteins BRD2 and BRD3 as new targets for clear cell carcinoma. The assay may lead to more effective targeted treatments for this subtype. Further drug sensitivity screening confirmed that the combination of BET protein and PI3K-AKT pathway inhibitor is a promising therapeutic approach for further research.
In an ovarian cancer cohort of 44 evaluable patients, researchers found that 3D cultures derived from ovarian cancer patients retained the histopathological and molecular characteristics of the original tumor samples. For 82% of patients, PARIS® test determined that at least one drug (approved by the FDA or proven effective in clinical trials) had a good response. In 22/24 patient (91%), the test results showed resistance of at least one drug on which the patient was in progression. The PARIS® test showed a good clinical response, which was concordant with the results of 10/12 patients (83%) evaluated for clinical prediction.
This study also provided an example of personalized treatment based on PARIS® test results. One patient was diagnosed with stage IV low-grade epithelial serous carcinoma, which progressed after multiple lines of chemotherapy. According to the PARIS® test results, the patient’s tumor responded to Ibrutinib, which is FDA approved for the treatment of mantle cell lymphoma and chronic lymphocytic leukemia. It has never been used for ovarian cancer.
参考文献 Reference Goldie Lui et al. AACR 2021, abstr 534
Copanlisib-rituximab组合可降低惰性非霍奇金淋巴瘤的疾病进展或死亡 (5/16/2021)
Combination of copanlisib-rituximab may reduce disease progression and death in indolent NHL
利妥昔单抗（rituximab）单药用于治疗复发性惰性（indolent）B细胞淋巴瘤患者, 但是单药利妥昔单抗的临床获益是短暂的。 Copanlisib是一种选择性的，静脉内给药的泛I类PI3K抑制剂，对α和δ亚型具有选择性活性，已被批准作为单药用于治疗已接受两种或两种以上以前疗法的复发性滤泡性淋巴瘤。
在III期随机试验（CHRONOS-3）中，将CD20阳性的惰性B细胞淋巴瘤患者（包括低度滤泡性淋巴瘤，边缘区淋巴瘤，小淋巴细胞淋巴瘤和淋巴浆细胞性淋巴瘤或Waldenstrom巨球蛋白血症）随机分配至copanlisib加利妥昔单抗（n = 307）或利妥昔单抗加安慰剂（n = 151）。 如果患者在接受利妥昔单抗治疗后12个月以上无进展, 或在接受利妥昔单抗治疗后6个月以上无进展而不愿接受或不适合化疗，都符合参加条件。该研究的主要终点是通过中央评估得出无进展生存期。 约有80％的患者参加试验时离最后一次利妥昔单抗治疗已超过12个月，并且大多数患者患有滤泡性淋巴瘤。
这项研究对不同组织类型的无进展生存期都有改善，无进展生存期改善了7.7个月（危险比[HR] = 0.52； P < 0.0001）。与单独使用利妥昔单抗相比，治疗组的缓解率也更高（81％比48％）。 联合用药方案还显示出可控的安全性，毒性与先前报道的单一疗法的相符。 Copanlisib联合利妥昔单抗最常见的不良事件是高血糖症和高血压。肺炎发生在6.8％的患者中，但只有2％的患者患了3级肺炎，少于1％的患者患有4级肺炎。
Copanlisib代表第一种安全地与利妥昔单抗联合使用的PI3K抑制剂，并且是第一种在所有惰性组织学亚型中均显示出与利妥昔单抗联合使用的活性。Copanlisib和利妥昔单抗的组合代表了一种新的治疗选择。
Rituximab alone is one of the choices to treat patients with relapsed indolent B-cell lymphoma, albeit the clinical benefit of rituximab as a single agent is short-lived. Copanlisib is a selective, intravenously administered pan-class I PI3K inhibitor with selective activity on α and δ subtypes. It has been approved as a single agent to treat recurrent follicular lymphoma patients who have received two or more previous therapies.
In a phase III randomized trial (CHRONOS-3), patients with CD20-positive, indolent B-cell lymphoma (including low-grade follicular lymphoma, marginal zone lymphoma, small lymphocytic lymphoma and lymphoplasmacytic lymphoma or Waldenstrom macroglobulinemia) were randomly assigned to copanlisib plus rituximab (n = 307) or rituximab plus placebo (n = 151). Patients were eligible if they were progression-free for more than 12 months after receiving rituximab treatment, or they were progression-free post-rituximab for more than 6 months if they were unwilling to receive or were not suitable for chemotherapy. The primary endpoint of the study was progression-free survival (PFS) through a central assessment. About 80% of patients participated in the trial had gone more than 12 months from the last rituximab treatment, and most of the patients had follicular lymphoma.
This study revealed that the combination showed PFS improvement across different histology types. PFS improved by 7.7 months (hazard ratio [HR] = 0.52; P <0.0001). Compared with rituximab alone, the treatment group also had a higher response rate (81% vs. 48%). The combination regimen also showed controllable safety, and the toxicity profile was consistent with that reported previously with monotherapy. The most common adverse events of copanlisib combined with rituximab were hyperglycemia and hypertension. Pneumonia occurred in 6.8% of patients, but only 2% of patients had grade 3 pneumonia, and less than 1% of patients had grade 4 pneumonia.
Copanlisib represents the first PI3K inhibitor that could be safely used in combination with rituximab, and is the first to show activity in combination with rituximab in indolent NHL of different histology. The combination of Copanlisib and Rituximab represents a new treatment option.
参考文献 Reference Matasar M et al. AACR, 2021 Abstr CT001
对已扩散到大脑的乳腺癌细胞的潜在新治疗策略 (5/15/2021)
Potential new treatment strategy for breast cancer metastatic to the brain
与人体其他组织相比，当乳腺癌细胞扩散到大脑时，脂肪的获取受到更多的限制, 因此必须改变其代谢方式, 促进脂肪酸的产生，才能在其中生存。 在小鼠中，阻断此类细胞合成脂肪酸的能力会减少大脑中乳腺肿瘤的生长。 这些发现可能有助于为癌症已经扩散到大脑的患者设计新的治疗方法。
为了研究这种可能性，研究人员在小鼠中设计了实验，以评估扩散到大脑和体内其他部位的乳腺肿瘤之间新陈代谢的差异。 研究显示，乳腺肿瘤在大脑中的生长受到了脂肪获取的限制。作为响应，这些肿瘤细胞中脂肪酸合成酶的活性会增加，而使脂肪酸合成增加。 同样, 来自病人脑部转移的临床标本相对于未转移的肿瘤也过表达了脂肪酸合成酶，
因此，潜在的治疗策略是,当癌症扩散到特定器官时，可以利用该部位的营养供应。抑制癌细胞利用这种营养素的能力可能导致其死亡。 迄今为止，靶向疗法主要集中在癌细胞的遗传脆弱性上。这项研究表明，癌细胞所处的环境也可以决定在制定治疗策略时可考虑的代谢脆弱性。目前正在转移性乳腺癌患者中评估一种称为TVB2166的脂肪酸合成酶抑制剂。 但这种化合物不能透脑。因此，这种策略在脑转移患者中的有效性和安全性尚待研究，应该使用可穿透脑的脂肪酸合成酶抑制剂。
Compared with other tissues of the human body, when breast cancer cells spread to the brain, their access to fat in brain tissue is more limited. Consequently, they may have to change their metabolism to promote the production of fatty acids in order to survive. In mice, blocking the ability of these cells to synthesize fatty acids reduces the growth of breast tumors in the brain. These findings may help design new treatments for patients whose cancer has spread to the brain.
To investigate this possibility, researchers designed experiments in mice to evaluate the metabolic differences between breast tumors that have spread to the brain and other parts of the body. Their studies have shown that the growth of breast cancer in the brain is limited by access to fat. In response, fatty acid synthase is increase in these tumor cells through the enhanced activity of fatty acid synthetase. Similarly, clinical specimens from patients with brain metastases also showed an overexpression of fatty acid synthase compared with non-metastatic tumors.
Therefore, a potential treatment strategy is that when cancer cells spread to a specific organ, they may use the nutrient supply from that part. Inhibiting cancer cells’ ability to use this nutrient may lead to their starvation and death. So far, targeted therapies have focused on genetic vulnerability of cancer cells. This study showed that the environment in which cancer cells were located could determine their metabolic vulnerability that can be utilized when formulating treatment strategies. A fatty acid synthase inhibitor called TVB2166 is currently being evaluated in patients with metastatic breast cancer. But this compound cannot penetrate the brain. Therefore, the effectiveness and safety of this strategy in patients with brain metastases remains to be studied, and brain-penetrating fatty acid synthase inhibitors would be preferable.
参考文献 Reference https://www.eurekalert.org/pub_releases/2021-04/mgh-pnt033121.php
新型雄激素受体激动剂Enobosarm治疗乳腺癌的II期临床研究 (5/9/2021)
A phase II trial of a novel androgen receptor agonist, Enobosarm, in breast cancer
IV期乳腺癌患者在经过他莫昔芬, 芳香化酶抑制剂（阿那曲唑或乳腺癌来曲唑），氟维司群和CDK4/6抑制剂治疗后病情进展后, 缺少有效的口服治疗药物。Enobosarm是一种口服的，新型选择性雄激素受体靶向激动剂，可激活雄激素受体阳性/雌激素受体阳性/HER2阴性转移性乳腺癌中的雄激素受体（肿瘤抑制因子）。
一项II期临床研究（G200802）是国际性，开放标签的随机研究，有136位己转移的雄激素阳性/雌激素受体阳性/HER2阴性乳腺癌病人参加, 她们在用多种内分泌疗法后癌症进展，包括CDK 4/6抑制剂和90％的化疗失败者, 在转移后接受过平均有3线的疗法。患者随机接受每天口服9毫克（n = 72）或18毫克（n = 64）的enobosarm。主要终点是24周临床获益率（包括完全响应, 部分响应和疾病稳定者）。次要终点包括客观响应率，最佳总体响应率，影像学无进展生存期和临床获益持续时间。
在可评估的患者中, 24周时的临床获益率为50％，并且最佳客观肿瘤响应为30％（包括2个完全响应和1个部分响应）。 接受9毫克剂量的中位放射学无进展生存期为10个月。此外，enobosarm的耐受性好，并显示出可以改善生活质量。试验结果的详细报告将在ESMO会议上报导。
研究者选择了9毫克剂量的Enobosarm用于第3期试验（ARTEST），该研究预计于2021年6月开始。
Stage IV breast cancer who have failed tamoxifen, aromatase inhibitors (anastrozole or letrozole), fulvestrant, and CDK4/6 inhibitors lack effective oral drugs. Enobosarm is an oral, first-in-class selective androgen receptor agonist that activates androgen receptor (tumor suppressor) in androgen receptor-positive/estrogen receptor-positive/HER2-negative metastatic breast cancer.
A phase II clinical study (G200802) is an international, open-label, randomized study. A total of 136 patients with androgen receptor-positive/estrogen receptor-positive/HER2-negative metastatic breast cancer participated. Their disease progressed after they received previously multiple endocrine therapies, including CDK 4/6 inhibitors and 90% failed chemotherapy. They received an average of 3 lines of prior therapy in the setting of metastasis. Patients were randomized to receive 9 mg (n = 72) or 18 mg (n = 64) of enobosarm orally everyday. The primary endpoint was 24-week clinical benefit rate (including complete response, partial response and stable disease). Secondary endpoints included objective response rate, best overall response rate, imaging progression-free survival, and duration of clinical benefit.
Among evaluable patients, the clinical benefit rate at 24 weeks was 50%, and the best objective tumor response was 30% (including 2 complete responses and 1 partial response). Median radiological progression-free survival period was 10 months at 9 mg dose. In addition, enobosarm was well tolerated and has been shown to improve quality of life. A detailed report of the trial results will be reported at the ESMO meeting. Researchers selected a dose of 9 mg of enobosarm for the phase 3 trial (ARTEST), which is expected to start in June 2021.
参考文献 Reference https://verupharma.com/news/veru-announces-the-presentation-of-positive-phase-2-clinical-data-of-enobosarm-in-arerher2-metastatic-breast-cancer-patients-that-have-progressed-on-estrogen-blocking-agents-and-cdk-4-6-inhibitor-a/
在术前化疗之前进行完全膀胱尿道切除术和膀胱癌生存率改善有关 (5/8/2021)
Complete transurethral resection of bladder tumor before neoadjuvant chemotherapy was associated with improved survival
一项针对93名肌肉浸润性膀胱癌患者的回顾性单机构研究（2000-2017）表明，在新辅助（术前）化疗前接受完全膀胱尿道切除术（TURBT）治疗的患者5年总生存率与不完全TURBT的患者相比为77％ vs. 46％（P = 0.003）, 癌症特异性生存率为85％ vs. 50%（P = 0.001）。 他们的无复发生存率（24％ vs. 6％）和肌肉浸润无复发生存率（59％ vs. 14％）也明显更高。在这些肌肉浸润性膀胱癌患者中，在新辅助化疗前接受完全TURBT治疗的患者的变异组织学（13％ vs. 32％）和肾积水（15％ vs. 39％）的发生率较低。 在研究的93位患者中，有62位（67％）在接受新辅助化疗之前接受了完全TURBT治疗。研究者将完整的TURBT定义为全部切除所有可见肿瘤，切除到正常外观的肌肉。
但是,在新辅助化疗前接受不完全TURBT的患者, 在基线时有更多的晚期癌症。完全TURBT组中没有患者患有cT3或更大的疾病，相比之下，不完全TURBT组中的患者为36％。完全TURBT的患者在膀胱切除术中的pT2发生率较低,分别为48％相对于75％。研究者认为尚不清楚完全TURBT是预后还是治疗因素。
A retrospective single-institution study (2000-2017) of 93 patients with muscle-invasive bladder cancer showed that those who received complete transurethral resection of bladder tumor (TURBT) before neoadjuvant chemotherapy, compared with those with incomplete TURBT, 5-year overall survival was 77% vs. 46% (P=0.003), and cancer-specific survival was 85% vs. 50% (P=0.001). Their recurrence-free survival (24% vs. 6%) and muscle infiltration recurrence-free survival rate (59% vs. 14%) were also significantly higher. Among these patients with muscle-invasive bladder cancer, the incidence of variant histology (13% vs. 32%) and hydronephrosis (15% vs. 39%) was lower in patients who received complete TURBT before neoadjuvant chemotherapy. Of the 93 patients studied, 62 (67%) received complete TURBT treatment before receiving neoadjuvant chemotherapy. The researchers defined complete TURBT as resection of all visible tumor in its entirety, resection to normal-appearing muscle, and/or repeat pre-neoadjuvant chemotherapy TURBT.
However, patients who received incomplete TURBT before neoadjuvant chemotherapy had more advanced cancer at baseline. No patient in the complete TURBT group had cT3 disease or greater, compared to 36% in the incomplete TURBT group. Patients with complete TURBT had a lower incidence of pT2 (48%) during cystectomy versus 75%. Researchers thought that it was unclear whether complete TURBT was a prognosis or a therapeutic factor.
参考文献 Reference Pak JS et al. Urol Oncol. Published online April 14, 2021. doi:10.1016/j.urolonc.2021.03.025
含有BRAF抑制剂的乳霜可以缓解表皮生长因子受体抑制剂引起的皮丘疹 (5/2/2021)
A novel BRAF-inhibitor containing cream may ameliorate skin rashes caused by EGFR inhibitor
皮疹是表皮生长因子受体（EGFR）抑制剂的常见副作用。EGFR抑制剂对癌症的治疗受到有丝分裂原激活的蛋白激酶（MAPK）途径抑制引起的皮肤毒性的限制。大约有75%以上的患者会经历某种形式的痤疮样皮丘疹，这常常导致生活质量受影响, 剂量降低, 或治疗中断，甚至或永久停止EGFR抑制剂。人们发现BRAF抑制剂会反常激活EGFR下游的MAPK，使用人类皮肤角质形成细胞证实了这一点。
一项首次I期临床试验有10位转移性结直肠癌病人参加, 这些患者接受西妥昔单抗或帕尼单抗治疗，并且在治疗时出现1级或2级皮疹。 所有这些病人均用新型局部用乳霜（称为LUTO14）进行治疗。 在10名患者中有6名患者的痤疮样皮疹得到了改善。
根据临床前模型和早期临床试验测试，局部用LUT014改善EGFR抑制剂治疗的不良事件, 可以维持生活质量和剂量强度。该乳膏耐受性良好，未观察到剂量限制性毒性或最大耐受剂量，尽管该乳膏似乎在较低剂量下更有效。 研究的下一阶段将招募大约120名患者。预计将于2021年底发布中期报告。
Skin rash is a common side effect of epidermal growth factor receptor (EGFR) inhibitors. Treatment by EGFR inhibitors can be limited by skin toxicity caused by the inhibition of the mitogen-activated protein kinase (MAPK) pathway. Approximately more than 75% of patients can experience some form of acneiform skin papules, which often results in poor quality of life, dose reduction, treatment interruption, or even permanent discontinuation of EGFR inhibitors. It was found that BRAF inhibitors paradoxically activate MAPK downstream of EGFR, and it was confirmed using human skin keratinocytes.
In a first phase I clinical trial, 10 patients with metastatic colorectal cancer participated. These patients were treated with cetuximab or panitumumab and they developed grade 1 or 2 skin rashes during treatment. All these patients were treated with a new topical cream (called LUTO14). The acneiform rashes were improved in 6 out of 10 patients.
According to preclinical models and early clinical trials, topical LUT014 may improve the adverse events of EGFR inhibitor, maintain the quality of life and dose intensity. The cream was well tolerated, and no dose limiting toxicity or maximum tolerated dose was observed, although the cream appeared to be more effective at lower doses. Approximately 120 patients will be recruited in the next phase of the study. Interim results are expected by the end of 2021.
参考文献 Reference Lacouture ME et al. Cancer Discovery April 28, 2021 doi: 10.1158/2159-8290.CD-20-1847
Trilaciclib开始在三阴性乳腺癌中进行III期注册临床试验 (5/1/2021)
A phase III clinical trial using Trilaciclib in triple-negative breast cancer is starting
吉西他滨/卡铂是转移性三阴性乳腺癌患者的标准一线化疗方案之一。在一项去年12月报导的随机II期研究数据表明，在接受吉西他滨/卡铂之前给予trilaciclib，与单独使用 化疗 相比，trilaciclib显著改善了总生存期, 并增强了免疫系统功能。患者被随机分配为仅接受吉西他滨/卡铂（对照组）或吉西他滨/卡铂加上trilaciclib的两种给药方案之一：Trilaciclib在化疗当天（第2组）, 或在化疗前一天及当天（第3组）给予。与单独使用对照组相比，两组接受trilaciclib组的总生存期均有统计学上的显著改善（第2组：HR = 0.31，p = 0.0016；第3组：HR = 0.40，p = 0.0004）。至2020年7月17日数据截止，对照组患者的中位总生存期为12.6个月，第2组尚未达到，而第3组为17.8个月。第2组和第3组的中位总生存期为19.8个月（ HR = 0.37，p <0.0001）。与对照组患者相比，接受trilaciclib和吉西他滨/卡铂治疗的PD-L1阳性和PD-L1阴性肿瘤患者的总生存期均有改善，PD-L1阳性亚组在统计学上有显著改善。对T细胞克隆的分析表明，化疗前服用trilaciclib可增强免疫系统功能。
PRESERVE 2是一项关键的III期随机临床试验，对局部晚期不可切除或转移性三阴性乳腺癌的患者中, 在接受一线或二线吉西他滨/卡铂化疗时加上trilaciclib的双盲，安慰剂对照研究。预计这项研究的结果将在2023年下半年发布。
该研究将招募两个队列: 队列1（n = 170）将评估接受过一线治疗但未接受过PD-1/PD-L1抑制剂的患者（无论其PD-L1状态如何）。队列2（n = 80）将评估在局部晚期不可切除/转移的患者中, 已经接受PD-1/PD-L1抑制剂治疗后接受二线治疗的PD-L1阳性患者。这两个队列具有足够的统计能力，并且彼此独立。因此，将分别分析每个队列收集的功效和安全性数据。 在每个队列中，患者将被随机分配（1:1），以在吉西他滨和卡铂治疗之前接受trilaciclib（在以上提到 的II期研究的第2组中使用相同的给药方案），或者在吉西他滨/卡铂之前接受安慰剂治疗。研究药物将在第1天和第8天（21天的周期）进行静脉内给药。研究药物的给药将持续进行，直到疾病进展，或不可接受的毒性，同意撤消，研究者决定或研究结束为止，队列1的主要终点是评估接受一线吉西他滨/卡铂治疗的患者与安慰剂相比，trilaciclib对总生存期的影响。队列2的主要终点是评估在接受PD-1/PD-L1抑制剂治疗后接受吉西他滨/卡铂作为二线治疗的患者中，trilaciclib与安慰剂相比对总生存期的作用。两项试验的关键次要终点均包括与安慰剂相比评估trilaciclib对患者生活质量的影响。
Gemcitabine/carboplatin is one of the standard first-line chemotherapy regimens for patients with metastatic triple-negative breast cancer. Data from a randomized phase II study reported in December 2020 showed that giving trilaciclib before receiving gemcitabine/carboplatin significantly improved overall survival and enhanced immune system function compared with chemotherapy alone. Patients were randomly assigned to receive either gemcitabine/carboplatin only (control group) or gemcitabine/carboplatin plus trilaciclib: Trilaciclib on the day of chemotherapy (group 2), or on the day before and on the day of chemotherapy (group 3). Compared with the control group, the overall survival of the two cohorts receiving trilaciclib was statistically significantly improved (group 2: HR = 0.31, p = 0.0016; group 3: HR = 0.40, p = 0.0004). As of the data cutoff on July 17, 2020, the median overall survival of patients in the control group was 12.6 months, cohort 2 has not yet reached, and the cohort 3 was 17.8 months. The median overall survival in cohort 2 and 3 was 19.8 months (HR = 0.37, p <0.0001). Compared with the control group, the overall survival of patients with PD-L1-positive and PD-L1-negative tumors treated with trilaciclib and gemcitabine/carboplatin was improved, while the PD-L1-positive subgroup was statistically significantly improved. Analysis of T cell clones showed that trilaciclib administered before chemotherapy could enhance immune function.
PRESERVE 2 is a planned pivotal phase III clinical trial. In patients with locally advanced unresectable or metastatic triple-negative breast cancer, trilaciclib was added to first-line or second-line gemcitabine/carboplatin. The results of this study are expected to be released in the second half of 2023.
The study will recruit two cohorts: Cohort 1 (n = 170) will evaluate patients who have received first-line treatment but have not received PD-1/PD-L1 inhibitors (regardless of their PD-L1 status). Cohort 2 (n = 80) will evaluate PD-L1-positive patients who have received second-line treatment after receiving PD-1/PD-L1 inhibitor treatment among locally advanced/unresectable/metastatic patients. These two cohorts are adequately powered and are independent of each other. Therefore, the efficacy and safety data collected for each cohort will be analyzed separately. In each cohort, patients will be randomly assigned (1:1) to receive trilaciclib before gemcitabine and carboplatin treatment (using the same dosing schedule as in the second group of the phase II study mentioned above), or receive placebo before gemcitabine/carboplatin. The study drug will be administered intravenously on day 1 and day 8 (a 21-day cycle). The administration of the study drug will continue until the disease progresses, unacceptable toxicity, withdrawal of consent, investigator decision, or the end of study, whichever occurs first.
The primary endpoint of cohort 1 is to evaluate the effect of trilaciclib on overall survival compared with placebo in patients receiving first-line gemcitabine/carboplatin. The primary endpoint of cohort 2 is to evaluate the effect of trilaciclib on overall survival compared with placebo in patients who received gemcitabine/carboplatin as second-line treatment after treatment with a PD-1/PD-L1 inhibitor. Key secondary endpoints of both cohorts included the effect of trilaciclib on the quality of life compared with placebo.
参考文献 Reference https://www.biospace.com/article/releases/g1-therapeutics-announces-initiation-of-phase-3-registrational-study-of-cosela-trilaciclib-in-triple-negative-breast-cancer-tnbc-/?s=69
放化疗前加上化疗提高局部晚期直肠癌的无病生存率 (4/25/2021)
Neoadjuvant chemotherapy prior to standard chemo-radiation improved DFS in locally advanced rectal cancer
一项随机试验显示，与标准的放化疗和术后化疗方案相比，在局部晚期直肠癌的术前放化疗之前增加新辅助化疗可带来更好的3年无病生存期和更低的毒性。
对于局部晚期直肠癌（T3，T4或N +）患者，当前的护理标准包括术前放化疗，直肠系膜切除术。但远处转移仍然是一个问题。 术后的辅助化疗仍存在争议，因为它并未改善总生存期。 法国35个中心的研究人员进行了一项随机试验（UNICANCER-PRODIGE 23）。参加者为461名新诊断，经活检证实，局部晚期直肠癌的患者。按1:1随机分配。 所有患者均接受标准治疗（术前放化疗，随后进行手术和辅助化疗（对照组为6个月）。随机分配到新辅助组（在放化疗前加上化疗）的患者放化疗前接受了改良的FOLFIRINOX和3个月的辅助化疗。 主要终点为3年无病生存期，次要终点包括总生存期，无转移生存期和癌症特异性生存期。中位随访46.5个月。
新辅助组3年的无病生存期为76%相对于对照组的69%, 风险降低了31％（95％CI 0.49-0.97，P = 0.034）。 3年时的总生存期无显著差异（91％相对于 88％），3年癌症特异性生存期也无显著差异（92％相对于 89％）。新辅助组在3年时的无转移生存期明显改善（79％相对于72％，P = 0.017）。
新辅助组中与治疗相关的3/4级不良事件明显少于对照组（45％相对于79％，P < 0.0001）。接受6个月辅助治疗的对照组中3/4级中性粒细胞减少症，血小板减少症和淋巴细胞减少症的发生率明显更高。
A randomized trial showed that compared with standard chemoradiation and postoperative chemotherapy, adding neoadjuvant chemotherapy before preoperative chemoradiation for locally advanced rectal cancer led to improved 3-year disease-free survival and lower toxicity.
For patients with locally advanced rectal cancer (T3, T4 or N +), current standard of care includes preoperative chemoradiotion, and mesorectal resection. However, distant metastasis is still a problem. Postoperative adjuvant chemotherapy is still controversial because it has not been shown to improve overall survival.
Researchers from 35 centers in France conducted a randomized trial (UNICANCER-PRODIGE 23). Participated were 461 patients with newly diagnosed and biopsy-proven, locally advanced rectal cancer. All patients received preoperative chemoradiation, followed by surgery and adjuvant chemotherapy (3 months for the neoadjuvant group and 6 months for the control group). Patients randomly assigned to the neoadjuvant group (additional chemotherapy prior to chemoradiation) received modified FOLFIRINOX6 versus control group. The primary endpoint was 3 years disease-free survival, and secondary endpoints included overall survival, metastasis-free survival, and cancer-specific survival. The median follow-up was 46.5 months,
The 3-year disease-free survival of the neoadjuvant group was 76% compared to 69% in the control group, and the risk was reduced by 31% (95% CI 0.49-0.97, P = 0.034). There was no significant difference in overall survival at 3 years (91% vs. 88%), nor was there a significant difference in 3-year cancer-specific survival (92% vs. 89%). The metastasis-free survival of the neoadjuvant group was significantly improved at 3 years (79% vs. 72%, P = 0.017).
Treatment-related grade 3/4 adverse events in the neoadjuvant group were significantly less than those in the control group (45% vs. 79%, P <0.0001). The incidence of grade 3/4 neutropenia, thrombocytopenia and lymphopenia was significantly higher in the control group who received 6 months of adjuvant therapy.
参考文献 Reference Conroy T et al. Lancet Onc 2021; April 13. DOI: 10.1016/S1470-2045(21)00079-6.
包括抗CD38药物daratumumab在内的四药治疗新诊断多发性骨髓瘤方案导致最小残留疾病（MRD） (4/24/2021)
Four drug combination including daratumumab achieved good MRD level in newly diagnosed multiple myeloma patients
MANHATTAN是一项单臂，单中心II期试验，对41例新诊断为骨髓瘤的患者评估了daratumumab联合KRd（carfilzomib, 来那度胺 和地塞米松）的疗效。患者的中位年龄为59岁，女性占61％，患有高危疾病的比例略低于一半。该研究的主要终点是MRD阴性（微小残留病, 骨髓敏感度为10-5） 。治疗包括8个周期的carfilzomib, 在每周期（28 天）的第1、8和15天静脉注射20/56 毫克/平方米; 来那度胺, 第1至21天口服25 毫克; 地塞米松, 第1至4周期每周口服或静脉40 毫克，然后为20毫克; daratumumab（16 毫克/公斤）, 在第1和2周期的第1、8、15和22天静脉给药, 第3至6周期的第1和15天给药, 第7和8周期的第1天给药。
研究中所有41位可评估的患者对治疗均有效，其中95％达到了完全缓解或很好的部分缓解。 1年无进展生存率和总生存率分别为98％（95％CI 93-100％）和100％。 MRD阴性与更长的无进展生存期和总生存期相关。年龄（< 60相对于≥ 60）与MRD阴性无显著相关，OR为0.48（95％CI 0.08-2.3，P = 0.32），细胞遗传风险状态（高风险与标准风险）也不相关，OR为1.7（95％CI 0.36-8.6，P ＝ 0.50）。 患者在中位6个周期达到MRD阴性。在MRD阴性并在1年进行评估的8例患者中，有7例维持了这一水平的缓解。在新诊断多发性骨髓瘤患者中，观察到的结果比以前报道的KRd的MRD率高约20％。
与标准的双周KRd相比，四药疗法没有产生额外的 ≥ 3级毒性。 常见的3/4级不良事件包括中性粒细胞减少症（27％），皮疹（9％），肺部感染（7％）和丙氨酸转氨酶水平升高（4％），没有发生 ≥ 3级的周围神经病变。队列中有18％的患者发生了严重的与治疗相关的不良事件，其中最常见的是肺部感染，其中一名患者在研究期间出现了急性冠状动脉综合征并退出了研究。 Daratumumab的2级输注相关反应发生在40％的患者中，所有这些都是在初始输注期间发生的，并未导致治疗中断。总体而言，有17例来那度胺剂量减少，22例地塞米松减少。 只有两名患者停止治疗，一名是在罹患肺癌后停止治疗，另一名是在COVID-19大流行期间减少临床就诊机会。
一些评论者认为, 尽管Daratumumab加KRd对某些患者可能是一个现实的方案，但在符合移植条件的情况下，仍无足够的证据证明四药方案作为移植前诱导疗法。
MANHATTAN is a single-arm, single-institution, phase II trial that evaluated the efficacy of daratumumab combined with KRd (carfilzomib, lenalidomide, and dexamethasone) in 41 newly diagnosed myeloma patients. The median age was 59 years old. Women accounted for 61%, and the proportion of patients suffering from high-risk diseases was slightly less than half. The primary endpoint of the study is MRD negativity (defined as sensitivity of110-5 in the bone marrow). Treatment consists of 8 cycles of carfilzomib, at 20/56 mg/m2 intravenously on days 1, 8 and 15 of each cycle (28 days); lenalidomide, 25 mg orally on days 1 to 21; dexamethasone , at 40 mg orally or intravenously every week for cycles 1 to 4, then 20 mg; daratumumab (16 mg/kg), intravenously administered on days 1, 8, 15 and 22 of cycles 1 and 2, on days 1 and 15 in cycles 3 to 6; and on day 1 for cycles 7 and 8.
All 41 evaluable patients in the study responded to treatment, and 95% of them achieved complete response or very good partial response One year PFS and OS rates were 98% (95% CI 93-100%) and 100%, respectively. Negative MRD was associated with longer PFS and OS. Age (< 60 vs. ≥ 60) was not significantly correlated with MRD negativity. OR was 0.48 (95% CI 0.08-2.3, P = 0.32), Cytogenetic risk status (high risk vs. standard risk) was neither correlated. OR was 1.7 (95% CI 0.36-8.6, P=0.50). Patients reached MRD negativity in a median of 6 cycles. Of the 8 patients who achieved MRD negativity and evaluated within 1 year, 7 maintained this level of remission. In this population of patients with newly diagnosed multiple myeloma, the observed MRD rates were approximately 20% higher than that previously reported with KRd.
Compared with the standard two-week KRd, the four-drug therapy did not produce additional ≥ grade 3 toxicity. Common grade 3/4 adverse events included neutropenia (27%), skin rash (9%), lung infection (7%) and elevated alanine aminotransferase levels (4%). There was no ≥ 3 grade peripheral neuropathy. Eighteen percentage of the patients in the cohort had serious treatment-related adverse events, the most common of which was pulmonary infection. One patient developed acute coronary syndrome during the study period and withdrew from the study. Grade 2 infusion-related reactions of daratumumab occurred in 40% of patients, all of which occurred during the initial infusion and did not lead to treatment interruption. Overall, there were 17 cases of lenalidomide dose reduction and 22 cases of dexamethasone reduction. Only two patients stopped treatment, one stopped treatment after suffering from lung cancer, and the other stopped clinical visits during the COVID-19 pandemic.
Some commented that although daratumumab plus KRd may be a realistic option for some patients, there is insufficient evidence to prove that the four-drug regimen is ready to be used as a pre-transplant induction therapy when the conditions for transplantation are already met.
参考文献 Reference Landgran O et al. JAMA Onc 2021; April 15. doi:10.1001/jamaoncol.2021.0611
卡博替尼可能是治疗转移性乳头状肾癌的新标准 (4/18/2021)
Carbozantinib may become the new standard for metastatic papillary kidney cancer
与舒尼替尼（sunitinib）和其他小分子MET激酶抑制剂相比, 卡博替尼（Carbozantinib）在转移性乳头状肾细胞癌中可显着延长无进展生存期。
这是一项多臂II期临床试验（SWOG 1500）, 有147例经病理学证实为乳头状肾细胞癌, 表现状态为0比1, 和可测量的转移性疾病的患者参加（中位年龄66岁； 76％为男性）。大多数患者（92％）未曾接受过治疗, 其他患者可能已经接受了最多一种先前的全身治疗（除VEGF或MET指导的治疗）。患者随机分配为在1) 每天接受50毫克舒尼替尼（n = 46），连续4周，休息2周; 2) 每天60 毫克卡博替尼（n = 44）; 3) 每日两次250 毫克crizotinib（n = 28）; 4) 每日 600毫克的savolitinib（n = 29）。 每个实验组与舒尼替尼的无进展生存期作为研究的主要终点。次要终点包括总生存期，客观响应率和不良事件。预先确定在无效性分析中, 无进展生存期 HR大于1的实验组（每个实验组发生15个无进展生存期事件，而sunitinib组发生20个事件）将会关闭。 根据这些标准, 研究人员提前停止了crizotinib和savolitinib组, 以免徒劳。 舒尼替尼和卡博替尼的按计划继续完成。
结果显示卡博替尼的中位无进展生存期与舒尼替尼相比显著延长（9个月相比5.6个月； HR = 0.6； 95％CI，0.37-0.97）。 研究人员还根据组织学亚型评估了结局。局部病理学检查确定18％的患者患有I型组织学, 54％的患者患有II型组织学, 28％的患者患有混合/其他组织学。 中心病理学检查的相应频率分别为30％，45％和25％。 不同组织学亚型对卡博替尼的益处是: I型（局部评估, HR = 0.26; 95％CI，0.07-1.01; 中央评估, HR = 0.56; 95％CI，0.22-1.45）; II型（局部评估，HR = 0.57； 95％CI，0.3-1.06；中心评估，HR = 0.62； 95％CI，0.31-1.24）。尽管在亚型分类中观察到不一致, 但卡博替尼似乎在各治疗组中益处趋势一致。
卡博替尼的客观响应率为23％（完全缓解，5％）, 显著高于舒尼替尼的4％（完全缓解，0％）（P = .01）。初步的总生存期结果显示, 卡博替尼为20个月, 相对于舒尼替尼组的16.4个月（95％CI 13-22），有改善的趋势, 但没有显著差异。
Compared with sunitinib and other small molecule MET kinase inhibitors, carbozantinib significantly prolonged progression-free survival in metastatic papillary renal cell carcinoma. This is a multi-arm Phase II clinical trial (SWOG 1500). There were 147 cases of papillary renal cell carcinoma confirmed pathologically, with a performance status of 0 to 1, and measurable metastatic diseases. (median age 66 years old; 76% were men). Most patients (92%) had not received treatment before, and others might have received at most one previous systemic therapy (except for drugs target at VEGF or MET). Patients were randomly assigned to 1) 50 mg of sunitinib everyday (n = 46) for 4 consecutive weeks with 2 weeks off; 2) 60 mg of cabozantinib everyday (n = 44); 3) 250 mg of crizotinib twice a day (n = 28); 4) 600 mg of savolitinib everyday (n = 29). Progression-free survival in each experimental arm and sunitinib was used as the primary endpoint of the study. Secondary endpoints included overall survival, objective response rate and adverse events. It was pre-determined that if in the invalidity analysis the experimental arm had a PFS HR greater than 1 (15 PGS events in experimental arm and 20 events in the sunitinib group), the arm would be closed. According to these criteria, the researchers stopped crizotinib and savolitinib arm ahead of schedule. Sunitinib and Cabozantinib continued to complete as planned.
The results showed that median PFS of cabozantinib was significantly longer than that of sunitinib (9 months vs. 5.6 months; HR = 0.6; 95% CI, 0.37-0.97). The researchers also assessed the outcome based on histological subtypes. Local pathological examination confirmed that 18% of patients had type I histology, 54% had type II histology, and 28% had mixed/other histology. The corresponding frequencies of the central pathological examination were 30%, 45%, and 25%, respectively. The benefits of different histological subtypes for cabozantinib were: Type I with local assessment, HR = 0.26; 95% CI, 0.07-1.01; central assessment, HR = 0.56; 95% CI, 0.22-1.45; Type II with local assessment, HR = 0.57; 95% CI, 0.3-1.06; central assessment, HR = 0.62; 95% CI, 0.31-1.24. Although inconsistencies had been observed in subtype analysis, cabozantinib appeared to have a consistent trend in benefit among treatment subtypes. The objective response rate of cabozantinib was 23% (complete remission, 5%), which was significantly higher than 4% in sunitinib arm (complete remission, 0%) (P = .01). Preliminary overall survival results showed that cabozantinib was 20 months, compared with 16.4 months in the sunitinib group (95% CI 13-22), there was a trend of improvement, but there was no significant difference.
参考文献 Reference Borhiellini D et al. Lancet 2021; 397:695
对胆管癌持久有效的另一种FGFR抑制剂:Futibatinib (4/17/2021)
Another FGFR inhibitor that generated durable response in cholangial carcinoma
约15％的肝内胆管癌具有成纤维细胞生长因子受体（FGFR）基因改变，特别是FGFR2的融合和重组。 Futibatinib是一种选择性的FGFR1-4不可逆抑制剂, 具有抗FGFR2激酶突变的活性。这是一项II期临床试验（FOENIX）, 参加者患有无法切除或转移性肝内胆管癌并伴有FGFR2融合或其他重组的患者。符合条件的患者在接受一种或多种先前方案，包括吉西他滨-铂类化学疗法的治疗且疾病进展后（不包括先前接受FGFR抑制剂治疗）。每天进行一次futibatinib治疗, 直至疾病进展, 或出现不可接受的毒性反应。主要终点是通过独立的放射学审查确定的总客观响应率。 患者的中位年龄为58岁, 女性占研究人群的56％。大多数患者（53％）曾接受过两种或两种以上的治疗方案。FGFR2融合畸变占78％，其余22％为重组。
中位随访期为17.1个月，分析显示43例患者有客观响应, 另有42例疾病稳定, 疾病控制率为82.5％。中位响应时间为2.5个月，其中72％的响应持续时间 ≥ 6个月，其中14％的持续时间 ≥ 12个月。该队列的中位无进展生存期为9.0个月，其中6个月无进展生存期为66％，12个月无进展生存期为40％。未成熟的存活数据显示中位总生存期为21.7个月，6个月总生存期为88％，12个月总生存期为72％。
最常见的任何等级的治疗相关的不良事件为高磷酸盐血症（91％），指甲毒性（47％），肝酶增加（27％）和手红斑感觉异常（21％）。最受关注的≥3级不良事件最常见的是高磷酸盐血症（31％）和肝酶增加（13％）。大多数严重的治疗相关的不良事件通过中断或减少剂量来控制。有2％的患者因治疗相关的不良事件停药, 但未发生致命的不良事件。
About 15% of intrahepatic cholangiocarcinomas have fibroblast growth factor receptor (FGFR) gene alterations, especially the fusion and rearrangement of FGFR2. Futibatinib is a selective FGFR1-4 irreversible inhibitor with activity against FGFR2 kinase mutations. This is a phase II clinical trial (FOENIX). Participants had unresectable or metastatic intrahepatic cholangiocarcinoma with FGFR2 fusion or other rearrangements. Eligible patients had received one or more previous regimens, including gemcitabine-platinum chemotherapy (excluding previous FGFR inhibitor treatment), and the disease progressed. Patients received futibatinib once a day until disease progresses or unacceptable toxicity. The primary endpoint was overall objective response rate determined by an independent radiological review. The median age of the patients was 58 years old, and women accounted for 56% of the study population. Most patients (53%) had received two or more treatment regimes. FGFR2 fusion aberration accounted for 78%, and the remaining 22% were rearrangements. The median follow-up period was 17.1 months.
The analysis showed that 43 patients had an objective response. Another 42 patients had stable disease, and the disease control rate was 82.5%. Median response time was 2.5 months. In total 72% had a response duration ≥ 6 months, and 14% had a response duration ≥ 12 months. Median progression-free survival of this cohort was 9.0 months, of which 6-month PFS was 66%, and the 12-month PFSwas 40%. Immature survival data showed that median overall survival was 21.7 months, 6-month OS was 88%, and 12-month OS was 72%.
The most common treatment-related adverse events of any grade were hyperphosphatemia (91%), nail toxicity (47%), increased liver enzymes (27%), and hand-foot erythema paresthesia (21%). The most common adverse events of grade ≥3 that received the most attention were hyperphosphatemia (31%) and increased liver enzymes (13%). Most serious treatment-related adverse events were controlled by interrupting or reducing dose. About 2% of patients discontinued the drug due to treatment-related adverse events, but no fatality related to treatment-elated adverse effects occurred during the trial.
参考文献 Reference Goyal L et al. AACR 2021; Abstract CT010.
LuPSMA优于卡巴他赛用于转移性去势抵抗性前列腺癌 (4/11/2021)
LuPSMA was superior to cabazitaxel in metastatic castration-resistant prostate cancer
前列腺特异性膜抗原（PSMA），是一种转移性前列腺癌细胞表达的细胞表面糖蛋白, 但在健康细胞上不表达。LuPSMA靶向表达PSMA的细胞, 传递高水平的β粒子辐射, 而向健康细胞传递极低剂量的辐射。卡巴他赛（Cabazitaxel）是抗雄激素（恩杂鲁胺和/或阿比特龙）和泰索帝治疗失败后对去势抵抗性前列腺癌的第三线治疗方法。
TheraP是一项开放性, II期临床试验, 有200名转移性去势抵抗性前列腺癌患者参加, 阳性镓Ga-68标记的PSMA PET/CT扫描用于选择要入组的患者。阴性扫描排除了患者。还进行了FDG PET/CT，排除了FDG阳性PSMA阴性的患者。在筛查的291例患者中，有91例被排除在外。中位年龄为72岁。91％的患者先前曾接受过阿比特龙, 恩杂鲁胺或两者同时治疗; 参加者都曾接受过泰索帝治疗。他们按1:1随机分配:1) 每6周静脉接受LuPSMA，共6个周期（起始剂量为8.5 GBq, 然后每个周期减少0.5 GBq）; 2) 卡巴他赛（20 毫克/平方米）每3周静脉滴注, 最多10个周期。 在研究期间, 共有15名患者退出了卡巴他赛组, 而LuPSMA组中没有患者退出。
TheraP达到了其主要终点, 接受LuPSMA的患者与卡巴他赛相比, PSA水平较基线水平降低50％或更高的比例分别为66％和37％（P <.0001）。客观响应率分别为49％相比于24％。 在5.1个月时，每组的中位放射学无进展生存率相似。但是, 在12个月时, 接受LuPSMA治疗的患者中有19％没有进展, 相对于卡巴他赛组的3％。此外, LuPSMA治疗导致治疗后疼痛评分的更大降低, 其中60％的患者报告改善，而卡巴他赛组为43％。总体生存数据尚未成熟。
LuPSMA组有33％的患者发生3或4级毒性，而卡巴他赛组则有53％。 两组中最常见的3级或4级事件分别是中性粒细胞减少症（4％相比于13％），血小板减少症（11％相比于0％），贫血（每组8％），腹泻（1 ％相比于 5％）和疲劳（5％相比于 4％）。
根据欧洲癌症研究与治疗组织（EORTC）核心生活质量问卷（QLQ-C30）的测量，LuPSMA显着改善了社会功能，疲劳，失眠和腹泻。与接受卡巴他赛治疗的患者相比，LuPSMA治疗组的皮疹，手掌/足底酸痛，消化不良，头晕，泌尿症状和腹泻的发生率显着降低。 在LuPSMA治疗的6个月和12个月中，无恶化生存率（定义为EORTC QLQ-C30问卷在整体健康状况，疾病进展或死亡方面至少下降10分的时间）得到了改善。两组在6个月时分别为29％对13％，在12个月时为21％对1％。
Prostate-specific membrane antigen (PSMA) is a cell surface glycoprotein expressed by metastatic prostate cancer cells, but not expressed on healthy normal cells. LuPSMA targets cells expressing PSMA and delivers high levels of β particle radiation, while very low doses of radiation to healthy cells. Cabazitaxel is a third-line treatment for castration-resistant prostate cancer after anti-androgen (enzalutamide and/or abiraterone) and taxotere treatment fail.
TheraP is an open label, phase II clinical trial involving 200 patients with metastatic castration-resistant prostate cancer. PSMA PET/CT scan with gallium and Ga-68 was used to select patients for enrollment. Negative scans excluded patients. FDG PET/CT was also performed, and patients with FDG-positive and PSMA-negative were excluded. Of the 291 patients screened, 91 were excluded. The median age was 72 years. Ninety-one percentage of patients had previously received abiraterone, enzalutamide or both; all participants had received taxotere. They were randomly assigned (1:1): 1) LuPSMA was given intravenously every 6 weeks for 6 cycles (starting dose was 8.5 GBq, and then reduced by 0.5 GBq each cycle); 2) Cabazitaxel (20 mg/m²) Intravenously every 3 weeks, up to 10 cycles. During the study period, a total of 15 patients dropped out of the cabazitaxel group, while no patients in the LuPSMA group dropped out.
TheraP reached its primary endpoint. Patients who received LuPSMA had a 50% or higher PSA level reduction from baseline levels in 66%, compared with 37% in cabazitaxel group (P <.0001). The objective response rates were 49% compared to 24%. At 5.1 months, the median radiological progression-free survival rate was similar in each group. However, at 12 months, 19% of patients treated with LuPSMA did not progress, compared to 3% in the cabazitaxel group. In addition, LuPSMA treatment resulted in a greater reduction in pain scores after treatment, with 60% of patients reporting improvement compared to 43% in the cabazitaxel group. The overall survival data was not yet mature.
Grade 3 or 4 toxicity occurred in 33% of patients in the LuPSMA group, vs. 53% in the cabazitaxel group. The most common grade 3 or 4 events in the two groups were neutropenia (4% vs. 13%), thrombocytopenia (11% vs. 0%), and anemia (8% in each group), diarrhea (1% compared to 5%) and fatigue (5% compared to 4%). As measured by the European Organization for Research and Treatment of Cancer (EORTC) core quality of life questionnaire (QLQ-C30), LuPSMA significantly improved the domains of social functioning, fatigue, insomnia and diarrhea. Compared with patients treated with cabazitaxel, the incidence of skin rash, palm/plantar soreness, indigestion, dizziness, urinary symptoms and diarrhea was significantly reduced in the LuPSMA group. During the 6 and 12 months of LuPSMA treatment, the deterioration-free survival rate (defined as the time for the EORTC QLQ-C30 questionnaire to decrease at least 10 points in terms of overall health, disease progression, or death) improved at 6 months and 12 months. The two groups were 29% vs. 13% at 6 months, and 21% vs. 1% at 12 months.
参考文献 Reference Hofman MS et al. Lancet 2021; 397:797
Tipifarnib用于HRAS突变型晚期头颈癌 (4/10/2021)
Tipifarnib used in advanced HRAS-mutant head and neck cancer
复发性或转移性头颈部鳞状细胞癌患者中, HRAS原癌基因发生突变的比例为4％至8％。Tipifarnib是一种farnesyltransferase抑制剂, 可破坏HRAS功能, Tipifarnib在具有HRAS突变和高等位基因频率（high variant allele frequency）的该患者群中产生了高响应率。
在一项II期临床试验中, 从2015年9月至2020年4月，由来自美国，韩国和欧洲的30名HRAS突变疾病患者参加。患者在第1至7天和第15至21天（每21天为一个周期）每天两次口服Tipifarnib 600或900 毫克。主要终点是高等位基因频率患者中客观响应率, 数据截止于2020年4月。
在22位等位基因变异频率较高的患者中，有20位在数据截止时可评估其响应。在11例患者中观察到客观响应（都为部分响应）（55％，95％置信区间[CI] = 31.5％–76.9％）。等位基因频率≥35％的12例患者中有7例（58.3％）观察到响应，等位基因频率<30％的8例中有4例（50.0％）观察到响应。 在第8周进行首次肿瘤评估时, 11位患者中有8位获得了响应。 在每天两次600 毫克的6名患者中，有5名观察到了响应; 其余9例患者，疾病稳定。在9名病情稳定的患者中，有3名患者接受了大约7个月的治疗。 在11例有部分响应的患者中, 有7例接受了≥ 6个月的治疗。 中位无进展生存期为5.6个月（95％CI = 3.6-16.4个月），相对于上次既往治疗的3.6个月（95％CI = 1.3-5.2个月）。有响应患者的中位无进展生存期为9.5个月（95％CI = 5.5个月-无法估计）, 病情稳定患者的为4.0个月（95％CI = 1.9个月-无法估计）。 中位总生存期为15.4个月（95％CI = 7.0-29.7个月）。
在接受Tipifarnib治疗的所有30位患者中，最常见的不良事件是血液学和胃肠道疾病。最常见的 ≥3级不良事件为贫血（37％）；淋巴细胞减少症（13％）和中性粒细胞减少症, 高钙血症，低血钾，低磷酸盐血症，肺炎和恶心（各占10％）。 不良事件导致三名患者由于喉管阻塞和一名呼吸衰竭而终止治疗。但认为与治疗无关。截止数据截止, 尚无高等位基因频率变异的患者因不良事件而中断治疗。没有观察到与Tipifarnib相关的死亡。
In patients with recurrent or metastatic head and neck squamous cell carcinoma, the proportion of HRAS proto-oncogene mutation is 4% to 8%. Tipifarnib is a farnesyltransferase inhibitor that can disrupt HRAS function. Tipifarnib produced a high response rate in this patient group with HRAS mutations and high variant allele frequency.
In a phase II clinical trial, from September 2015 to April 2020, 30 patients from the United States, South Korea and Europe participated. Patients took Tipifarnib was administered at 600 or 900 mg orally twice a day on days 1 to 7 and 15 to 21 (every 21 days as a cycle). The primary endpoint was objective response rate in patients with high variant allele frequencies, and the data cut-off was in April 2020.
Of the 22 patients with high variant allele frequency, 20 had their response assessed at the time of data cutoff. Objective responses (all partial responses) were observed in 11 patients (55%, 95% confidence interval [CI] = 31.5%-76.9%). Response was observed in 7 out of 12 patients with an allele frequency ≥35% (58.3%), and a response was observed in 4 out of 8 patients (50.0%) with an allele frequency <30%. At the first tumor assessment at week 8, 8 out of 11 patients exhibited a response. Of the 6 patients who received 600 mg twice daily, a response was observed in 5 patients; the remaining 9 patients had stable disease. Among the 9 stable patients, 3 patients received treatment for approximately 7 months. Of the 11 patients with partial responses, 7 received treatment for ≥ 6 months. The median progression-free survival was 5.6 months (95% CI = 3.6-16.4 months), compared to 3.6 months (95% CI = 1.3-5.2 months) on last prior therapy. Median progression-free survival for responding patients was 9.5 months (95% CI = 5.5 months-not estimable), and for stable patients was 4.0 months (95% CI = 1.9 months- not estimable). Median overall survival was 15.4 months (95% CI = 7.0-29.7 months).
Among all 30 patients treated with Tipifarnib, the most common adverse events were hematologic and gastrointestinal. The most common grade ≥3 adverse events were anemia (37%); lymphopenia (13%) and neutropenia, hypercalcemia, hypokalemia, hypophosphatemia, pneumonia, and nausea ( 10% each). Adverse events caused three patients to discontinue treatment due to laryngeal obstruction and one respiratory failure, none was considered related to treatment. As of data cutoff, no patients with high variant allele frequency discontinued treatment due to adverse events. No deaths related to Tipifarnib were observed.
参考文献 Reference Lo A et al. J Clin Onc 2021; DOI: 10.1200/JCO.20.02903
Tesetaxel在转移性乳腺癌中实现了主要终点:提高了无进展生存期 (4/4/2021)
Tesetaxel reached primary ob in metastatic breast cancer: improved PFS
CONTESSA是一项随机，3期研究, 正在北美，欧洲和亚洲18个国家/地区的180个研究地点进行。有685位激素受体阳性，HER2-阴性转移性乳腺癌的患者参加, 患者必须接受过内分泌治疗（有或没有细胞周期蛋白依赖性激酶抑制剂）。她们分成两组（1:1）, 一组在每个21天周期的第一天口服Tesetaxel（27毫克/平方米）. 加上降低剂量的卡培他滨（每21天周期的14天口服1,650 毫克/平方米/天）; 另一组为单独使用标准剂量卡培他滨（2,500毫克/平方米/天，每21天周期的14天口服）。主要终点是独立放射学评审委员会评估的无进展生存期。次要疗效终点是总体生存率，客观响应率和疾病控制率。
CONTESSA达到了改善无进展生存期的主要终点。联合用药组的中位无进展生存期为9.8个月，而单用卡培他滨组的为6.9个月。疾病发展或死亡的风险降低了28.4％[危险比= 0.716（95％置信区间：0.573-0.895，p = 0.003）]。联合用药组的的客观响应率57％，而单药组的为41％（p = 0.0002）。 疾病控制率为67％相比于50％（p <0.0001）。协议规定的总体生存率最终分析预计将在2022年进行。
联合用药组的不良反应与以前的临床研究结果一致。 ≥5％的患者发生≥3级治疗紧急不良事件为：中性粒细胞减少（联合用药组为70.9％，而单药组为8.3％）；腹泻（13.1％相比于8.9％）；手足综合征（6.8％相比于12.2％）；发热性中性粒细胞减少症（13.1％相比于1.2％）；贫血（8.0％相比于2.4％）。 导致≥1％的患者中止治疗的不良事件为：中性粒细胞减少或发热性中性粒细胞减少（4.2％相比于1.5％）；神经病变（3.6％相比于0.3％）；败血症或败血性休克（1.8％相比于0.6％）；腹泻（0.9％相比于1.5％）；和手足综合症（0.6％相比于2.1％）。联合用药组的患者中有23.1％的患者因任何不良事件而终止治疗，而单药组的患者为11.9％。联合用药组的患者中有76％的替塞他赛剂量减少，主要是由于中性粒细胞减少症。单药组的患者中有61％的患者出现剂量减少，这主要是由于手足综合征。联合用药组的患者中有8.0％发生2级脱发，单药组的患者中有0.3％发生了2级脱发。
在CONTESSA中观察到Tesetaxel的优处, 包括无进展生存期的改善，每三周一次口服给药,以及脱发和神经病变的低发生率。目前尚不清楚该药物是否会进一步发展。
CONTESSA is a randomized, phase 3 study, being conducted at 180 research sites in 18 countries/regions in North America, Europe and Asia. There are 685 hormone receptor-positive, HER2-negative metastatic breast cancer patients. The patients must have received endocrine therapy (with or without cyclin-dependent kinase inhibitors). They were divided into two groups (1:1). One group took Tesetaxel (27 mg/m²) orally on the first day of each 21-day cycle, plus a reduced dose of capecitabine (orally administered on 14 days of every 21-day cycle, at 1,650 mg/m2/day); the other group received saproved dose of capecitabine alone (2,500 mg/m2/day, orally for 14 days of every 21-day cycle). The primary endpoint was progression-free survival as assessed by the independent radiology review committee. The secondary endpoints were overall survival, objective response rate and disease control rate.
CONTESSA reached the primary endpoint of improved progression-free survival (PFS). The median PFS in the combination group was 9.8 months, while that of the capecitabine alone group was 6.9 months. The risk of disease development or death was reduced by 28.4% [hazard ratio = 0.716 (95% confidence interval: 0.573-0.895, p = 0.003)]. The objective response rate of the combination group was 57%, while that of the single-drug group was 41% (p = 0.0002). Disease control rate was 67% compared to 50% (p <0.0001). A final analysis of overall survival rate stipulated in the agreement is expected to be performed in 2022.
Adverse reactions of the combination group were consistent with the results of previous clinical studies. Equal to or greater than 5% of patients with ≥ grade 3 adverse events were: neutropenia (70.9% in the combination group and 8.3% in the monotherapy group); diarrhea (13.1% compared to 8.9%); hand-foot synthesis Signs (6.8% vs. 12.2%); febrile neutropenia (13.1% vs. 1.2%); anemia (8.0% vs. 2.4%). Adverse events leading to discontinuation of treatment in ≥1% of patients were: neutropenia or febrile neutropenia (4.2% vs. 1.5%); neuropathy (3.6% vs. 0.3%); sepsis or Septic shock (1.8% vs. 0.6%); diarrhea (0.9% vs. 1.5%); and hand-foot syndrome (0.6% vs. 2.1%). In the combination group, 23.1% of patients discontinued treatment due to any adverse events, compared with 11.9% in the single-drug group. In the combination group 76% of patients had one dose reduction of tecetaxel, mainly due to neutropenia, compare with 61% of patients in the single-drug group experienced dose reduction, which was mainly due to hand-foot syndrome. Grade 2 alopecia occurred in 8.0% of patients in combination group vs. 0.3% in the single-drug group.
The advantages of Tesetaxel observed in CONTESSA included improvement in PFS, oral administration once every three weeks, and low incidence of hair loss and neuropathy. It is not clear though at present whether the drug will undergo further development.
参考文献 Reference O’Shaughnessy J et al. 2020 San Antonio Breast Cancer Symposium. Abstract GS4-01
WEE1抑制剂用于复发性子宫浆液性癌 (4/3/2021)
WEE1 inhibitor in recurrent uterine serous carcinoma
WEE1激酶是G2 / M和S期细胞周期检查点的关键调节剂。由于细胞周期调节受损和高复制压力的细胞可能易受WEE1抑制作用, Adavosertib是WEE1激酶的强效和选择性口服抑制剂。 在这项单中心 II期临床试验中，34名妇女在第21天（为一周期）的第1至5天和第8至12天每天接受一次口服300毫克 Adavosertib，直到疾病进展或出现不可接受的毒性。试验主要终点是6个月时的客观响应率和无进展生存期。预先确定的是，当客观响应率≥20％和6个月无进展生存率≥30％, 将对该药物进行进一步研究。 初次分析时的中位随访时间为5.9个月（95％置信区间[CI] = 4.0-7.2个月）。
在34例患者中，有10例观察到客观响应（29.4％，95％CI = 15.1％–47.5％），包括1例完全响应。中位响应时间为9.0个月（95％CI = 5.3个月–未达到）。另有7例患者病情稳定≥6个月，临床受益率为50％。 共有16例患者在6个月时无进展，其6个月无进展生存率为47.1％（95％CI = 29.8％–64.9％）。中位无进展生存期为6.1个月（95％CI = 4.21-9.92个月）。 在探索性生物标志物分析中，使用下一代测序对32例患者的标本进行分子表征未发现客观响应或临床获益与特定分子改变之间存在显著关联。
与该治疗有关的血液学不良事件很常见，包括贫血的患者占67.6％（≥3级，占23.5％），血小板减少的占61.8％（≥3级，占17.6％），中性粒细胞减少的占44.1％（≥3级, 占32.4％）。最常见的≥3级非血液学不良事件是疲劳（23.5％）。 总体而言，有26名患者（76.5％）需要至少暂停一次剂量，11名（32.4％）需要减少一种剂量，9名（26.5％）需要减少两次剂量，还有2名（5.9％）由于不良事件而中止治疗。
Adavosertib单一疗法显示了对子宫浆液性癌的有希望的活性，和进一步研究的前景。
WEE1 kinase is a key regulator of cell cycle checkpoint in G2/M and S phases. Because cells with impaired cell cycle regulation and high replication pressure may be susceptible to WEE1 inhibition, Adavosertib was designed as a potent and selective oral inhibitor of WEE1 kinase. In this single-institution phase II clinical trial, 34 women received 300 mg of Adavosertib orally once a day on days 1 to 5 and 8 to 12 in a 21-day cycle until disease progression or unacceptable toxicity. The primary endpoint of the trial was objective response rate and progression-free survival at 6 months. It is predetermined that when the objective response rate was ≥20% and 6-month progression-free survival rate was ≥30%, the drug will be further studied. The median follow-up time at the initial analysis was 5.9 months (95% confidence interval [CI] = 4.0-7.2 months).
Among the 34 patients, objective response was observed in 10 cases (29.4%, 95% CI = 15.1%-47.5%), including 1 complete response. The median response time was 9.0 months (95% CI = 5.3 months-not reached). Another 7 patients were in stable condition for more than 6 months, and the clinical benefit rate was 50%. A total of 16 patients were progression-free at 6 months, and their 6-month progression-free survival rate was 47.1% (95% CI = 29.8%-64.9%). The median progression-free survival was 6.1 months (95% CI = 4.21-9.92 months). In the exploratory biomarker analysis, molecular characterization of 32 patients’ specimens using next-generation sequencing did not find objective response or clinical benefit had a significant correlation with specific molecular changes.
Hematological adverse events related to this treatment were common, including 67.6% of patients with anemia (23.5 ≥ Grade 3), thrombocytopenia in 61.8% (17.6% ≥ Grade 3), and neutropenia accounted for 44.1% (32.4% ≥ grade 3). The most common non-hematological adverse event of grade ≥3 was fatigue (23.5%). In total, 26 patients (76.5%) required at least one dose hold, 11 (32.4%) required one dose reduction, 9 (26.5%) required two dose reductions, and 2 (5.9%) discontinued treatment due to adverse events.
Adavosertib monotherapy has shown promising activity against uterine serous carcinoma, and deserves further research.
参考文献 Reference Liu JF et al. J Clin Onc 2021 March 11. DOI: 10.1200/jco.20.03167
FDA加速批准Yescarta用于复发或难治性滤泡性淋巴瘤的三线治疗 (3/28/2021)
FDA has granted accelerated approval to Yescarta as third-line therapy for relapsed or refractory follicular lymphoma
2021年3月FDA批准了Axicabtagene ciloleucel（Yescarta, 一种CD19定向嵌合抗原受体[CART]细胞疗法），用于经过两次或两次以上全身性治疗的复发性或难治性滤泡性淋巴瘤。 这项批准是基于一项单臂，开放标签，多中心试验（ZUMA-5; NCT03105336），该试验包括了病人接受过抗CD20单克隆抗体和烷化剂的组合。在淋巴细胞清扫化疗后，Yescarta以单次静脉内输注的方式给药。由独立评审委员会确定的主要疗效指标是客观缓解率和缓解持续时间。
在主要疗效分析的81例患者中，客观缓解率为91％（95％CI：83-96），完全缓解率为60％，中位反应时间为1个月。未达到中位缓解持续时间，并且1年持续缓解率是76.2％（95％CI：63.9-84.7）。对于该试验中的所有白细胞清除患者（n = 123），客观缓解率为89％（95％CI：83-94），完全缓解率为62％。
Yescarta的处方信息对细胞因子释放综合征和神经系统毒性有黑框（black box）警告。在所有接受过Yescarta的非霍奇金淋巴瘤患者中，细胞因子释放综合征发生率为88％（10%≥3级），神经毒性为81％（26%≥3级）。 最常见的非实验室不良反应（发生率≥20％）为细胞因子释放综合征，发烧，低血压，脑病，心动过速，疲劳，头痛，发热性中性粒细胞减少，恶心，病原体感染，食欲下降，发冷，腹泻，震颤，肌肉骨骼疼痛，咳嗽，缺氧，便秘，呕吐，心律不齐和头昏眼花。
FDA根据缓解率加速批准Yescarta。继续批准可能要取决于临床益处的验证。
In March 2021, FDA granted accelerated approval for Axicabtagene ciloleucel (Yescarta, a CD19-directed chimeric antigen receptor [CART] cell therapy) in relapsed or refractory follicular lymphoma after two or more lines of systemic treatments. This approval is based on a single-arm, open-label, multicenter trial (ZUMA-5; NCT03105336), which included patients who had received a combination of anti-CD20 monoclonal antibodies and alkylating agents. Following lymphodepleting chemotherapy, Yescarta was administered as a single intravenous infusion. The main efficacy measures were objective remission rate and duration of response as determined by the independent review committee.
Among the 81 patients in the main efficacy analysis, the objective response rate was 91% (95% CI: 83-96), with a complete response rate of 60%, and the median time to response of 1 month. The median duration of remission was not reached, and the 1-year sustained remission rate was 76.2% (95% CI: 63.9-84.7). For all leukapheresed patients in this trial (n = 123), the objective response rate was 89% (95% CI: 83-94), and the complete response rate was 62%.
Yescarta’s prescription information has a boxed warning about cytokine release syndrome and neurotoxicity. Among all non-Hodgkin’s lymphoma patients who received Yescarta, the incidence of cytokine release syndrome was 88% (grade≥ grade 3, 10%), and neurotoxicity was 81% (≥ grade 3, 26%). The most common non-laboratory adverse reactions (incidence ≥20%) are cytokine release syndrome, fever, hypotension, encephalopathy, tachycardia, fatigue, headache, febrile neutropenia, nausea, pathogen infection, Loss of appetite, chills, diarrhea, tremors, musculoskeletal pain, cough, hypoxia, constipation, vomiting, irregular heartbeat and dizziness. FDA granted accelerated approval based on the remission rate. Continued approval of this indication may be contingent upon the verification of clinical benefits in confirmatory trial.
参考文献 Reference https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-axicabtagene-ciloleucel-relapsed-or-refractory-follicular-lymphoma
III期临床研究显示atezolizumab延长早期非小细胞肺癌患者的寿命 (3/27/2021)
A pivotal phase III study showed atezolizumab prolonged disease-free survival in early-stage non-small cell lung cancer
IMpower010是一项III期，全球，开放标签，随机研究，评估了IB-IIIA期非小细胞肺癌患者，在手术切除后和经过4个周期的基于顺铂的辅助化疗后，atezolizumab与最佳支持治疗相比的疗效和安全性。这项研究以1:1的比例对1,005非小细胞肺癌患者进行了随机分组，分别接受最多16个周期的atezolizumab或最佳支持治疗。主要终点是由研究者确定的PD-L1阳性/II-IIIA期患者的无疾病生存期，以及所有II-IIIA期者, 和意向治疗的IB-IIIA期人群的无疾病生存期。次要终点包括所有参加人群的总生存期，和意向治疗的IB-IIIA期参加人群的生存期。
中期分析显示, 该试验达到了其无疾病生存期的主要终点; 无疾病生存期的获益程度在PD-L1阳性人群中尤为明显。Atezolizumab的安全性与其已知的安全性一致，未发现新的安全信号。
IMpower010研究的结果将在即将举行的医学会议上发表。
IMpower010 is a phase III, global, open-label, randomized study that evaluated efficacy and safety of atezolizumab in patients with stage IB-IIIA non-small cell lung cancer after surgical resection and after 4 cycles of cisplatin-based adjuvant chemotherapy, compared to best supportive care. This study randomly assigned 1,005 non-small cell lung cancer patients at a 1:1 ratio to receive up to 16 cycles of atezolizumab or best supportive care. The primary endpoint was disease-free survival in PD-L1 positive/stage II-IIIA patients as determined by the investigator, as well as disease-free survival of all stage II-IIIA patients, and the intent-to-treat stage IB-IIIA population. Secondary endpoints included overall survival of all participants, and overall survival of stage IB-IIIA intention-to-treat participants.
The interim analysis showed that the trial reached its primary endpoint of disease-free survival; the benefit of disease-free survival was particularly obvious among PD-L1 positive populations. The safety of atezolizumab was consistent with its known safety, and no new safety signals have been found. The results of the IMpower010 study will be presented at an upcoming medical conference.
参考文献 Reference https://www.roche.com/media/releases/med-cor-2021-03-22.htm
夜班工作会使DNA修复基因的昼夜节律失调: 导致患癌症风险增加的机制? (3/21/2021)
Circadian dysregulation of DNA repair genes among night-shift workers: a mechanism of increase cancer risk?
流行病学研究表明，夜班工人中癌症更多，世界卫生组织国际癌症研究机构也将夜班工作归为可能的致癌因素。
这是一个对照实验室试验, 进行了模拟的轮班工作实验，有14名志愿者在睡眠实验室里呆了7天。他们中的一半完成了为期3天的模拟夜班时间表，而另一半则按照了3天的模拟昼班时间表。在完成模拟班次后，所有参与者都将按照恒定的常规规程进行操作，该规程用于研究人类内部产生的生物学节律，而不受任何外部影响。 作为实验方案的一部分，他们在恒定的光照和室温下以半躺着的姿势保持清醒24小时，并每小时给予相同的零食。每3小时抽一次血样。
对血液样本中的白细胞进行的分析表明，与昼班条件相比，夜班条件下许多与癌症相关的基因的节律有所不同。值得注意的是，与DNA修复相关的基因在昼班条件下表现出明显的节律，而在夜班条件下失去了节奏。 然后，研究人员研究了癌症相关基因表达变化可能带来的后果。他们发现，从夜班参与者的血液中分离出的白细胞比日班参与者的DNA损伤证据更多。更重要的是，在研究人员在一天中的两个不同的时间将分离的白细胞暴露于电离辐射之后，在夜间工作的情况下，与白天工作的情况相比，晚上辐射的细胞显示出更大的DNA损伤。
这些发现表明，夜班时间表推迟了癌症相关基因的表达时间，从而降低了人体最需要的DNA修复过程的有效性。研究人员的下一步是对长期从事白天或夜班的现实轮班工人进行相同的实验，以确定夜班工人中未修复的DNA损伤是否会随着时间的推移而积累，这最终会增加患癌症的风险。
Epidemiological studies have shown that there are more cancers among night-shift workers. The International Agency for Research on Cancer of WHO has also classified night shift work as probable carcinogenic. This is a controlled laboratory experiment. A simulated shift-work experiment was conducted. Fourteen volunteers spent 7 days in the sleep laboratory. Half of them completed the 3-day simulated night-shift schedule, while the other half followed the 3-day simulated day-shift schedule. After completing the simulation shift, all participants were kept on a constant routine protocol that is used to study the internally regulated biological rhythms independent of any external influences. As part of the experimental protocol, they were kept awake for 24 hours in a semi-reclined position under constant light exposure and room temperature, and were given the same snacks every hour. Blood samples are drawn every 3 hours.
Analyses of white blood cells in blood samples showed that the rhythm of many cancer-related genes was different under night-shift conditions compared to day-shift conditions. It is worth noting that the genes related to DNA repair showed obvious rhythms in the day-shift condition, but lost the rhythm in the night-shift condition. Then, the researchers studied the possible consequences of changes in cancer-related gene expression. They found that white blood cells isolated from the blood of nigh- shift participants had more evidence of DNA damage than day-shift participants. More importantly, after the researchers exposed the isolated white blood cells to ionizing radiation at two different times of the day, the cells irradiated at night showed increased DNA damage in the night-shift condition as compared to the day-time condition.
These findings indicate that night-shift schedule disrupts the timing of the expression of cancer-related genes, thereby reducing the effectiveness of the DNA repair process when the body needs most. The next step for the researchers is to perform the same experiment on real-world shift workers who have been engaged in day or night shifts for a long time to determine whether unrepaired DNA damage in night-shift workers will accumulate over time, which ultimately would increase cancer risk.
参考文献 Reference Koritala BSC et al. J Pineal Res 2021; https://doi.org/10.1111/jpi.12726
口服紫杉醇/ensequidar组合可提高转移性乳腺癌的生存率 (3/20/2021)
Oral paclitaxel/ensequidar improved overall survival in metastatic breast cancer
根据随机III期KX-ORAX-001试验的最新发现，与静脉注射紫杉醇相比，口服紫杉醇和encequidar联合使用可使转移性乳腺癌的死亡风险降低26.5％。
在该试验中, 转移性乳腺癌病人按2:1的比例随机接受口服紫杉醇205 毫克/平方米加上15毫克的encequidar每周3次（n=265）, 或每3周静脉注射紫杉醇175 毫克/平方米（n=137），直到疾病进展或出现不可接受的毒性。 主要的终点为肿瘤响应；次要终点包括响应时间，无进展生存期和总生存期。 两个组之间的基线特征相似。
在意向性治疗人群中，口服紫杉醇/encequida的确诊肿瘤响应率为35.8％，而静脉使用紫杉醇的确诊肿瘤响应率为23.4％（P = 0.011）。联合使用紫杉醇的中位总生存期为23.3个月，对于静脉输注紫杉醇的16.3个月（HR，0.735； 95％CI，0.556-0.972； P = .0262 ）。 此外，联合使用紫杉醇的中位无进展生存期为8.4个月，相对于静脉输注紫杉醇的7.4个月，导致疾病进展或死亡的风险降低了26％（HR，0.739 ； 95％CI，0.561-0.974； P = .0223 ）。
与静脉注射制剂相比，联合使用紫杉醇显示出较低的神经病和脱发发生率。然而，感染，低度胃肠道不良事件和4级中性粒细胞减少症的发生率更高。 由于受到胃肠道p-糖蛋白排泄的影响，紫杉醇的口服生物利用度较差。 Encequidar是一种有效的，特异性的, 吸收很少的 p-糖蛋白抑制剂，可帮助吸收口服紫杉醇。这两种药物的组合是紫杉醇的液体填充胶囊和encequidar片剂，并不含Cremophor。
According to the latest findings of the randomized phase III KX-ORAX-001 trial, the combination of oral paclitaxel and encequidar reduced the risk of death from metastatic breast cancer by 26.5% compared with intravenous paclitaxel. In this trial, patients with metastatic breast cancer were randomized at a 2:1 ratio to receive oral paclitaxel 205 mg/m2 plus 15 mg encequidar 3 times a week (n=265), or intravenous paclitaxel 175 mg/M² every 3 weeks (n=137) until disease progresses or unacceptable toxicity. The primary endpoint was tumor response; secondary endpoints included response duration, progression-free survival and overall survival. The baseline characteristics between the two groups were similar.
In the intention-to-treat population, response rate of oral paclitaxel/encequidar was 35.8%, while that of intravenous paclitaxel was 23.4% (P = 0.011). The median overall survival for combination regime was 23.3 months, compared to 16.3 months for intravenous paclitaxel (HR, 0.735; 95% CI, 0.556-0.972; P = .0262). In addition, median progression-free survival of the paclitaxel combination was 8.4 months, compared with 7.4 months of intravenous paclitaxel. The risk of disease progression or death was reduced by 26% (HR, 0.739; 95% CI, 0.561- 0.974; P = .0223).
Compared with intravenous paclitaxel, combination regime showed a lower incidence of neuropathy and hair loss. However, the incidence of infections, low-grade gastrointestinal adverse events and grade 4 neutropenia was higher. Due to the presence of p-glycoprotein in the gastrointestinal tract, oral bioavailability of paclitaxel was poor. Encequidar is an effective, specific, and low-absorption p-glycoprotein inhibitor that helped absorption of oral paclitaxel. The combination of these two drugs is a liquid-filled capsule of paclitaxel and an encequidar tablet, that does not contain cremophor.
参考文献 Reference Umanzor G et al. 2020 San Antonio Breast Cancer Symposium; 2020; virtual. Abstr PD1-08.
SY-1425加阿扎胞苷将用于RARA-阳性的骨髓增生异常综合征 临床试验 (3/14/2021)
SY-1425 plus Azacitidine will be used in RARA-positive MDS clinical trial
最近的数据表明，在某些AML亚组中使用SY-1425加上阿扎胞苷具有令人鼓舞的反应率。RARA阳性急性髓细胞性白血病亚组是一种新型的患者亚群，大约30％的急性髓细胞性白血病患者RARA呈阳性。SY-1425是一种选择性视黄酸受体α（RARα）激动剂，
这是一项II期临床试验, 有51位RARA阳性和RARA阴性的新诊断的急性髓细胞性白血病患者参加（他们都不适合诱导化疗）。 其中有18位RARA阳性可评估临床反应。数据显示： 总响应率为67％（12/18），复合缓解率为61％（11/18），其中9例患者（50％）达到完全缓解，2例患者（11％）的完全缓解其血细胞计数不完全恢复。 89％（8/9）的完全缓解取得深分子或细胞遗传学缓解。 在所有急性髓细胞性白血病风险人群中都观察到了反应，包括具有不良预后突变的患者。 初步反应的中位时间为1.2个月。 中位反应持续时间为10.8个月，达到完全缓解的中位总生存期为18个月。 在基线时依赖输血的患者中有86％（6/7）不需要输血，而有67％（12/18）的患者达到或维持了输血独立性。 SY-1425与阿扎胞苷合用通常耐受良好，没有证据表明毒性相对于其中一种单药增加，包括与单药阿扎胞苷相关的骨髓抑制。
基于SY-1425与阿扎胞苷联用的临床活性和良好的安全性和耐受性，药品公司计划将SY-1425与阿扎胞苷联用发展到针对RARA阳性的新诊断的高危骨髓增生异常综合征（HR-MDS）患者的3期临床试验。 约30％的HR-MDS患者为RARA阳性。 计划在双盲安慰剂对照试验中招募约190名RARA阳性的新诊断HR-MDS患者，以2:1的比例随机接受SY-1425或安慰剂与阿扎胞苷合用。试验的主要终点完全缓解率，根据完全缓解率可望支持该患者人群的加速批准。 将于2021年第一季度启动3期试验。
Recent data has showen that SY-1425 plus Azacitidine used in certain AML subset was shown to have encouraging response rate. RARA-positive acute myeloid leukemia subgroup is a new type of patient subgroup. About 30% of patients with AML are RARA positive. SY-1425 is a selective retinoic acid receptor alpha (RARα) agonist, There was a phase II clinical trial involving 51 newly diagnosed treatment-naïve AML patients who were unfit for intensive induction chemotherapy and were RARA positive or negative. Among them, 18 RARA positive patients were evaluable for clinical response. The data showed overall response rate was 67% (12/18), and the composite complete remission rate was 61% (11/18). Among them, 9 patients (50%) achieved complete remission, and 2 patients (11%) achieved complete remission with incomplete blood count recovery (CRi). Eighty-nine percentage (8/9) of complete remission were deep molecular or cytogenetic remission. Responses were observed across all AML risk groups, including patients with mutations typically associated with poor outcomes. Median time to initial response was 1.2 months. Median duration of response was 10.8 months, and median overall survival among those who achieved complete remission or CRi was 18 months. Eighty-six percentage (6/7) of patients who were transfusion-dependent at became transfusion-independent, and 67% (12/18) of patients achieved or maintained transfusion independence.
The combination of SY-1425 and azacitidine was generally well tolerated, and there was no evidence that the toxicity was increased relative to either agents, including myelosuppression rates that were comparable to single agent azacitidine.
Based on the clinical activity and good safety and tolerability of SY-1425 in combination with azacitidine, the drug company plans to develop the combination of SY-1425 and azacitidine in RARA-positive, newly-diagnosed, high-risk myelodysplastic syndrome (HR-MDS) patients in a phase 3 clinical trial. About 30% of HR-MDS patients are RARA positive. It is planned to recruit about 190 newly diagnosed HR-MDS patients with positive RARA in a double-blind placebo-controlled trial, and randomly receive SY-1425 vs. placebo plus azacitidine in a 2:1 ratio. The primary endpoint of the trial is complete response rate, which is expected to support accelerated approval for this patient population. Phase 3 trials will be launched in the first quarter of 2021.
参考文献 Reference De Botton et al. ASH Ann Meeting and Exposition (Virtual) 2020; abstr 112
卡培他滨和奥沙利铂结合腹膜内紫杉醇有益于腹膜转移的胃癌患者 (3/13/2021)
Systemic oxaliplatin and capecitabine plus intraperitoneal paclitaxel may benefit gastric cancer patients with peritoneal metastases
腹膜转移是胃癌患者的常见问题，仅靠全身化疗不能有效地治疗这一问题，在新加坡进行的一项临床试验旨在评估全身化疗结合腹膜内紫杉烷是否可能有益于同步腹膜转移的胃癌患者。
这是一项II期临床试验, 有44例胃癌腹膜转移患者参加，中位年龄61±9岁, 90％为华人； 56.8％为女性。患者在第1天接受静脉注射奥沙利铂100毫克/平方米; 第1天至第14天，口服卡培他滨（剂量为1,000毫克/平方米）; 第1天和第8天接受40毫克/平方米 紫杉醇腹膜内治疗。每21天为一个周期, 最多8个周期。 如果腹膜转移患者（n = 36）对化疗反应良好，连续两次腹膜液细胞学检查阴性，手术期间无腹膜外转移且无腹膜转移，则可以进行根治性胃切除术。符合这些标准的13名患者接受了手术。 研究人员将结果与39例单纯接受全身化疗的患者（中位年龄56±12岁； 61.5％为华人； 46.2％为女性）的回顾性历史队列进行了比较。总生存期为主要终点。无进展生存期和安全性是次要指标。
结果显示，腹膜内紫杉醇组的1年总生存率比历史队列比例更高（分别为67.8％和32.1％），中位总生存率为14.6个月和10.6个月（HR = 0.44； 95％CI，0.26-0.74）。接受腹膜内紫杉醇治疗的35.4％的患者取得了1年无进展生存期，而历史队列的这一比例为8.5％，中位无进展生存期分别为9.5个月和4.4个月（HR = 0.39； 95％CI，0.25- 0.66）。
中性粒细胞减少症是最常见的3级或更严重的血液不良事件，发生在腹膜内紫杉醇组的18％。 3级或更严重的最常见非血液学不良事件包括电解质失衡（14％），腹泻（7％）和发烧（5％）。与导管口有关的并发症发生在10例患者中，其中四名需要移动或拆除导管口。
Peritoneal metastasis is a common problem in patients with gastric cancer. Systemic chemotherapy alone usually does not effectively deal with this problem. A clinical trial conducted in Singapore aims to evaluate whether systemic chemotherapy in combination with intraperitoneal paclitaxel may benefit gastric cancer patients with synchronous peritoneal metastasis.
This is a phase II clinical trial. Forty-four patients with gastric cancer and peritoneal metastasis participated. The median age was 61±9 years, 90% were Chinese; 56.8% were women. The patient received intravenous oxaliplatin 100 mg/m2 on day 1; oral capecitabine (1,000 mg/m2, bid) on day 1 to day 14; intraperitoneal paclitaxel 40 mg/m2 on day 1 and 8. Every 21 days is a cycle. Patients received up to 8 cycles. If the patients with peritoneal metastasis (n = 36) responded well to chemotherapy, peritoneal fluid cytology was negative for two consecutive times, there was no extraperitoneal metastasis and no peritoneal metastasis was found during operation, radical gastrectomy could be performed. Thirteen patients who met these criteria underwent surgery. The researchers compared the results with a retrospective historical cohort of 39 patients (median age 56 ± 12 years; 61.5% were Chinese; 46.2% were women) who received systemic chemotherapy alone. Overall survival was the primary endpoint. Progression-free survival and safety were secondary endpoint.
The results showed that one-year overall survival rate of the intraperitoneal paclitaxel group was higher than that of the historical cohort (67.8% and 32.1%, respectively), and the median overall survival rate was 14.6 months and 10.6 months (HR = 0.44; 95% CI , 0.26-0.74). For progression-free survival, 35.4% of patients receiving intraperitoneal paclitaxel treatment achieved 1-year PFS, compared with 8.5% in the historical cohort. Median PFS was 9.5 months and 4.4 months, respectively (HR = 0.39; 95% CI, 0.25-0.66).
Neutropenia was the most common grade 3 or more serious hematological adverse event, occurring in 18% of the intraperitoneal paclitaxel group. The most common non-hematological adverse events of grade 3 or more included electrolyte imbalance (14%), diarrhea (7%), and fever (5%). Port-related complications occurred in 10 patients, four of whom required intervention to relocate or remove the port.
参考文献 Reference Chia D et al. GI Cancer Symposium Virtual Meeting Jan 2021. Abstr 165Neratinib对HER2阳性雌激素受体阳性的早期乳腺癌的最终疗效结果 (3/7/2021)
Final results of efficacy results of Neratinib in HER-2/ER-positive early breast cancer
ExteNET是一项多中心，随机，双盲，III期临床试验，研究了2,840例术前/后曲妥珠单抗治疗的HER2 +阳性雌激素受体阳性早期乳腺癌患者。根据雌激素受体状况 对患者进行分层, 参加病人随机分配1年口服neratinib 240 毫克/天或安慰剂。试验的终了目标为无侵袭性疾病生存率。对接受neratinib是在曲妥珠单抗治疗后≤1年开始（HR+/≤1年）和> 1年（HR+/>1年）开始的患者进行分析。
结果：HR+/≤1年和HR+/>1年人群分别包括1,334（neratinib，n = 670；安慰剂，n = 664）和297（neratinib，n = 146；安慰剂，n = 151）患者。 HR+/≤1年的5年绝对无侵袭性疾病生存率获益为5.1％（危险比，0.58； 95％置信区间[CI]，0.41-0.82），在HR+/>1年的人群中, 绝对无侵袭性疾病生存率获益为1.3％（危险比，0.74； 95％CI，0.29-1.84）。在HR+/≤1年的人群中，neratinib与8年总生存率的改善相关（绝对获益2.1％；危险比0.79； 95％CI 0.55-1.13）。在HR+/≤1年组的354例接受术前辅助治疗的患者中，有295例残存疾病，结果显示5年无侵袭性疾病生存率时绝对获益为7.4％（危险比，0.60； 95％CI，0.33-1.07）和8年总生存率获益9.1％（危险比为0.47; 95％CI为0.23-0.92）。 Neratinib的中枢神经系统事件（转移）较少。不良事件与先前报道的相似。
结论：Neratinib显著改善HER2/雌激素受体阳性/≤年人群的无侵袭性疾病生存率，在术前治疗后残留疾病的患者中观察到类似趋势。中枢神经系统事件和总生存率的改善与无侵袭性疾病生存率获益一致，表明Neratinib在该人群中具有长期获益。
ExteNET is a multi-center, randomized, double-blind, phase III clinical trial that studied 2,840 patients with HER2-positive, estrogen receptor-positive early breast cancer patients who received neratinib treated with neoadjuvant and adjuvant trastuzumab. The patients were stratified according to their estrogen receptor status, and the participating patients were randomly assigned to take 240 mg neratinib or placebo orally for 1 year. The primary end point of the trial is invasive disease-free survival (iDFS). Patients who received neratinib started ≤1 year (HR+/≤1 year) and >1 year (HR+/>1 year) after trastuzumab treatment were analyzed.
Results: The HR+/≤1 and HR+/>1 population included 1,334 (neratinib, n = 670; placebo, n = 664) and 297 (neratinib, n = 146; placebo, n = 151) patients, respectively. The 5-year absolute iDFS benefits for HR+/≤1 were 5.1% (hazard ratio, 0.58; 95% confidence interval [CI], 0.41-0.82). In the population with HR+/>1, absolute The benefits of iDFS were 1.3% (hazard ratio, 0.74; 95% CI, 0.29-1.84). In the population with HR+/≤1, neratinib was associated with an improvement in the 8-year overall survival (absolute benefit 2.1%; hazard ratio 0.79; 95% CI 0.55-1.13). Among the 354 patients in the HR+/≤1 group who received neoadjuvant therapy, there were 295 patients with residual disease. The results showed that the absolute benefits at 5-year iDFS were 7.4% (hazard ratio, 0.60; 95% CI, 0.33-1.07) and 8-year overall survival rate benefit of 9.1% (hazard ratio 0.47; 95% CI 0.23-0.92). Neratinib was associated with fewer central nervous system events (metastasis). The adverse events were similar to those previously reported.
Conclusion: Neratinib significantly improved the iDFS of the HER2/estrogen receptor positive/≤1 population. A similar trend was observed in patients with residual disease after neoadjuvant treatment. The improvement of central nervous system events and overall survival was consistent with the benefit of iDFS, indicating that Neratinib has long-term benefits in this population.
参考文献 Reference Chen, A et al. Clin Breast Cancer 2021; 21:80
PVSRIPO作为孤儿药治疗晚期黑色素瘤 (3/6/2021)
PVSRIPO was granted orphan drug by FDA to treat advanced stage melanoma
新型病毒免疫疗法PVSRIPO旨在刺激患者的先天性和适应性免疫系统，从而促进抗肿瘤反应, 并建立长期的免疫记忆，以帮助阻止癌症。 FDA已将新型病毒免疫疗法PVSRIPO授予孤儿药治疗，用于治疗IIB–IVB期黑色素瘤患者。
一项开放标签，随机，2期LUMINOS-102（NCT04577807）试验,正在招募对PD-1抑制剂难治性黑色素瘤患者接受PVSRIPO治疗。该试验计划研究单独PVSRIPO肿瘤内注射或与PD-1抑制剂联合使用的安全性，耐受性和初功效。LUMINOS-102试验将遵循PVSRIPO在抗PD-1难治性晚期黑色素瘤中进行的1期单药研究（其结果已在2020年癌症免疫治疗学会年会上发表）。在这项研究中，PVSRIPO注射剂耐受性良好，没有严重不良事件或剂量限制性毒性的报道。所有出现治疗的副作用均为1级或2级，其中1级瘙痒最为常见，占58％。
尽管相对于总病变负荷而言，PVSRIPO治疗的次数有限（67％的患者> 5个病变），但12例患者中有4例（33％）取得了客观响应（独立放射学审查委员会确定），包括6例中的4例（66％）接受了3次最大给药剂量。在4例中的2例（50％）的过境疾病（in-transit）患者中取得了病理完全响应。 在PVSRIPO治疗后，12名患者中的10名（83％）再次接受了免疫检查点抑制剂的治疗，这12名患者中的6名（50％）在数据截止时仍无进展。
The new viral immunotherapy PVSRIPO is designed to stimulate the patient’s innate and adaptive immune system to promote anti-tumor response and build long-term immune memory to help to keep cancer in check. FDA has granted PVSRIPO orphan drug designation as new viral immunotherapy for the treatment of patients with stage IIB-IVB melanoma.
An open-label, randomized, phase 2 LUMINOS-102 (NCT04577807) trial is recruiting patients with melanoma refractory to PD-1 inhibitors to receive PVSRIPO treatment. The trial is designed to study the safety, tolerability and initial efficacy of PVSRIPO intratumor injection alone or in combination with PD-1 inhibitors. The LUMINOS-102 trial will follow the phase 1 single-agent study of PVSRIPO in anti-PD-1 refractory advanced melanoma (results have been published at the 2020 Annual Meeting of the Society for Cancer Immunotherapy). In this study, PVSRIPO injection was well tolerated, and there were no reports of serious adverse events or dose-limiting toxicity. All the side effects of treatment were grade 1 or 2. Among them, grade 1 pruritus was the most common, accounting for 58%.
In spite of limited number of PVSRIPO treatments relative to the total lesion burden (67% of patients> 5 lesions), 4 out of 12 patients (33%) achieved an objective response (determined by an independent radiology review board), including 4 out of 6 cases (66%) who received the maximum administered dose of 3 injections. Pathological complete response was achieved in 2 out of 4 (50%) patients with in-transit disease. Following PVSRIPO treatment, 10 of the 12 patients (83%) were again started with immune checkpoint inhibitor-based therapy, and 6 of these 12 patients (50%) remained progress-free at the data cut-off.
参考文献 Reference https://istarioncology.com/press-release-fda-grants-orphan-drug-designation-for-pvsripo-for-the-treatment-of-advanced-melanoma January 19, 2021 Beasley G. et al J Immunotherapy of Cancer 2020;8(suppl 2): A185. Abstract 302.
蓝光膀胱镜检查非肌肉浸润性膀胱癌 (2/28/2021)
Application of blue-light flexible cystoscopy in non-muscle invasive bladder cancer
这是一项连续队列患者的前瞻性研究，患者接受了针对非肌肉浸润性膀胱癌的办公室内的蓝光膀胱镜检查。六乙酰基乙酰丙酸酯的光学成像溶液通过导管注入到患者的膀胱中。液体优先被膀胱癌细胞吸收。 泌尿科医生将内窥镜光源从白光切换为光动力蓝光发射电极，该电极能够以不容错过的辉光显著地识别癌细胞。总共对190例患者进行了322次检查。中位年龄为71岁，男性为83％。 蓝光膀胱镜检查之前的最高分期为Ta（45.3%），原位癌（18.4%），T1（30%）和T2（2%）。在蓝光膀胱镜检查之前，低等级，高等级和原位癌分别为16.8％，60.5％和16.8％。接受膀胱内卡介苗和膀胱内化疗的患者分别占54.2％和18.4％。
有173例（53.7％）患者的白光膀胱镜检查和蓝光膀胱镜均正常。 白光膀胱镜检查正常，但蓝光膀胱镜异常者26例（8％）。在这些患者中，有15例进行了办公室活检，其中13例被检出癌症（87％； 6例原位癌，4例高等级 Ta，3例低等级 Ta）。 白光膀胱镜检和蓝光膀胱镜在83例（25.8％）病例中均呈阳性，另有33％的患者还发现了它处肿瘤。在白光膀胱镜和蓝光膀胱镜检查均为 阳性的27例（75％）患者接受了办公室活检，发现了癌变，包括19例低等级Ta，6例高等级Ta和2例原位癌。
结论：蓝光膀胱镜可以在白光膀胱镜正常的情况下发现癌症。
This is a prospective cohort of consecutive of patients who underwent blue light flexible cystoscopy in the office for non-muscle invasive bladder cancer. The optical imaging solution of hexaminolevulinate is injected into the patient’s bladder through a catheter. The fluid is preferentially absorbed by bladder cancer cells. The urologist switches the light source of the endoscope from white light to a photodynamic blue light emitting electrode, which can distinguish cancer cells with easy-seen glow.
A total of 322 cases were performed on 190 patients. The median age was 71 years and 83% of were male. The highest stage prior to blue light cystoscopy was Ta (45.3%), carcinoma in situ (18.4%), T1 (30%) and T2 (2%). Prior to blue light cystoscopy, low-grade, high-grade, and carcinoma in situ were 16.8%, 60.5%, and 16.8%, respectively. Patients receiving intravesical BCG and intravesical chemotherapy accounted for 54.2% and 18.4%, respectively. White light cystoscopy and blue light cystoscopy were normal in 173 cases (53.7%). White light cystoscopy was normal, but blue light cystoscopy was abnormal in 26 cases (8%). Of these patients, 15 cases underwent office biopsy, and cancer was detected in 13 cases (87%; 6 cases of carcinoma in situ, 4 cases of high-grade Ta, 3 cases of low-grade Ta). Both white light cystoscopy and blue light cystoscopy were positive in 83 cases (25.8%), and 33% had additional tumors found. Cancer was found in 27 patients (75%) who were positive for both white light cystoscopy and blue light cystoscopy and who underwent office biopsy, including 19 low-grade Ta, 6 high-grade Ta, and 2 carcinomas in situ.
Conclusion: Blue light cystoscope could detect cancer when the white light cystoscope was normal.
参考文献 Reference Lotan Y. et al. BJU Int 2021; 127:108
宫颈癌患者术后序贯性放化疗相比于同时放化疗或单独放疗 (2/27/2021)
Sequential chemotherapy/radiation (RT) compared with concurrent chemo/RT or RT alone in cervical cancer following hysterectomy
这是一项III期多中心，开放标签的临床试验（STARS NCT00806117）, 有1,048位FIGO IB到IIA期的宫颈癌病人参加。参加者按1:1:1的比例随机分配，以接受单独放疗（350名），同时放化疗（245名）或顺序放化疗（353名）。这项研究的主要终点是3年的无进展生存率。 各治疗组之间的基线人口统计学特征和疾病特征取得平衡，但不同的是，单独放疗组的淋巴结受累率最低（18.3％），相比于同时放化疗组（30.1％）或顺序放化疗组（29.7%）。 另外, 顺序放化疗组的手术和辅助治疗之间的中位间隔（8天）比其他两组（放疗组为32天，同时放化疗组为33天）要短得多。该试验没有对手术方法（腹腔镜与腹腔镜）进行分层。但研究中的大多数患者（92.3％）接受了剖腹手术，并且接受腹腔镜手术的人数平均分布在3个研究组中。
在意向治疗人群中，与化疗组相比，顺序放化疗组的3年无进展生存率较高（90.0％）相比于放疗组（82.0％；HR，0.52； 95％CI，0.35-0.76） 和同时放化疗组（85.0％； HR：0.65； 95％CI：0.44-0.96）。将淋巴结受累调整后，与放疗组相比，顺序放化疗组仍显示出降低的5年癌症死亡风险（生存率92.0％vs 88.0％； HR，0.58； 95％CI，0.35-0.95）。
关于安全性，总共有921名患者的毒性可以评估。放疗组的3或4级不良事件发生率最低（12.9％）相比于同时放化疗组（28.5％）和顺序放化疗组（25.3％。同时放化疗组的3级或4级胃肠道毒性反应与顺序放化疗组相比发生率更高，例如恶心（6.4％vs 2.5％）和呕吐（5.4％vs 1.9％）。
本网站编辑注: 该试验中顺序放化疗组的手术和辅助治疗之间的间隔比其他两组要短，在其他癌症模型中（如在高风险的结肠癌和乳腺癌中），过去的研究已经显示肿瘤切除后延迟开始辅助化疗可能对总体生存不利。该报导的作者认为, 在资源有限的国家中，顺序放化疗仍可考虑作为辅助治疗的方法。
This is a phase III multicenter, open-label clinical trial (STARS NCT00806117) involving 1,048 FIGO IB to IIA cervical cancer patients. Participants were randomly assigned at a ratio of 1:1:1 to receive radiation alone (350 patients), concurrent chemo-radiation or (245 people) or sequential chemo-radiation (353 people). The primary endpoint of this study was 3-year progression-free survival. The baseline demographic characteristics and disease characteristics between the three treatment groups were balanced. However, the radiation alone group had the lowest lymph node involvement rate (18.3%), compared to the concurrent chemo-radiation group (30.1%) or sequential chemo-radiation group (29.7%). In addition, median interval between surgery and adjuvant therapy in the sequential chemoradiation group was much shorter (8 days) than that of the other two groups (32 days for the radiation group and 33 days for the concurrent chemo-radiation group). The trial did not stratify the surgical method (laparoscopic vs. laparoscopy). However, the majority of patients in the study (92.3%) underwent laparotomy, and the number of patients who underwent laparoscopic surgery was evenly distributed among the 3 study groups.
In the intention-to-treat population, 3-year progression-free survival rate of the sequential chemo-radiation group was higher (90.0%) compared with the radiation group (82.0%; HR, 0.52; 95% CI, 0.35-0.76) and concurrent chemo-radiation group (85.0%; HR: 0.65; 95% CI: 0.44-0.96). After adjusting for lymph node involvement, compared with the radiation group, the sequential chemo-radiation group still showed a reduced 5-year risk of cancer death (survival rate 92.0% vs 88.0%; HR, 0.58; 95% CI, 0.35-0.95).
Regarding safety, there are a total of 921 patients whose toxicity were evaluated. The incidence of grade 3 or 4 adverse events in the radiation group was the lowest (12.9%) compared with the concurrent chemo-radiation group (28.5%) and sequential chemo-radiation group (25.3%. More grade 3 or 4 gastrointestinal toxicity occurred in concurrent chemo-radiation group than the sequential chemo-radiation group group, such as nausea (6.4% vs 2.5%) and vomiting (5.4% vs 1.9%).
Note of the editor: The interval between surgery and adjuvant treatment in the sequential chemo-radiation group in this trial was much shorter than that in the other two groups. In other cancer models (such as high-risk colon cancer and breast cancer), it has been shown that delay in starting adjuvant chemotherapy after tumor resection was associated with inferior overall survival. The author of this article believed that sequential chemo-radiation group could still be considered as a choice of adjuvant treatment in countries with limited resources.
参考文献 Reference Huang H et al. JAMA Oncol. Published online January 14, 2021. doi: 10.1001/jamaoncol.2020.7168
乳腺癌的内部乳腺和内侧锁骨上淋巴结链照射:一项3期临床试验的15年结果 (2/21/2021)
Impact of internal mammary and medial supraclavicular lymph node chain irradiation: 17-year follow-up results
这是一项来自13个国家/地区的46个放射肿瘤学部门进行的随机III期临床试验（EORTC 22922/10925）15年分析，该试验旨在研究选择性内部乳腺和锁骨上内侧（IM-MS）淋巴结链辐射对总体生存的影响。
参加病人为75岁以下，I–III期乳腺腺癌，她们或为腋窝淋巴结阳性, 或原发肿瘤位于中央, 或原发肿瘤位于中央内侧的女性。手术包括乳房切除术或保乳手术和腋窝淋巴结分期。患者由中心进行分配（1:1），接受IM-MS照射（以50 Gy分25次照射）（IM-MS照射组）或不使用IM-MS照射（对照组）。分配以病人来自的机构，更年期状态，乳腺内原发肿瘤的部位，乳腺和腋窝手术的类型以及病理性T和N期进行分层。主要终点是根据意向治疗原则分析的总体生存率。次要终点是无病生存期，无远处转移生存期，乳腺癌死亡率，任何乳腺癌复发和死亡原因。随机分组后的20年中一直进行随访。
在1996年8月5日至2004年1月13日期间，一共招募了4,004例患者，其中2,002位被随机分配到IM-MS照射组，而2,002位被分配到对照组。中位随访15.7年，IM-MS照射组中554例（27.7％），对照组中569例（28.4％）死亡。 IM-MS照射组的总生存率为73.1％（95％CI 71.0–75.2），对照组为70.9％（68.6–72.9）（HR 0.95; 95％CI 0.84-1.06，p = .36）。任何乳腺癌复发率24.5％（95％CI 22.5–26.6） 相比于27.1％（25.1–29.2）（HR 0.87 ; 95％CI 0.77-0.98，p = .024）。IM-MS照射组乳腺癌死亡率低于对照组, 为16.0％（14.3–17.7） 相比于 19.8％（18.0–21.7）；HR 0.81 （0.70– 0.94），p = .0055。 IM-MS照射组与对照组的无病生存率无显着差异, 为60.8％（ 95％CI 58.4–63.2） 相比于59.9％（57.5–62.2）（HR 0.93 ; 95％CI 0.84-1.03，p = .18）。无远处转移的生存率无显着差异, 为70.0％（67.7–72.2 ）相比于 68.2％（65.9–70.3）（HR 0.93 [0.83-1.04]，p = .18）。各组之间的死亡原因相似。
15年的结果表明，在I–III期乳腺癌中，通过IM-MS照射可显着降低乳腺癌的死亡率和任何乳腺癌的复发率。但是，这并未转化为改善的总生存期。
This is a 15-year analysis of a randomized phase III clinical trial (EORTC 22922/10925) conducted by 46 radiation oncology departments from 13 countries/regions. The trial aimed to study the impact of selective internal mammary and medial supraclavicular (IM- MS) irradiation on overall survival.
Participating patients were women under 75 years of age with stage I–III breast cancer. They had involved axillary lymph nodes, or central or medially located primary tumor. Surgery consisted of mastectomy or breast-conserving surgery and axillary staging. The patients were randomly assigned centrally (1:1) to receive IM-MS irradiation (at 50 Gy in 25 fractions) (IM-MS irradiation group) or no IM-MS irradiation (control group). The allocation was stratified by the institutions, menopausal status, the location of the primary tumor in the breast, the type of breast and axillary surgery, and pathological T and N stages. The primary endpoint was overall survival rate analyzed according to the intention-to-treat principle. Secondary endpoints were disease-free survival, survival without distant metastasis, breast cancer mortality, any breast cancer recurrence and cause of death. Follow-up has been conducted for 20 years after randomization.
Between August 5, 1996 and January 13, 2004, a total of 4,004 patients were recruited, of which 2,002 were randomly assigned to the IM-MS irradiation group, and 2,002 were assigned to the control group. With a median follow-up of 15.7 years, 554 cases (27.7%) in the IM-MS irradiation group and 569 cases (28.4%) in the control group died. Overall survival of the IM-MS irradiation group was 73.1% (95% CI 71.0-75.2), and the control group was 70.9% (68.6-72.9) (HR 0.95; 95% CI 0.84-1.06, p = .36). Recurrence rate of any breast cancer was 24.5% (95% CI 22.5–26.6) vs. 27.1% (25.1–29.2) (HR 0.87; 95% CI 0.77-0.98, p = .024). Breast cancer mortality in the IM-MS irradiation group was lower than that in the control group. It was 16.0% (14.3–17.7) compared to 19.8% (18.0–21.7) (HR 0.81 [0.70–0.94], p = .0055). There was no significant difference in disease-free survival rate between the IM-MS irradiation group and the control group. It was 60.8% (95% CI 58.4-63.2) vs. 59.9% (57.5-62.2) (HR 0.93; 95% CI 0.84-1.03, p = .18). There was no significant difference in distance metastasis-free survival. They were 70.0% (67.7–72.2) and 68.2% (65.9–70.3) respectively (HR 0.93 [0.83-1.04], p = .18). The causes of death were similar between the groups.
The 15-year results showed that in stage I–III breast cancer, IM-MS irradiation significantly reduced breast cancer mortality and any breast cancer recurrence. However, this did not translate into improved overall survival.
参考文献 Reference Poortmans PM et al. Lancet Onc 2020; 21: 1610
开发一种精确的肿瘤活检技术 (2/20/2021)
New technique offers more accurate tumor biopsy
英国剑桥大学的癌症研究人员开发出一种新的计算技术，将计算机断层扫描（CT）扫描与超声图像相结合，可以提供视觉指导，以较少的活检样本来采样复杂性的肿瘤。 肿瘤内不同类型的癌细胞被称为肿瘤异质性, 需要选择代表性肿瘤部位活检。例如高级别浆液性卵巢癌倾向于具有高水平的肿瘤异质性。研究人员对临床上可疑的6名高级别浆液性卵巢癌患者, 患者首先进行了标准的CT扫描, 然后，研究人员使用了一种称为放射学的过程 （空间放射线图来确定具有相似或不同放射线模式的肿瘤区域，并使用高斯混合模型来识别肿瘤栖息地）, 使用强大的计算方法来分析和提取CT扫描仪创建的图像中的信息-识别并绘制肿瘤的不同区域和特征。然后将肿瘤图叠加在肿瘤的超声图像上，并将合成的图像用于指导活检过程。 使用这种方法在开始化疗之前进行超声引导的活检，研究团队成功捕获了肿瘤内癌细胞的多样性。对于较大的骨盆肿瘤，CT/超声融合准确性较高（dice similarity coefficient, DSC：0.76-0.79），而对于较小的网膜转移，其CT/超声融合准确性较低（DSC：0.37-0.53）。
Cancer researchers at the University of Cambridge in England have developed a new computing technology that combines computed tomography (CT) scans with ultrasound images to provide visual guidance to sample complex tumors with smaller biopsy samples. Different types of cancer cells in a tumor are called tumor heterogeneity, and a representative tumor biopsy is required. For example, high-grade serous ovarian cancer tends to have a high level of tumor heterogeneity. The researchers studied 6 patients with clinically suspicious high-grade serous ovarian cancer. The patients first had standard CT scan. Then, the researchers used a process called radiomic tumor habitats (spatial radiography to determine whether the tumor was similar or different, and Gaussian mixture model used to identify tumor habitat). Powerful calculation methods were used to analyze and extract information in images created by CT scanners, to identify and draw different areas and features of tumors. The tumor map is then superimposed on the ultrasound image of the tumor. The synthesized image is used to guide the biopsy process. Using this method to perform ultrasound-guided biopsy before starting chemotherapy, the research team successfully captured the diversity of cancer cells in the tumor. For larger pelvic tumors, the accuracy of CT/ultrasound fusion was higher (dice similarity coefficient, DSC: 0.76-0.79), while for smaller omental metastases, the accuracy of CT/ultrasound fusion was lower (DSC: 0.37- 0.53).
参考文献 Reference Beer L et al. European Radiology, 2020; DOI: 10.1007/s00330-020-07560-8
Enfortumab Vedotin在耐药性晚期尿路上皮癌中胜过化疗 (2/14/2021)
Enfortumab Vedotin demonstrated benefit in refractory uroepithelial cell carcinoma
Enfortumab Vedotin （EV）是一种针对Nectin-4（一种在尿路上皮癌中高度表达的细胞粘附分子）的抗体-药物偶联物，EV已为FDA批准。 研究人员进行了一项开放标签的3期研究，纳入了608名经组织学证实为局部晚期或转移的尿路上皮癌的患者，这些患者先前曾接受过铂类化疗，并且其疾病在PD-1 / L1抑制剂治疗期间或之后已进展。患者在每个28天周期的第1、8和15天以1:1的比例随机接受EV（1.25 毫克/公斤），或由研究者选择的泰索帝，紫杉醇或长春氟宁（docetaxel, paclitaxel, or vinflunine）化疗。 主要终点是总生存。次要终点包括研究者评估的无进展生存期，总体响应率，疾病控制率和安全/耐受性。
研究人员计划进行两项分析：439例死亡后的最终分析和285例死亡时的中期分析。 在中期分析时，研究人员将化疗的中位总生存期定为8个月，以进行统计分析。 中位总生存期为12.9个月（EV），比化疗组长3.9个月（危险比[HR] 0.70； 95％CI：0.56-0.89，P = 0.001）。 无进展生存期为与5.6个月相对于3.7个月（化疗）。总响应率为40.6％相对于17.9％。疾病控制率为71.9％相对于53.4％。
EV显示出可容忍的安全性。 疾病进展是退出研究的最常见原因。导致停药的不良事件发生在EV组14％的患者和化疗组15％的患者。导致死亡的治疗（不包括疾病进展）发生在EV组和化疗组的患者中，分别占2.4％和1％。
EV为局部晚期或转移的尿路上皮癌患者提供了一项有用的治疗选择。
Enfortumab Vedotin (EV) is an antibody-drug conjugate directed against Nectin-4 (a cell adhesion molecule highly expressed in urothelial cancer). EV has been approved by the FDA. Researchers conducted an open-label phase 3 study that included 608 patients with locally advanced or metastatic urothelial cancer confirmed by histology. These patients had previously received platinum-based chemotherapy and their disease had progressed on or after PD-1 / L1 inhibitor. Patients were assigned randomly at a ratio of 1:1 to receive either EV (1.25 mg/kg) on days 1, 8 and 15 of each 28-day cycle, or standard chemotherapy with taxotere, paclitaxel or vinflunine. The primary endpoint was overall survival. Secondary endpoints include progression-free survival as assessed by the investigators, overall response rate, disease control rate, and safety/tolerability.
Two analyses were planned: a final analysis after 439 deaths and an interim analysis at 285 deaths. In the interim analysis, median overall survival of 8 months was set for chemotherapy for statistical analyses. Median overall survival was 12.9 months in the EV group, which was 3.9 months longer than the chemotherapy group (hazard ratio [HR] 0.70; 95% CI: 0.56-0.89, P = 0.001). Progression-free survival was 5.6 months versus 3.7 months (chemotherapy). Overall response rate is 40.6% vs. 17.9%. Disease control rate was 71.9% versus 53.4%. EV showed tolerable safety profile. Disease progression was the most common reason for withdrawal from the study. Adverse events leading to discontinuation occurred in 14% of patients in the EV group and 15% in the chemotherapy group. Treatments that led to death (excluding disease progression) occurred in 2.4% and 1% respectively in the EV group and the chemotherapy group.
EV provides a useful treatment option for patients with locally advanced or metastatic urothelial cancer.
参考文献 Reference Powels T. ASCO 2021 GU Cancers Symposium abstr 393
双重HER2阻断与芳香酶抑制剂联合治疗绝经后激素受体/HER2阳性的转移性乳腺癌 (2/13/2021)
Dual HER-2 blockade plus aromatase inhibitor for postmenopausal women with metastatic ER/HER2-positive breast cancer
这是一项III期临床试验（ALTERNATIVE）, 有355位激素受体/HER2阳性的转移性乳腺癌转移病人参加。患者被随机分配（1:1:1）接受1) 拉帕替尼加曲妥珠单抗加芳香酶抑制剂（n = 120）; 2) 曲妥珠单抗加芳香酶抑制剂（n = 117）; 3) 拉帕替尼加芳香酶抑制剂（n = 118）。打算进行化疗的患者被排除在外。主要终点是研究人员评估的无进展生存期。次要终点是与其他组别进行比较的无进展生存期，总生存期，总缓解率响应率，临床受益率和安全性。
该研究达到了其主要终点。 三种药物联合优于曲妥珠单抗加芳香酶抑制剂（中位无进展生存期为11个月相比于5.6个月（危险比为0.62; 95％CI，0.45至0.88； P = .0063）。 总生存期，总缓解率响应率，和临床受益率也有利于三药联合用。 拉帕替尼加芳香酶抑制剂与曲妥珠单抗加芳香酶抑制剂的中位无进展生存期分别为8.3个月相比于5.6个月（危险比，0.85 [95％CI，0.62至1.17]； P = .3159）。 这三组常见不良事件（≥15％）为腹泻（分别为69％，9％和51％），皮疹（36％，2％和分别为28％），恶心（分别为22％，9％和22％）和甲沟炎（分别为30％，0％和15％），主要是1级或2级不良事件。 导致停药的不良事件很低。
结论: 对激素受体/HER2阳性的转移性乳腺癌病人，拉帕替尼加曲妥珠单抗双重HER2阻滞优于曲妥珠单抗加芳香酶抑制剂。这种组合为该患者群体提供了有效安全而免去化疗的治疗方案。
This is a phase III clinical trial (ALTERNATIVE), with 355 hormone receptor/HER2-positive, metastatic female patients participants. They were randomly assigned (1:1:1) to receive 1) lapatinib plus trastuzumab plus aromatase inhibitor (n = 120); 2) trastuzumab plus aromatase inhibitor (n = 117); 3) lapatinib plus aromatase inhibitor (n = 118). Patients who were planning to undergo chemotherapy were excluded. The primary endpoint was progression-free survival (PFS) as assessed by the investigators. The secondary endpoints were progression-free survival, overall survival, overall response rate, clinical benefit rate, and safety as compared with other cohorts.
The study reached its primary endpoint. The median PFS of the three-drugs combination group vs. trastuzumab plus aromatase inhibitor was11 months vs. 5.6 months (hazard ratio 0.62; 95% CI, 0.45-0.88; P = .0063). Overall survival, overall response rate and the clinical benefit rate were also favored by the three-drugs combination group. Median PFS in lapatinib plus aromatase inhibitor group vs. trastuzumab plus aromatase inhibitor group was 8.3 months vs. 5.6 months (hazard ratio, 0.85; 95% CI, 0.62 to 1.17; P = .3159). Common adverse events (≥15%) in the 3 cohorts were diarrhea (69%, 9%, and 51%, respectively), rash (36%, 2%, and 28%, respectively), and nausea (22%, 9%, and 28%, respectively) and paronychia (30%, 0% and 15% respectively). They were mainly grade 1 or 2 adverse events. Discontinuation rates due to adverse events were very low.
Conclusion: for patients with hormone receptor/HER2-positive metastatic breast cancer patients, double HER2 block with lapatinib plus trastuzumab was superior to trastuzumab plus aromatase inhibitor. This chemotherapy-free combination provides an effective and safe treatment alternative for this patient population.
参考文献 Reference Johnston SRD et al. J Clin Onc 2021; 39: 79Margetuximab加上化疗优于曲妥珠单抗加上化疗治疗对HER2阳性晚期乳腺癌 (2/7/2021)
Margetuximab plus chemotherapy more beneficial than trastuzumab/chemo combination in advanced HER-2 positive breast cancer
这是一项III期临床试验（SOPHIA），从2015年8月26日至2018年10月10日，在17个国家/地区的166个地点招募了536名患者。符合条件的患者在接受1-3线转移性疾病治疗和>2种抗HER2疗法后疾病进展。中位年龄为56（27-86）岁；margetuximab组中有266名（100％）妇女，曲妥珠单抗组中有267名（98.9％）妇女。除1名患者外，所有患者均接受过帕妥珠单抗的治疗，其中489例（91.2％）患者接受了ado-trastuzumab emtansine （KADCYLA）的治疗。研究人员在1:1随机分组之前选择了化疗方案，每个疗程为3周，分别接受15 毫克/公斤的margetuximab（一种Fc部分改良设计过的靶向HER2的单克隆抗体）或6 毫克/公斤的曲妥珠单抗（负荷剂量8 毫克/公斤）。主要终点是通过中央盲法分析获得的无进展生存期和总体生存期。次要终点是由研究者评估的无进展生存期和通过中央盲法分析得出的客观缓解率。
与曲妥珠单抗联合化疗相比，margetuximab联合化疗延长了无进展生存期（5.8个月相比于4.9个月； P = .03）。Margetuximab组患者的总体响应率更高（25％相比于 14％； P < .001）。两组的中期平均总生存期相当，在第二次中期分析后，接受margetuximab的中位总生存期为21.6个月，而使用曲妥珠单抗的中位为19.8个月（HR，0.89; P = .33;）。最终的总生存期分析尚在进行中。
Margetuximab的输注相关反应的发生率（主要在第1周期中）更高（13.3％相比于3.4％）；否则，安全性是可比的。两组的停药率相似。两组的心脏功能障碍发生率相当。 这些初步结果表明，对于先前治疗过的HER2阳性的晚期乳腺癌患者，margetuximab能改善无进展生存期。
This is a phase III clinical trial (SOPHIA). From August 26, 2015 to October 10, 2018, 536 patients were recruited from 166 locations in 17 countries/regions. Eligible patients had disease progression after receiving 1-3 lines of treatment for metastatic disease and >2 anti-HER2 therapies. The median age was 56 (27-86) years; there were 266 (100%) women in the margetuximab group and 267 (98.9%) women in the trastuzumab group. Except for one patient, all patients had received pertuzumab treatment, and 489 patients (91.2%) had received ado-trastuzumab emtansine (KADCYLA) treatment. The researchers chose a chemotherapy regimen before 1:1 randomization. Each cycle of treatment was 3 weeks. The dose was15 mg/kg for margetuximab (Fc engineered monoclonal antibody targeting HER2) or 6 mg/kg for trastuzumab (loading dose of 8 mg/kg). The primary endpoints were progression-free survival and overall survival by central blinded analysis. The secondary endpoints were investigator-assessed progression-free survival and objective response rate by central blinded analysis. Compared with trastuzumab combined with chemotherapy, margetuximab combined with chemotherapy prolonged progression-free survival (5.8 months vs. 4.9 months; P = .03). Patients in margetuximab group had a higher overall response rate (25% vs. 14%; P <.001). Median overall survival of the two groups was similar. After the second interim analysis, the median overall survival in patients receiving margetuximab was 21.6 months, while that in trastuzumab group was 19.8 months (HR, 0.89; P = .33;). The final overall survival analysis is still in progress. The incidence of infusion-related reactions (mainly in cycle 1) was higher with margetuximab (13.3% vs. 3.4%); otherwise, the safety was comparable. The discontinuation rates in the two groups were similar. The incidence of cardiac dysfunction in the two groups was similar. These preliminary results indicate that margetuximab can improve progression-free survival in patients with advanced breast cancer who have been previously treated with HER2 therapy.
参考文献 Reference Hugo HS et al. JAMA Onc 2021; Jan. 21
激素受体阳性淋巴结阳性绝经后乳腺癌患者可以避免化疗 (2/6/2021)
Some ER-positive, HER-2-negative and lymph-node-positive postmenopausal breast cancer patients avoid chemotherapy
SWOG S1007 （RxPONDER）试验评估了化疗对激素受体阳性，HER2阴性, 淋巴结阳性的早期乳腺癌的益处。这是首次针对这一特定人群回答这一问题的大型随机试验。
RxPONDER对9个国家/地区的9,383名妇女进行了筛查，最终包括5,015名患有一到三个淋巴结且RS （recurrent score）≤25的II或III期乳腺癌。这些妇女中，三分之二是绝经后的女性，三分之一是绝经前的女性。她们随机分配接受内分泌治疗或内分泌治疗加化疗。通过RS（0-13 vs 14-25），绝经状态，腋窝淋巴结清扫和前哨淋巴结活检对数据进行分层。 主要终点是无侵入性性疾病生存期，定义为局部或远距离复发，任何第二次侵入性癌症或任何原因引起的死亡。
在中位随访5.1年的中，发生了54％的预期事件后，整个人群（RS从0至25）的化疗获益与RS值之间均无关联（P = .30）。但是，一项预先指定的分析发现化疗获益与更年期状态之间存在显著关联（P = .004），在绝经前亚组中，5年绝对收益为5.2％。化疗为绝经前队列的总体生存率带来了1.3％的绝对获益：98.6％vs 97.3％（危险比[HR] = 0.47； P = .032）。绝经后妇女的存活率分别为96.2％和96.1％（HR = 0.96; P = .79）。
这项临床试验数据显示，激素受体阳性，HER2阴性, 1-3个淋巴结阳性, RS ≤25的乳腺癌患者，可以安全地避免使用化疗。
The SWOG S1007 (RxPONDER) trial evaluated the benefit of chemotherapy for hormone receptor-positive, HER2-negative, and lymph node-positive early breast cancer patients. This is the first large randomized trial to answer this question in this specific population. RxPONDER screened 9,383 women in 9 countries/regions, eventually including 5,015 stage II or III breast cancers with one to three lymph nodes and RS (recurrent score) ≤ 25. Of these women, two thirds are postmenopausal women and one third are premenopausal women. They were randomly assigned to receive either endocrine therapy or endocrine therapy plus chemotherapy. The data were stratified by RS (0-13 vs 14-25), menopausal status, axillary lymph node dissection, and sentinel lymph node biopsy. The primary endpoint is non-invasive disease survival, defined as local or remote recurrence, any second invasive cancer or death from any cause. At a median follow-up of 5.1 years, after 54% of the anticipated events, there was no association between the chemotherapy benefit and the RS value (P = .30) in the entire population (RS from 0 to 25). However, a pre-specified analysis found a significant association between chemotherapy benefit and menopausal status (P = .004). In the premenopausal subgroup, the 5-year absolute benefit was 5.2%. Chemotherapy brought an absolute benefit of 1.3% in overall survival rate among the premenopausal cohort: 98.6% vs 97.3% (hazard ratio [HR] = 0.47; P = .032). The survival rates of postmenopausal women were 96.2% and 96.1% (HR = 0.96; P = .79). Data from this clinical trial showed that breast cancer patients with hormone receptor-positive, HER2-negative, and 1-3 lymph node-positive breast cancer with RS≤25 can safely avoid chemotherapy.
参考文献 Reference Kalinsky K et al. 2020 San Antonio Breast Cancer Symp Abstr GS3-00
Mobocertinib对EGFR 外显子 20插入突变的IV期非小细胞肺癌有效 (1/31/2021)
Mobocertinib effective to Non-small cell lung cancer harboring EGFR exon 20 insertion mutation
Mobocertinib是一种有效的口服酪氨酸激酶抑制剂（TKI），专门设计用于选择性靶向表皮生长因子受体（EGFR）Exon20插入突变。该突变约占非小细胞肺癌患者的1-2％。而目前的EGFR TKI和化疗对这些患者的益处有限。
这是一项临床I/II期试验（TAK-788）,在114位可评估的己转移的非小细胞肺癌病人中, 先前接受了铂类化疗。所有患者每日一次口服160 毫克Mobocertinib。根据独立审查委员会确认的客观响应率为 28％（32/114; 95％CI 20-37）, 中位响应时间为17.5个月（95％CI 7.4-20.3）, 中位无进展生存期 为7.3个月（95％CI 5.5-9.2）, 疾病控制率为78％（89/114; 95％CI 69-85）。
最常见（≥20％）的治疗相关不良事件为腹泻（90％），皮疹（45％），甲沟炎（34％），恶心（32％），食欲下降（32％），皮肤干燥（30％）和呕吐（30％）。 3或3级以上治疗相关不良事件（≥5％）包括腹泻（21％）。 19名患者（17％）因不良事件停药，最常见的原因是腹泻和恶心。
2019年，FDA授予mobocertinib孤儿药物称号，用于治疗具有EGFR 2（HER2）突变或包括外显子20插入突变在内的EGFR突变的肺癌。 2020年4月，mobocertinib获得了FDA针对EGFR 外显子20插入突变的转移性非小细胞肺癌患者在铂类化疗治疗后有进展的突破性治疗的指定。
Mobocertinib is a potent oral tyrosine kinase inhibitor (TKI), specifically designed to selectively target the epidermal growth factor receptor (EGFR) exon20 insertion mutation. This mutation accounts for about 1-2% of patients with non-small cell lung cancer. The current EGFR TKI and chemotherapy have limited benefits for these patients.
The data came from a clinical phase I/II trial (TAK-788). Among 114 evaluable patients with metastatic non-small cell lung cancer, they had previously received platinum-based chemotherapy. All patients took 160 mg of Mobocertinib orally once a day. The objective response rate determined by the independent review committee was 28% (32/114; 95% CI 20-37). The median response time was 17.5 months (95% CI 7.4-20.3) and the median progression-free survival was 7.3 months (95% CI 5.5-9.2). The disease control rate was 78% (89/114; 95% CI 69-85).
The most common (≥20%) treatment-related adverse events were diarrhea (90%), rash (45%), paronychia (34%), nausea (32%), decreased appetite (32%), dry skin (30 %) and vomiting (30%). Treatment-related adverse events of grade 3 or higher (≥5%) included diarrhea (21%). Nineteen patients (17%) discontinued the drug due to adverse events, of which the most common were diarrhea and nausea.
In 2019, FDA granted mobocertinib orphan drug designation for the treatment of lung cancer patients with EGFR 2 (HER2) or EGFR mutations including exon 20 insertion mutation. In April 2020, mobocertinib was designated by the FDA as a breakthrough treatment for patients with metastatic non-small cell lung cancer with EGFR exon 20 insertion mutation after platinum chemotherapy treatment.
参考文献 Reference https://www.takeda.com/newsroom/newsreleases/2021/takeda-presents-positive-results-for-mobocertinib-in-patients-with-egfr-exon20-insertion-mnsclc-who-received-prior-platinum-based-chemotherapy/
血液聚糖检查可识别耐受辅助化疗的胰腺癌 (1/30/2011)
A serum glycan biomarker may detect chemotherapy-resistant pancreatic cancer
手术切除胰腺导管腺癌后的辅助化疗使约50％的患者生存期更长（中位总生存期约为2年）。另一半化疗则无益处，并在一年内复发。对化疗具有高度耐药性的这个胰腺癌亚型，在临床环境中没有可用的标记物来识别。 研究者评估了一种称为唾液酸化肿瘤相关抗原（sialylated tumor-related antigen, sTRA）的聚糖生物标志物, 这种聚糖通常是由对化学疗法无反应的胰腺癌产生的, 通过验血可用于此识别目的。
在以前的研究中发现，胰腺导管腺癌存在不同亚型，其对化疗的反应有所不同。它们被分为经典亚型或基础/鳞状亚型。经典亚型在细胞培养和其他模型中，对药物具有抗药性并且不能从辅助化疗中获益。研究者发现sTRA的表达通常与经典亚型一致。与非表达sTRA模型相比，表达sTRA的模型倾向于具有干细胞样基因表达和间充质分化能力。 sTRA细胞系还显著提高了对通常用于胰腺癌的七种不同化疗药物的抵抗力。 sTRA基因表达阳性的原发肿瘤患者, 在辅助化疗后没有获得统计学上显著的获益，这与那些sTRA基因表达阴性的患者相反。在另一个队列中，通过直接测量组织芯片中的sTRA，那些高sTRA的患者仍然没有从辅助化疗中获益。此外，通过sTRA聚糖的血浆测试, 研究者还能确定术前化疗后快速复发的胰腺导管腺癌。
在临床环境中，sTRA聚糖生物标志物可能对检测耐化疗药物的胰腺导管腺癌具有价值。
Adjuvant chemotherapy after surgical removal of pancreatic ductal adenocarcinoma can make about 50% of patients survive longer (median overall survival pf about 2 years), while chemotherapy does not benefit the other half and they usually relapse within a year. This subtype of highly resistant pancreatic cancer does not have clinically available markers to identify. Some researchers evaluated a glycan biomarker called sialylated tumor-related antigen (sTRA), which is usually produced by pancreatic cancer that does not respond to chemotherapy. Researchers hope yo recognize this resistant subtype via blood test.
It was found previously that there are different subtypes of pancreatic ductal adenocarcinoma, and their response to chemotherapy is different. They are classified into classical or basal/squamous subtypes. The classical subtype is resistant to drugs in cell culture and other models. It does not benefit from adjuvant chemotherapy. Researchers found that the expression of sTRA is usually consistent with the classic subtype. Compared with non-expressing models, the sTRA model tends to have stem-like gene expression and the capacity for mesenchymal differentiation. The sTRA cell line also significantly increased resistance to seven different chemotherapeutic drugs commonly used for pancreatic cancer. Patients with primary tumors that were positive for sTRA gene expression did not achieve statistically significant benefits from adjuvant chemotherapy, contrary to those with negative sTRA gene expression. In another cohort, those patients with high sTRA, as measured directly in tissue microarrays, did not benefit from adjuvant chemotherapy. In addition, researchers were able to identify pancreatic ductal adenocarcinoma that recurred quickly after preoperative chemotherapy via plasma testing of sTRA glycan,.
In a clinical setting, sTRA glycan biomarkers may have value in detecting chemotherapy-resistant pancreatic ductal adenocarcinoma.
参考文献 Reference Gao G et al. Clin Cancer Res 2021; 27:226 Collisson EA et al. Nat Med 2011; 17:500
三阴性乳腺癌的癌基因TRIM37与转移和化疗耐药性 (1/24/2021)
Oncogenic TRIM37 links tumor metastasis and chemotherapy resistance in triple negative breast cancer
三阴性乳腺癌（TNBC）患者的死亡大多数是由于转移和化疗耐药性引起的，一项研究报导了癌基因TRIM37不仅会导致三阴性乳腺癌扩散，而且使其对化疗具有抵抗力。
三阴性乳腺癌对TRIM37网络的分子依赖性，这使肿瘤细胞能够抵抗化疗以及转移性应激。 TRIM37指导的组蛋白H2A单泛素化（monoubiquitination）使DNA修复发生变化，从而使TP53突变的三阴性乳腺癌细胞对化疗产生抗性。化疗药物通过ATM / E2F1 / STAT信号触发了正反馈回路，从而放大了化疗耐药癌细胞中的TRIM37网络。 临床上，高TRIM37与较差的总体存活率有关。TRIM37的高表达诱导了具有转移表型特征的转录变化，但若抑制TRIM37则大大降低了三阴性乳腺癌细胞的体内行为。使用抗叶酸受体偶联的纳米颗粒结合化学疗法选择性递送TRIM37的特异性反义寡核苷酸（antisense oligonucleotides），可在自发转移性鼠模型中抑制肺转移。由于这些纳米颗粒中的大多数被肝脏清除，因此研究人员通过鼻腔途径输送纳米颗粒，提高了肺部摄取率而绕过了这个问题。
这项研究显示了肿瘤转移与耐药性之间的联系。它还为TRIM37特异性靶标治疗提供了平台。
Treatment failure in triple-negative breast cancer (TNBC) is usually due to metastasis and chemotherapy resistance. A study reported that the oncogenic TRIM37 not only causes the spread of triple-negative breast cancer, but also makes it resistant to chemotherapy.
The molecular dependence of triple-negative breast cancer on the TRIM37 network allows tumor cells to resist chemotherapy and metastatic stress. TRIM37-directed histone H2A monoubiquitination changes DNA repair, which makes triple-negative breast cancer cells with TP53 mutations resistant to chemotherapy. Chemotherapy drugs trigger a positive feedback loop through ATM/E2F1/STAT signals, thereby amplifying the TRIM37 network in chemotherapy-resistant cancer cells. Clinically, high TRIM37 is associated with poor overall survival. High expression of TRIM37 induces transcriptional changes characteristic of metastatic phenotype, while inhibition of TRIM37 greatly reduces the in vivo propensity of triple-negative breast cancer cells. Using antifolate receptor-coupled nanoparticles combined with chemotherapy to selectively deliver TRIM37 specific antisense oligonucleotides can inhibit lung metastasis in spontaneously metastatic mouse models. Since most of these nanoparticles are cleared by the liver, the researchers bypassed this problem by delivering the nanoparticles through the nasal route to increase the lung uptake rate.
This study shows a link between tumor metastasis and drug resistance. It also provides a platform for TRIM37 specific target therapy.
参考文献 Reference Przanowski P et al. Cancer Res 2020; 80: 4791
Bemarituzumab加化学疗法可改善晚期胃/胃食管连接癌的结局 (1/22/2021)
Bemarituzumab in combination with chemotherapy improves outcome of advanced gastric and GE junction cancer
胃癌有一个新的靶标：成纤维细胞生长因子受体2b（FGFR2b）。Bemarituzumab是人源化IgG1单克隆抗体，可选择性结合FGFR2b，抑制配体结合并介导抗体依赖性细胞介导的细胞毒性。
这是一项随机，双盲，安慰剂对照的II期试验（FIGHT）。在对910例先前未经治疗的胃或胃食管连接癌患者进行了评估，其中有275例（30％）为FGFR2b阳性。最终，有155名患者（HER2阴性）参加了该试验。接受了改良的FOLFOX6治疗，并随机分配为1：1，每2周接受一次15毫克/公斤的bemarituzumab 或安慰剂，并在第8天再接受另一次7.5 毫克/公斤的bemarituzumab。主要终点是研究者评估的无进展生存期。
该试验达到了主要终点，安慰剂组的中位无进展生存期从7.4个月提高到bemarituzumab组的9.5个月（危险比[HR] = 0.68，P = .07）。还达到了总生存的次要终点，对照组为12.9个月, 而bemarituzumab组未达到中位值，（HR = 0.58，P = .03）。响应率率从40％增加到53％，安慰剂组的中位响应持续时间为7.1个月，bemarituzumab组为12.2个月。 随着FGFR2b表达的增加，接受bemarituzumab组的无进展生存期和总体生存期受益也增加。免疫组织化学染色最高（ 2 + 和 3 +≥10％）的亚组的无进展生存率为0.44，总生存率为0.41。
大约34％的患者由于毒性反应需要停用bemarituzumab，而安慰剂组为5％。主要是眼毒性，这是FGFR抑制剂的已知副作用。 在bemarituzumab组中有67％的患者发生了任何等级的角膜事件（主要是干眼症，角膜炎和点状角膜炎），安慰剂组为10％，其中≥3级为24％相比于 0％。但是，该药物未产生视网膜脱离或高磷酸盐血症。 60％的患者角膜毒性在中位时间27周可消失。 下一步是推进III期临床试验，以确认这些重要结果。
Gastric cancer has a new target: fibroblast growth factor receptor 2b (FGFR2b). Bemarituzumab is a humanized IgG1 monoclonal antibody that can selectively bind to FGFR2b, inhibit ligand binding and mediate antibody-dependent cell-mediated cytotoxicity.
This is a randomized, double-blind, placebo-controlled Phase II trial (FIGHT). In the evaluation of 910 patients with previously untreated gastric or gastroesophageal junction cancer, 275 (30%) of them were FGFR2b positive. In the end, 155 patients (HER2 negative) participated in the trial. They received modified FOLFOX6 treatment, and randomized 1:1, to receive 15 mg/kg bemarituzumab or placebo once every 2 weeks, and received another dose of 7.5 mg/kg bemarituzumab on the day 8. The primary endpoint is progression-free survival as assessed by the investigator. The trial reached the primary endpoint. The median progression-free survival in the placebo group improved from 7.4 months to 9.5 months in the bemarituzumab group (hazard ratio [HR] = 0.68, P = .07). The secondary endpoint of overall survival was also reached. The control group was 12.9 months, while the bemarituzumab group did not reach the median (HR = 0.58, P = .03). Response rate increased from 40% to 53%, with a median duration of response of 7.1 months in the placebo group vs 12.2 months in the bemarituzumab group. With the increase in FGFR2b expression, the benefit of progression-free survival and overall survival from bemarituzumab was also increased. The subgroup with the highest immunohistochemical staining (2 + and 3 + ≥10%) had a progression-free survival rate of 0.44 and an overall survival rate of 0.41.
Approximately 34% of patients needed to stop bemarituzumab due to toxicity, compared with 5% in the placebo group. The main toxicity is ocular, which is a known side effect of FGFR inhibitors. In the bemarituzumab group, 67% of patients had any grade of corneal events (mainly dry eye, keratitis and punctate keratitis), vs 10% in the placebo group. Twenty-four percent had ≥3 grade toxicity in the bemarituzumab group compared to 0 %. However, the drug did not produce retinal detachment or hyperphosphatemia. In 60% of patients, corneal toxicity resolved in a median time of 27 weeks. The next step is to advance phase III clinical trials to confirm these important results.
参考文献 Reference Wainberg Z. 2021 Gastrointestinal Cancer Symp, abstr 160
PLK1抑制剂与阿比特龙组合在前列腺癌中显示出初步疗效和安全性 (1/17/2021)
PLK1 inhibitor and abiraterone combination shows preliminary efficacy and safety
在一项2期试验中（NCT03414034），PLK1（polo-like kinase 1）抑制剂, onvansertib与阿比特龙联合治疗, 对具有早期阿比特龙耐药性的转移性去势抵抗性前列腺癌患者，在3个给药方案中均表现出良好的安全性，并在可评估组中具有疗效。 PLK1是G2/M检查点的调节剂，onvansertib是PLK1的高度选择性和短半衰期抑制剂。从临床前细胞系和异种移植模型来看，PLK1抑制剂与阿比特龙之间似乎存在协同作用。
这项临床试验有3组, 在21天为一个周期的第1至第5天，A组以24 毫克/平方米的onvansertib剂量治疗（n = 24）； B组（n = 32）在14天为一个周期的第1至5天以18 毫克/平方米的剂量服用；在21天周期的第1至14天，C组（n = 32）以12 毫克/平方米的剂量服用。治疗时间为12周（A组和C组为4个周期，B组为6个周期）。 在疗效的初步评估中，这种组合在A组和B组（n = 26）的8名（31％）可评估患者中达到了PSA稳定的主要终点。在12周时有14位（54％）患者观察到稳定的疾病，在8位（31％）患者中观察到超过7个月的持久反应。
在8例与阿比特龙耐药相关的雄激素受体改变的患者中，3例达到了疾病控制，4例疾病稳定。在这项研究中，阿比特龙耐药的雄激素受体机制包括AR-V7，AR T878A突变和雄激素受体扩增。 此外，onvansertib加上阿比特龙引起的循环肿瘤细胞从不利转变为有利，这与患者的持久反应相关。循环肿瘤细胞计数是该生存的预后因素，在基线时对27例（73％）患者不利。在12周时重新评估的10例患者中，有5例的循环肿瘤细胞下降了80％或更多，有4例从不利转为有利，其中3例未检测到循环肿瘤细胞。
研究人员确定了一种协同基因特征（synergistic gene signature），该基因特征主要与有丝分裂相关的基因组成，与其他亚型相比，这种亚型的患者对组合反应的可能更大。
最常见的3/4级不良事件是血液学的, 这是由于onvansertib的作用机理有关, 如贫血，中性粒细胞减少，和血小板减少。这些事件是可逆的，并通过剂量延迟，剂量减少和/或生长因子支持来控制。
In a phase 2 trial (NCT03414034), PLK1 (polo-like kinase 1) inhibitor, onvansertib combined with abiraterone, was used to treat patients with metastatic castration-resistant prostate cancer with early abiraterone resistance. All of the 3 dosing regimens showed good safety and efficacy in the evaluable group. PLK1 is a regulator of G2/M checkpoint. Onvansertib is a highly selective and short half-life inhibitor of PLK1. From the studies of preclinical cell lines and xenograft models, there seems to be a synergistic effect between PLK1 inhibitors and abiraterone.
The study has three arms. On days 1 to 5 of a cycle of 21 days, group A was treated with a dose of 24 mg/m² onvansertib (n = 24); group B (n = 32) was treated on day 1 to 5 of a cycle on 14 days at a dose of 18 mg/m²; on days 1 to 14 of the 21-day cycle, group C (n = 32) was taken at a dose of 12 mg/m². The treatment duration is 12 weeks (4 cycles for group A and C, 6 cycles for group B). In the initial evaluation of efficacy, this combination achieved the primary endpoint of stable PSA in 8 (31%) evaluable patients in groups A and B (n = 26). Stable disease was observed in 14 (54%) patients at 12 weeks, and lasting response over 7 months was observed in 8 (31%) patients.
Among the 8 patients with androgen receptor alterations associated with abiraterone resistance, 3 patients achieved disease control and 4 patients had stable disease. In this study, the mechanisms of abiraterone resistance in relations to androgen receptor alterations include AR-V7, AR T878A mutations and androgen receptor amplification. In addition, onvansertib plus abiraterone caused circulating tumor cells to turn from unfavorable to favorable, which is related to the patient’s lasting response. Circulating tumor cell count is a prognostic factor for this survival, and it is unfavorable for 27 patients (73%) at baseline. Among the 10 patients reassessed at 12 weeks, 5 had a decrease of 80% or more in circulating tumor cells, 4 cases turned from unfavorable to favorable, and 3 of them did not have detectable circulating tumor cells. The researchers also identified a synergistic gene signature. The gene signature is mainly related to mitosis-associated genes. Compared with other subtypes, patients with the subtype of synergistic gene signature are more likely to respond to the combination treatment. The most common grade 3/4 adverse events are hematological, which is due to the mechanism of action of onvansertib. They include anemia, neutropenia, and thrombocytopenia. These events are reversible and controlled by treatment delay, dose reduction and/or growth factor support.
参考文献 Reference Einstein DJ, et al. 27th Ann Prostate Cancer Foundation Virtual Sci Retreat 2020. https://bit.ly/3dQbTnW
CAR T细胞疗法的新策略 (1/16/2021)
A new strategy in CAR T-cell therapy
一种针对血液癌的新型可转换CAR T细胞疗法最近进入了早期临床试验。FDA批准了该研究疗法在I期研究中用于治疗复发性或难治性B细胞恶性肿瘤（包括非霍奇金淋巴瘤和慢性淋巴细胞性白血病）。临床前研究表明，这种新疗法针对癌症的控制和通用性更好，同时还可以减轻免疫系统对这些基因工程改变了的免疫细胞所产生的有害副作用，例如细胞因子释放综合征。
目前FDA批准B细胞恶性肿瘤CAR T细胞疗法的主要靶标, 都针对CD19，它是许多（但不是全部）B细胞恶性肿瘤的常见生物标志物。但是, 这种新型CAR-T细胞对任何人类内源性靶标都没有特异性，该平台设计有可能使研究人员靶向众所周知的癌症抗原和新发现的抗原，而不是一次靶向一个靶标。
研究的目标是在美国五个中心招募约36名患者，他们首先要接受已经改变的自身T细胞，然后再接受可转换约抗体，这个抗体形成与CD19阳性靶细胞的桥梁。随着肿瘤的发展，利用可转换抗体可以根据需要靶向任何肿瘤细胞。这种能力将来可能会对治疗实体瘤有用，因为实体瘤通常比血液癌具有更高的免疫抑制作用，而且其中的微环境更为复杂; 还可能扩大供体库以包括供体T细胞，从而将治疗范围扩大到更多患者。
然而, 许多具体问题首先需要解决。如可转换抗体的局部和全身浓度是否足以产生强大而持久的抗肿瘤反应？这个系统,特别是转换抗体的免疫原性如何？将来仍然需要做很多工作。
A new “switchable” CAR T cell therapy for blood cancer has recently entered early clinical trials. The FDA approved the investigational therapy for the treatment of relapsed or refractory B-cell malignancies (including non-Hodgkin’s lymphoma and chronic lymphocytic leukemia) in a phase I study. Preclinical studies have shown that this new therapy may have better control and versatility against cancer, and it can also reduce the harmful side effects of the immune system on these genetically engineered immune cells, such as cytokine release syndrome.
At present, the main targets of CAR T cell therapy approved by the FDA for B-cell malignancies are all targeting CD19, which is a common biomarker for many (but not all) B-cell malignancies. However, this new type of CAR-T cell is not specific to any human endogenous target, and the platform design may allow researchers to target well-known cancer antigens and newly discovered antigens instead of targeting one target at a time. The goal of the study is to recruit about 36 patients in five centers in the United States. They first receive their own altered T cells, and then receive a switchable antibody that forms a bridge to the CD19-positive target cells. As the tumor evolves, the use of switchable antibodies can target any tumor cells as needed. This ability may be useful in the treatment of solid tumors in the future, because solid tumors usually have a higher immunosuppressive effect than hematological cancers, and the microenvironment is more complex; it may also expand the donor pool to include donor T cells, thereby expanding the treatment to more patients.
However, many specific issues need to be resolved first. For example, are the local and systemic concentrations of switchable antibodies sufficient to produce a strong and long-lasting anti-tumor response? How is the immunogenicity of this system, especially the switchable antibody? A lot of work still needs to be done in the future.
参考文献 Reference Oncology Times 2020; 42:34
案例报告：新生儿在分娩过程中会患上怀孕母亲的癌症 (1/10/2021)
Case report: Newborns can contract cancer from their pregnant mother during delivery
在极少数情况下，新生儿在分娩过程中会患上怀孕母亲的癌症。 据日本研究人员报道，两个男孩，分别为23个月大和6岁，患上了肺癌，结果发现他们的肿瘤与出生时母亲的子宫颈癌有着完全的基因匹配（下一代测序）。研究人员认为肿瘤是由于出生时吸入受肿瘤污染的阴道液体而传播来的。 从母亲向子代的癌症传播是非常罕见的，每50万名患癌症的母亲中只有1名婴儿发生。以前观察到的少数病例通常涉及癌细胞穿过胎盘进入发育中的胎儿。白血病，淋巴瘤和黑色素瘤是儿童中最常见这样传播的癌症。 据说，这是新生儿通过呼吸子宫颈肿瘤的癌细胞而患上肺癌的首例病例。
其中一个23个月大的男孩咳嗽持续了两周之后, 家人将他送到医院，结果在他的双肺中发现了癌症。婴儿出生三个月后，他的母亲被诊断出患有宫颈癌。 另一个6岁男孩，因左侧胸痛去了医院，CT扫描显示他的左肺有6厘米的肿块。他的母亲患有子宫颈癌，在分娩时被认为是良性的。她两年死于宫颈癌。
第一个孩子的某些病变自发消退，第二个孩子的肿瘤块生长缓慢，这表明他们存在针对已传播肿瘤的同种免疫反应。Nivoulmab免疫检查点抑制剂治疗使第一个孩子的所有剩余肿瘤剧烈消退。这两个男孩仍然活着。
In very rare cases, newborns may contract cancer from their pregnant mother during delivery. According to a Japanese report, two boys, 23 months old and 6 years old, had lung cancer. It was found that their tumors had exact genetical match, via next-generation sequencing, to their mother’s cervical cancer at birth. Researchers believe that the transmission occurred as a result of aspiration of vaginal fluid contaminated by the tumor during birth.
The transmission of cancer from mother to her offspring is extremely rare, occurring in only one infant in every 500,000 mothers with cancer. The few cases previously observed usually involved cancer cells crossing the placenta into the developing fetus. Leukemia, lymphoma and melanoma are the most common cancers that spread this way in infants. It is said that this is the first cases in which newborns developed lung cancer by inhaling cancer cells from cervical cancer.
The 23-month-old boys sought medical attention due to a cough that lasted for two weeks. This led to the diagnosis of his lung cancer. Three months after the baby was born, his mother was diagnosed with cervical cancer. Another 6-year-old boy went to the hospital with chest pain. A CT scan showed a 6 cm mass in his left lung. His mother had cervical cancer, which was considered benign at the time of delivery. She died of cervical cancer two years after she gave birth to the boy. Certain lesions in the first child resolved spontaneously, and the tumor mass in the second child grew slowly, suggesting the existence of alloimmune response against the transmitted tumor. Immune checkpoint inhibitor therapy with nivolumab led to a strong regression of all remaining tumors in the first child. These two boys are still alive
参考文献 Reference Arakawa A et al. New Engl J Med 2021; 384: 42
FDA批准奥西替尼（osimertinib）作为具有EGFR突变的非小细胞肺癌的术后治疗 (1/9/2020)
FDA has approved osimertinib as adjuvant therapy for non-small cell lung cancer that harbors EGFR mutation
FDA批准奥西替尼用于非小细胞肺癌手术切除后表皮生长因子受体（EGFR）突变的患者。 在一项随机，双盲，安慰剂对照试验（ADAURA，NCT02511106）中, 参加的IB-IIIA期病人肿瘤已完全切除，接受或没有接受过辅助化疗。患者必须具有主要的非鳞状组织学特征，并且需要通过cobas®EGFR突变测试从肿瘤组织中预先鉴定出EGFR外显子19缺失或外显子21 L858R突变。总共682例患者, 在手术和标准辅助化疗恢复后被随机分为（1:1）接受口服奥西替尼80毫克每天一次，或安慰剂。 主要疗效结果指标是通过研究者评估的II-IIIA期病人的无病生存期。与安慰剂组19.6个月（16.6-24.5）相比，奥西替尼组患者未达到中位无病生存期（38.8-未达到）（HR 0.17 95％CI：0.12-0.23; p < 0.0001）。总体研究人群中的无病生存期是次要疗效指标。与安慰剂组的27.5个月（22-36）相比，奥西替尼组的患者未达到中位值（未达到-未达到）（HR 0.20 95％CI：0.15，0.27; p < 0.0001）。 对于早期非小细胞肺癌的辅助治疗，推荐的奥西替尼推荐剂量为每天口服80 毫克一次，直至疾病复发, 或出现不可接受的毒性, 或长达3年。
FDA has approved osimertinib for patients of non-small cell lung cancer with epidermal growth factor receptor (EGFR) mutations after surgical resection. In a randomized, double-blind, placebo-controlled trial (ADAURA, NCT02511106), the participants with stage IB-IIIA lung cancer had their tumors completely removed and they either received or did not receive adjuvant chemotherapy. The patient must have predominantly non-squamous histological characteristics. The EGFR exon 19 deletion or exon 21 L858R mutation must be pre-identified from the tumor tissue through the cobas® EGFR mutation test. A total of 682 patients were randomly assigned (1:1) to receive oral osimertinib 80 mg once a day or placebo after recovery from surgery and standard adjuvant chemotherapy. The major efficacy outcome measure was disease-free survival in patients with stage II-IIIA non-small cell lung cancer evaluated by the investigator. Compared with 19.6 months (16.6-24.5) in the placebo group, median disease-free survival in the osimertinib group was not reached (38.8-not reached) (HR 0.17 95% CI: 0.12-0.23; p <0.0001). Disease-free survival in the overall study population was a secondary efficacy outcome measure. Compared with 27.5 months (22-36) in the placebo group, median PFS in the osimertinib group was not reached (not reached-not reached) (HR 0.20 95% CI: 0.15, 0.27; p <0.0001). For the adjuvant treatment of early non-small cell lung cancer, the recommended dose of osimertinib is 80 mg orally once a day until disease recurrence, or unacceptable toxicity, or for up to 3 years.
参考文献 Reference Herbst RS et al. J Clin Oncol. 2020;38(suppl; abstr LBA5).
FDA批准首个口服激素药物治疗晚期前列腺癌(1/3/2020)
FDA approved first oral hormone drug for advanced prostate cancer
Relugolix是一种口服的促性腺激素释放激素受体拮抗剂，可通过阻止垂体产生黄体生成激素和促卵泡激素，从而减少睾丸能够制造的睾丸激素的量。 这是一项随机，开放标签，III期临床试验（HERO），对晚期前列腺癌男性评估了Relugolix的安全性和有效性。这些患者每天随机服用Relugolix一次，或每3个月注射一次leuprolide，持续48周。目的是确定从第29天直至治疗过程结束时，Relugolix是否达到并维持足够低的睾丸激素水平（去势水平）。接受Relugolix治疗的患者（n = 622）的去势率为96.7％，而接受leuprolide（n = 308）的患者为88.8％。
Relugolix最常见的副作用包括潮热，葡萄糖增加，甘油三酸酯增加，肌肉骨骼疼痛，血红蛋白减少，疲劳，便秘，腹泻和某些肝酶水平升高。禁忌将Relugolix与抑制P-糖蛋白（p-glycoprotein）的药物同时使用; P-糖蛋白在将毒素泵出细胞中发挥作用。剥夺雄激素的治疗, 包括Relugolix, 可能会影响心脏的电生理, 或引起电解质异常，因此，医生应考虑定期监测心电图和电解质。 根据动物中的发现和药物机制，当孕妇服用时，Relugolix可引起胎儿伤害和失去妊娠。建议有生殖潜能女伴的男性, 在治疗期间以及服用最后一剂Relugolix后2周内，使用有效的避孕方法。
Relugolix is an oral gonadotropin releasing hormone receptor antagonist that can reduce the amount of testosterone produced from the testicles by blocking the pituitary from producing luteinizing hormone and follicle-stimulating hormone. This is a randomized, open-label, phase III clinical trial (HERO) that evaluated the safety and efficacy of Relugolix in men with advanced prostate cancer. The patients were randomized to take Relugolix once a day or leuprolide injection every 3 months for 48 weeks. The goal is to determine whether Relugolix reaches and maintains a sufficiently low testosterone level (castrate levels) from day 29 until the end of the treatment course. The castration rate of patients who received Relugolix (n = 622) was 96.7%, while that of patients who received leuprolide (n = 308) was 88.8%.
The most common side effects of Relugolix include hot flashes, increased glucose, increased triglycerides, musculoskeletal pain, decreased hemoglobin levels, fatigue, constipation, diarrhea and elevated levels of certain liver enzymes. Concomitant use of Relugolix with drugs that inhibit p-glycoprotein is contraindicated; P-glycoprotein plays a role in pumping toxins out of the cell. Androgen deprivation treatments, including Relugolix, may affect the electrophysiology of the heart or cause electrolyte abnormalities. Therefore, doctors should consider regular monitoring of the ECG and electrolytes. According to findings in animals and drug mechanisms, it is possible that Relugolix can cause fetal harm and loss of pregnancy when taken by pregnant women. Men with female partners of reproductive potential are advised to use effective contraceptive methods during treatment and 2 weeks after taking the last dose of Relugolix.
参考文献 Reference https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-relugolix-advanced-prostate-cancer
降压药可以改善肿瘤免疫疗法结果吗？(1/2/2021)
Could certain anti-hypertensives improve outcomes in cancer immunotherapy?
根据一项近600名患者的观察性报道，用于治疗高血压的血管紧张素受体阻滞剂可能会改善用抗PD-1 /L1药物治疗肿瘤患者的预后。
一项回顾性研究评估了597例美国国立卫生研究院在临床试验中治疗的各种癌症类型的患者。所有患者均接受抗PD-1 /L1抗体（无论是否接受其他免疫疗法，例如抗细胞毒性T淋巴细胞相关蛋白4（CTLA-4）检查点抑制剂或靶向药物）。 其中有些病人还在基线时接受血管紧张素受体阻滞剂（n = 71）或ACE抑制剂（n = 83）, 或没有接受两种药物（n = 444）。研究者比较了他们的结局。
血管紧张素II不仅可以调节血压，还可以通过导致下游产生两种蛋白来影响癌症的生长：血管内皮生长因子（VEGF）和转化生长因子-β（TGF- β）；两者都与癌症的生长和肿瘤对免疫系统攻击的抵抗力有关。血管紧张素II通过与AT1受体结合而增加VEGF和TGF-β，但是当与AT2受体结合时却具有相反的作用，导致两种生长因子的减少。
在汇总的试验数据中，未接受血管紧张素受体阻滞剂或ACE抑制剂患者对抗PD-1 / L1抗体的响应率为17.0％，而接受血管紧张素受体阻滞剂的患者为33.8％（P = .001），接受ACE抑制剂治疗的患者为19.5％（P =.60）, 完全响应率分别为3.1％, 11.3％（P = .002）和3.7％（P = .81）。 在控制年龄，性别，体重指数，肿瘤类型和给予其他治疗的多元回归分析中，添加血管紧张素受体阻滞剂对于响应率（P = .039）和完全响应率（P = .002）仍然有显著差异。 血管紧张素受体阻滞剂还具有统计学意义的总体生存获益，将中位生存期从无ACE抑制剂或血管紧张素受体阻滞剂的18.8个月提高到35.2个月（P = .0078）。 ACE抑制剂的中位生存期为26.2个月, 无显著差异（P = .13）。 在回归分析中，对于血管紧张素受体阻滞剂，总体生存获益仍然很显著（P = .006），而对于ACE抑制剂则没有（P = .078）。在评估的单个肿瘤类型中，血管紧张素受体阻滞剂对膀胱癌的益处最明显。 其中未接受ACE抑制剂或血管紧张素受体阻滞剂的患者的响应率为77.8％，而未接受血管紧张素受体阻滞剂的患者的缓响应为30.2％（P = .019），完全响应率分别为55.6％和9.3％（P = .005）。 使用血管紧张素受体阻滞剂尚未达到中位总生存期，而未使用它们时则为14.2个月（P = 0.005）。
According to a retrospective report of nearly 600 patients, angiotensin receptor blockers used to treat hypertension may improve the prognosis of tumor patients treated with anti-PD-1/L1 inhibitors. A retrospective study evaluated 597 patients with various cancer types treated in clinical trials at the U.S. National Institutes of Health. All patients received anti-PD-1/L1 antibodies (regardless of whether they received other immunotherapy, such as anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) checkpoint inhibitors or targeted drugs). Some of these patients also received angiotensin receptor blockers (n = 71) or ACE inhibitors (n = 83) at baseline, or did not receive either drugs (n = 444). The researchers compared their outcomes.
Angiotensin II not only regulates blood pressure, but also affects the growth of cancer by causing the downstream production of two proteins: vascular endothelial growth factor (VEGF) and transforming growth factor-β (TGF-β); both have been linked to cancer growth and tumor resistance to immune system attack. Angiotensin II increases VEGF and TGF-β by binding to the AT1 receptor, but when it binds to the AT2 receptor, it has the opposite effect, resulting in a decrease in the two growth factors.
In pooled trial data, response rates of anti-PD-1/L1 antibodies in patients who did not receive angiotensin receptor blockers or ACE inhibitors were 17.0%, while that of patients who received angiotensin receptor blockers were 33.8 % (P = .001), and 19.5% in patients treated with ACE inhibitors (P =.60). Complete response rates were 3.1%, 11.3% (P = .002) and 3.7% (P = .81) respectively. In the multiple regression analysis controlling of age, gender, body mass index, tumor type and other treatments given, the addition of angiotensin receptor blockers was still significant in response rate (P = .039) and complete response rate (P = .002). Angiotensin receptor blockers also had a statistically significant overall survival benefit, increasing the median survival from 18.8 months without ACE inhibitors or angiotensin receptor blockers to 35.2 months (P = .0078). The median survival of ACE inhibitors was 26.2 months, with no significant difference (P = .13). In the regression analysis, the overall survival benefit was still significant for angiotensin receptor blockers (P = .006), but not for ACE inhibitors (P = .078). Among the individual tumor types evaluated, angiotensin receptor blockers had the most obvious benefits for bladder cancer, where the response rate of patients who received angiotensin receptor blockers was 77.8% vs 30.2% in those who did not receive ACE inhibitors or angiotensin receptor blockers (P = .019), The complete response rates were 55.6% vs. 9.3%, respectively (P = .005). The median overall survival has not been reached in patients received angiotensin receptor blockers, compared to 14.2 months without them (P = 0.005).
参考文献 Reference Strauss J. et al. 2020 EORTC-NCI-AACR Virtual Symposium. Abstr 7