2024

Trastuzumab Duocarmazine治疗HER 2 阳性晚期或转移性乳腺癌： III 期试验 (TULIP)  (12/22/2024)

Trastuzumab Duocarmazine inpPretreated HER 2+ advanced or metastatic breast cancer: A phase III trial

曲妥珠单抗二甲肼 (Trastuzumab Duocarmazine, T-Duo) 是一种第三代 HER2 靶向抗体-药物偶联物，在接受大量治疗的 HER2+/HER2-low 乳腺癌患者的 I 期研究中，已证明其疗效和可接受的安全性。

方法: 在这项开放标签, 随机, III 期试验中，在 ≥2 种 HER2 靶向治疗期间/之后或曲妥珠单抗 emtansine (T-DM1) 后出现进展的不可切除局部晚期/转移性 HER2+ 乳腺癌患者中，比较了 T-Duo 与医生选择方案。主要终点是无进展生存期。

结果: 总共有 437 名患者按 2:1 的比例随机分配到 T-Duo (n = 291) 或医生选择组 (n = 146)。中位年龄为 56.0 岁（范围为 24-86）；大多数患者 (93.6%) 患有转移性疾病。从诊断转移性疾病到进入试验的中位时间为 3.5 年；转移性环境中先前接受的 HER2 靶向治疗的中位数量为 3。 T-Duo 组的中位无进展生存期为 7.0 个月（95% CI，5.4 至 7.2），而医生选择组为 4.9 个月（95% CI，4.0 至 5.5；风险比 [HR]，0.64 [95% CI，0.49 至 0.84]；P = 0.002）。大多数预先定义的亚组均保持了无进展生存期获益。中位总生存期（首次分析）为 20.4 个月（T-Duo）相对于 16.3 个月（医生选择组；HR，0.83 [95% CI，0.62 至 1.09]；P = 0.153）。客观响应率为 27.8%（T-Duo）相对于29.5%（医生选择组）；其他疗效终点——临床获益率, 响应持续时间和靶病变测量减少量——倾向于支持 T-Duo。 ≥3 级治疗引起的不良事件发生率为 52.8% (T-Duo)，而医生选择组为 48.2%。

结论: T-Duo 治疗可控，但耐受性受到普遍的眼部毒性影响，导致 T-Duo 组的停药率更高。T-Duo 显著降低了在 ≥2 次 HER2 靶向治疗期间/之后或 T-DM1 后出现进展的晚期 HER2+ 乳腺癌患者的进展风险。

Trastuzumab Duocarmazine (T-Duo) is a third-generation HER2-targeted antibody-drug conjugate that has demonstrated efficacy and an acceptable safety profile in a phase I study of heavily pretreated patients with HER2+/HER2-low breast cancer.

Methods: In this open-label, randomized, phase III trial, T-Duo was compared with physician’s choice in patients with unresectable locally advanced/metastatic HER2+ breast cancer who had progressed during/after ≥2 HER2-targeted therapies or after trastuzumab emtansine (T-DM1). The primary endpoint was progression-free survival.

Results: A total of 437 patients were randomly assigned 2:1 to T-Duo (n = 291) or physician’s choice (n = 146). The median age was 56.0 years (range, 24-86); most patients (93.6%) had metastatic disease. The median time from diagnosis of metastatic disease to trial entry was 3.5 years; the median number of prior HER2-targeted therapies in the metastatic setting was 3. The median progression-free survival was 7.0 months in the T-Duo group (95% CI, 5.4 to 7.2) and 4.9 months in the physician’s choice group (95% CI, 4.0 to 5.5; hazard ratio [HR], 0.64 [95% CI, 0.49 to 0.84]; P = .002). The progression-free survival benefit was maintained across most predefined subgroups. Median overall survival (first analysis) was 20.4 months (T-Duo) vs. 16.3 months (physician’s choice; HR, 0.83 [95% CI, 0.62 to 1.09]; P = .153). Objective response rate was 27.8% (T-Duo) vs. 29.5% (physician’s choice); other efficacy endpoints—clinical benefit rate, duration of response, and target lesion measurement reduction—favored T-Duo. Grade ≥3 treatment-emergent adverse events occurred in 52.8% (T-Duo) vs. 48.2% in the physician’s choice group.

 Conclusions: T-Duo treatment was manageable, but tolerability was affected by widespread ocular toxicity, which resulted in a higher discontinuation rate in the T-Duo group. T-Duo significantly reduced the risk of progression in patients with advanced HER2+ breast cancer who had progressed during/after ≥2 prior HER2-targeted therapies or after T-DM1.

参考文献 Reference

Turner N et al. J Clin Onc 2024 ; https://doi.org/10.1200/JCO.24.005

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侵袭性甲状腺癌患者的双重免疫检查点抑制 (12/21/2024)

Dual immune checkpoint inhibition in aggressive thyroid cancer

侵袭性甲状腺癌，包括放射性碘难治性 (RAIR) 分化型甲状腺癌 (DTC)、髓样甲状腺癌 (MTC) 和未分化甲状腺癌 (ATC)，与高发病率和高死亡率相关，且治疗选择有限。

方法: 这是一项非随机的 II 期临床试验，涉及 49 名患者， 每 2 周静脉注射 3 mg/kg nivolumab 和每 6 周静脉注射 1 mg/kg ipilimumab，直至病情进展, 无法耐受的不良事件或最长持续时间为 2 年。 主要终点是放射性碘难治性分化型甲状腺癌的客观响应率。关键次要终点包括安全性, 无进展生存期、总生存期和生物标志物分析。

结果: 共登记 51 名患者，其中 49 名患者可进行分析评估。中位年龄（范围）为 65 岁（30-88 岁），25 名参与者（51%）为女性。分化型甲状腺癌队列的客观响应率为 9.4%（3/32 [95% CI，2.8%-28.5%]），嗜酸细胞癌（2/6 [33.0%]）或低分化甲状腺癌（1/5 [20.0%]）均出现部分缓解。整个分化型甲状腺癌队列的临床获益率为 62.5%（20/32），其中嗜酸细胞癌为 83.3%（5/6），低分化甲状腺癌为 40%（2/5）。探索性未分化甲状腺癌队列的客观响应率为 30.0% (3/10 [95% CI, 6.7%-65.2%])，临床受益率为 50.0% (5/10)。在探索性髓样甲状腺癌队列中未观察到任何反应。

安全性与之前关于双重免疫检查点抑制的报告相似（瘙痒, 皮疹, 腹泻, 疲劳以及脂肪酶和肝酶升高）。NRAS 肿瘤基因序列变异（而非 BRAF V600E）的存在与更差的结果相关。

结论和相关性: 这项 II 期非随机临床试验报告了双重免疫检查点抑制在侵袭性甲状腺癌中的临床活性。该研究在放射性碘难治性分化型甲状腺癌的主要人群中未达到终点，也不支持在非生物标志物选择的分化型甲状腺癌中进一步研究。然而，在未分化甲状腺癌中观察到的信号可能值得进一步评估。

Aggressive thyroid cancer, including radioiodine-refractory differentiated thyroid cancer, medullary thyroid cancer, and anaplastic thyroid cancer, is associated with high morbidity and mortality with limited treatment options.

Methods: This was a nonrandomized phase II clinical trial involving 49 patients who received 3 mg/kg nivolumab IV every 2 weeks and 1 mg/kg ipilimumab IV every 6 weeks until disease progression, intolerable adverse events, or a maximum duration of 2 years. The primary endpoint was objective response rate in radiation-refractory differentiated thyroid cancer. Key secondary endpoints included safety, progression-free survival, overall survival, and biomarker analysis.

Results: A total of 51 patients were enrolled, of whom 49 were evaluable for analysis. The median age (range) was 65 years (30-88 years), and 25 participants (51%) were female. The objective response rate in the differentiated thyroid cancer cohort was 9.4% (3/32 [95% CI, 2.8%-28.5%]), and partial responses were observed in either oncocytic (2/6 [33.0%]) or poorly differentiated thyroid cancer (1/5 [20.0%]). The clinical benefit rate was 62.5% (20/32) in the entire differentiated thyroid cancer cohort, including 83.3% (5/6) in oncocytic cancer and 40% (2/5) in poorly differentiated thyroid cancer. The objective response rate in the exploratory anaplastic thyroid cancer cohort was 30.0% (3/10 [95% CI, 6.7%-65.2%]), and the clinical benefit rate was 50.0% (5/10). No responses were observed in the exploratory medullary thyroid cancer cohort.

Safety was similar to previous reports of dual immune checkpoint inhibition (pruritus, rash, diarrhea, fatigue, and elevated lipase and liver enzymes). The presence of NRAS tumor gene sequence variants, but not BRAF V600E, was associated with worse outcomes.

Conclusions and relevance: This phase II nonrandomized clinical trial reported clinical activity of dual immune checkpoint inhibition in aggressive thyroid cancer. The study did not meet endpoints in the primary population of radioiodine-refractory differentiated thyroid cancer and does not support further study in nonbiomarker-selected differentiated thyroid cancer. However, the signals observed in anaplastic thyroid cancer may warrant further evaluation.

参考文献 Reference

Sehgal K et al. JAMA Onc 2024; 10:1663  

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阿霉素-Trabectedin 联合Trabectedin维持治疗平滑肌肉瘤 (12/15/2024)

Doxorubicin-Trabectedin with Trabectedin Maintenance in Leiomyosarcoma

方法: 这是一项III期临床试验（ NCT02997358），试验对象为之前未接受过化疗的转移性或不可切除的平滑肌肉瘤患者。患者被随机分配接受单药阿霉素（六个周期）或阿霉素加曲贝替定（Trabectedin, 六个周期）治疗，阿霉素-曲贝替定组未出现疾病进展的患者继续接受曲贝替定维持治疗。每组在六个周期治疗后均允许进行手术切除残留疾病。无进展生存期（主要终点）和总生存期（次要终点）的分析根据两个分层因素进行了调整：肿瘤起源部位（子宫 vs. 软组织）和疾病分期（局部晚期 vs. 转移性）。主要终点结果之前已报告。

结果: 共有 150 名患者接受随机分组。在 55 个月的中位随访期（四分位距，49 至 63）中，共有 107 名患者死亡（阿霉素 – 曲贝替定组 47 名，阿霉素组 60 名）。阿霉素 – 曲贝替定组的中位总生存期（33 个月；95% 置信区间 [CI]，26 至 48）长于阿霉素组（24 个月；95% CI，19 至 31）；调整后的死亡风险比为 0.65（95% CI，0.44 至 0.95）。与早期报告一致的发现是，阿霉素 – 曲贝替定组的无进展生存期（12 个月；95% CI，10 至 16）比阿霉素组（6 个月；95% CI，4 至 7）更长；调整后的进展或死亡风险比为 0.37（95% CI，0.26 至 0.53）。与单独使用阿霉素相比，阿霉素加曲贝替定的不良事件发生率和剂量减少的患者百分比更高。

结论: 对于转移性或无法手术切除的子宫或软组织平滑肌肉瘤患者，与单独使用阿霉素相比，阿霉素和曲贝替定诱导治疗联合治疗，随后使用曲贝替定维持治疗，可改善总体生存率和无进展生存率。

Methods: It was a phase III trial ( NCT02997358 ) in patients with metastatic or unresectable leiomyosarcoma who had not received prior chemotherapy. Patients were randomly assigned to receive either doxorubicin alone (for six cycles) or doxorubicin plus trabectedin (for six cycles), with maintenance trabectedin for patients who did not have disease progression in the doxorubicin-trabectedin group. Surgical resection of residual disease after six cycles was permitted in each group. Analyses of progression-free survival (primary end point) and overall survival (secondary end point) were adjusted for two stratification factors: tumor site of origin (uterine vs. soft tissue) and disease stage (locally advanced vs. metastatic). The results of the primary end point have been reported previously.

Results: A total of 150 patients underwent randomization. During a median follow-up of 55 months (interquartile range, 49 to 63), a total of 107 patients died (47 in the doxorubicin-trabectedin group and 60 in the doxorubicin group). Median overall survival was longer with doxorubicin-trabectedin (33 months; 95% confidence interval [CI], 26 to 48) than with doxorubicin (24 months; 95% CI, 19 to 31); the adjusted hazard ratio for death was 0.65 (95% CI, 0.44 to 0.95). Findings consistent with earlier reports were that progression-free survival was longer with doxorubicin-trabectedin (12 months; 95% CI, 10 to 16) than with doxorubicin (6 months; 95% CI, 4 to 7); the adjusted hazard ratio for progression or death was 0.37 (95% CI, 0.26 to 0.53). The incidence of adverse events and the percentage of patients who had dose reductions were higher with doxorubicin plus trabectedin than with doxorubicin alone.

Conclusions: For patients with metastatic or unresectable uterine or soft tissue leiomyosarcoma, combination therapy with doxorubicin and trabectedin induction therapy followed by maintenance therapy with trabectedin improved overall and progression-free survival compared with doxorubicin alone.

参考文献 Reference

Pautier P et al. N Engl J Med 2024; 191:789

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局限期小细胞肺癌放化疗后使用 Durvalumab  可有益于总生存期 (12/8/2024)

Durvalumab after chemoradiotherapy can improve overall survival in limited-stage small-cell lung cancer

方法: 在一项 3 期双盲随机安慰剂对照试验中（NCT03703297），在标准同步铂类放化疗后未出现疾病进展的局限期小细胞肺癌患者分配到1)接受剂量为 1500 mg 的 durvalumab, 2) 剂量为 1500 mg 的 durvalumab加剂量为 75 mg 的 tremelimumab（仅四剂）或3) 每 4 周一次的安慰剂治疗，最长 24 个月。根据疾病分期（I 或 II vs. III）和是否接受预防性颅脑照射, 对随机分组进行分层。数据截止日期为 2024 年 1 月 15 , 对两个主要终点（总生存期和无进展生存期）进行的第一次计划中期分析结果；durvalumab-tremelimumab 组的结果仍为盲法。

结果: 共有 264 名患者被分配到 durvalumab 组，200 名患者被分配到 durvalumab-tremelimumab 组，266 名患者被分配到安慰剂组。与安慰剂相比，Durvalumab 治疗显著延长总生存期（中位数为 55.9 个月 [95% 置信区间，37.3 至未达到] vs. 33.4 个月 [95% CI，25.5 至 39.9]；死亡风险比为 0.73；98.321% CI，0.54 至 0.98；P =0.01），无进展生存期也显著延长（中位数为 16.6 个月 [95% CI，10.2 至 28.2] vs. 9.2 个月 [95% CI，7.4 至 12.9]；进展或死亡风险比为 0.76；97.195% CI，0.59 至 0.98；P =0.02）。

接受度伐durvalumab治疗的患者中，最高级别为 3 级或 4 级的不良事件发生率为 24.4%，接受安慰剂治疗的患者中为 24.2%；不良事件导致 16.4% 和 10.6% 的患者停药，2.7% 和 1.9% 的患者死亡。durvalumab组 3.1% 的患者和安慰剂组 2.6% 的患者发生最高级别为 3 级或 4 级的肺炎或放射性肺炎。

结论: 与安慰剂相比，在局限期小细胞肺癌放化疗后，使用durvalumab辅助治疗可显著延长总生存期和无进展生存期。

Methods: In a phase 3, double-blind, randomized, placebo-controlled trial (NCT03703297), patients with limited-stage SCLC who had not progressed after standard concurrent platinum-based chemoradiotherapy were assigned to 1) durvalumab at a dose of 1500 mg, 2) durvalumab at a dose of 1500 mg plus tremelimumab at a dose of 75 mg (four doses only), or 3) placebo every 4 weeks for up to 24 months. Randomization was stratified by disease stage (I or II vs. III) and receipt of prophylactic cranial irradiation. Data cutoff was January 15, 2024. At the first planned interim analysis of the two primary endpoints (overall survival and progression-free survival), results for the durvalumab-tremelimumab group remained blinded.

Results: A total of 264 patients were assigned to the durvalumab group, 200 patients to the durvalumab-tremelimumab group, and 266 patients to the placebo group. Durvalumab treatment significantly prolonged overall survival (median, 55.9 months [95% confidence interval, 37.3 to not reached] vs. 33.4 months [95% CI, 25.5 to 39.9]; hazard ratio for death, 0.73; 98.321% CI, 0.54 to 0.98; P = .01) and progression-free survival (median, 16.6 months [95% CI, 10.2 to 28.2] vs. 9.2 months [95% CI, 7.4 to 12.9]; hazard ratio for progression or death, 0.76; 97.195% CI, 0.59 to 0.98; P = .02) compared with placebo.

Adverse events up to grade 3 or 4 occurred in 24.4% of patients receiving durvalumab and 24.2% of patients receiving placebo; adverse events led to discontinuation of treatment in 16.4% and 10.6% of patients and death in 2.7% and 1.9% of patients respectively. Pneumonitis up to grade 3 or 4 or radiation pneumonitis occurred in 3.1% of patients in the durvalumab group and 2.6% of patients in the placebo group.

Conclusion: Compared with placebo, adjuvant therapy with durvalumab after chemoradiotherapy for limited-stage small-cell lung cancer significantly prolonged overall survival and progression-free survival.

参考文献 Reference

Cheng Y et al. N Engl J Med 2024; 391:1313

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针对 HER2+ 不可切除或转移性胃或胃食管交界处腺癌的治疗有总生存期益处  KEYNOTE-811 (12/7/2024)

Overall survival benefit combination therapy for HER2+ unresectable or metastatic G/GEJ adenocarcinoma KEYNOT

方法: 年龄≥18 岁，患有未经治疗不可切除或转移性的 HER2+ 胃或胃食管交界处腺癌，无论 PD-L1 状态如何，均按 1:1 随机分配接受派姆单抗 200 mg 每3星期一次静脉注射或安慰剂 每3星期一次静脉注射加化疗（5-FU 和顺铂或卡培他滨和奥沙利铂 [CAPOX] 和曲妥珠单抗 [SOC]）。随机化按地区, PD-L1 状态和化疗选择分层。双重主要终点是无进展生存期和总生存期。最终分析的数据截止时间为 2024 年 3 月 20 日。

结果: 共随机分配了 698 名患者（350 名接受派姆单抗 + SOC；348 名接受安慰剂 + SOC）。中位随访时间为 50.2 个月。在所有患者中，使用派姆单抗 + SOC 的无进展生存期比使用安慰剂 + SOC 的无进展生存期更长（中位数 10.0 vs 8.1 个月；HR 0.73；95% CI，0.61-0.87）。对于 PD-L1 CPS ≥1 的患者，中位无进展生存期为 10.9 vs 7.3 个月（HR 0.72；95% CI，0.60-0.87）。最终分析显示，与安慰剂 + SOC 相比，派姆单抗 + SOC 的总生存期显著改善（中位数 20.0 vs 16.8 个月；HR 0.80；95% CI，0.67-0.94；p =0.0040。PD-L1 CPS ≥1 的患者中，中位总生存期为 20.1 vs 15.7 个月（HR 0.79；95% CI，0.66-0.95）。与安慰剂 + SOC 相比，派姆单抗 + SOC 的响应率 为 72.6% vs 60.1%。≥3 级药物相关不良反应发生率分别为 59% vs 51%。      

结论: 对于所有无法切除的 HER2+ 不可切除或转移性癌症患者，一线派姆单抗加曲妥珠单抗和化疗与派姆单抗加曲妥珠单抗和化疗相比，在总生存期方面具有统计学意义和临床意义的改善。

Methods: Patients aged ≥18 years with previously untreated unresectable or metastatic HER2+ gastric or gastroesophageal junction adenocarcinoma were randomized 1:1 to receive either pembrolizumab 200 mg IV every 3 weeks or placebo IV every 3 weeks plus chemotherapy (5-FU and cisplatin or capecitabine and oxaliplatin [CAPOX] and trastuzumab [SOC]), regardless of PD-L1 status. Randomization was stratified by region, PD-L1 status, and chemotherapy choice. Dual primary endpoints were progression-free survival and overall survival. Data cutoff for final analysis was March 20, 2024.

Results: A total of 698 patients were randomized (350 to pembrolizumab + SOC; 348 to placebo + SOC). The median follow-up was 50.2 months. Among all patients, progression-free survival was longer with pembrolizumab + SOC than with placebo + SOC (median 10.0 vs 8.1 months; HR 0.73; 95% CI, 0.61-0.87). For patients with PD-L1 CPS ≥1, median progression-free survival was 10.9 vs 7.3 months (HR 0.72; 95% CI, 0.60-0.87). The final analysis showed that overall survival was significantly improved with pembrolizumab + SOC compared with placebo + SOC (median 20.0 vs 16.8 months; HR 0.80; 95% CI, 0.67-0.94; p = 0.0040. In patients with PD-L1 CPS ≥1, median overall survival was 20.1 vs 15.7 months (HR 0.79; 95% CI, 0.66-0.95). The overall response rate with pembrolizumab + SOC was 72.6% vs 60.1% compared with placebo + SOC. The incidence of grade ≥3 drug-related adverse reactions was 59% vs 51%, respectively.

Conclusion: For all unresectable HER2+ patients with unresectable or metastatic cancer, first-line pembrolizumab plus trastuzumab and chemotherapy showed a statistically significant and clinically meaningful improvement in overall survival compared with pembrolizumab plus trastuzumab and chemotherapy.

参考文献 Reference

Janjjgjan YY et al. ESMO Ann Onc 2024; 35 (suppl_2): S877

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围手术期 Durvalumab 联合新辅助化疗治疗膀胱癌提高生存率 (12/1/2024)

Perioperative Durvalumab with neoadjuvant chemotherapy in bladder cancer improves survival

方法: 这是一项III期临床试验（NIAGARA NCT03732677），肌层浸润性膀胱癌患者 (适合接受顺铂治疗并计划接受根治性膀胱切除术) 以 1:1 的比例分配到以下组：每 3 周接受一次新辅助 durvalumab 加吉西他滨-顺铂治疗，共 4 个周期；然后行根治性膀胱切除术, 和每 4 周接受一次辅助 durvalumab 治疗，共 8 个周期（durvalumab 组）；或接受新辅助吉西他滨-顺铂治疗，然后单独接受根治性膀胱切除术（对照组）。无事件生存期是两个主要终点之一。总生存期是关键的次要终点。 

结果: 总共有 533 名患者被分配到 durvalumab 组，530 名患者被分配到对照组。Durvalumab 组 24 个月的估计无事件生存率为 67.8%（95% 置信区间 [CI]，63.6 至 71.7），对照组为 59.8%（95% CI，55.4 至 64.0）（进展, 复发, 未接受根治性膀胱切除术或因任何原因死亡的风险比为 0.68；95% CI，0.56 至 0.82；分层对数秩检验 P <0.001）。预计 24 个月总生存率在 durvalumab 组为 82.2%（95% CI，78.7 至 85.2），在对照组为 75.2%（95% CI，71.3 至 78.8）（死亡风险比为 0.75；95% CI，0.59 至 0.93；分层对数秩检验 P =0.01）。

Durvalumab 组 40.6% 的患者和对照组 40.9% 的患者发生了严重程度为 3 级或 4 级的治疗相关不良事件；两组各有 0.6% 的患者发生了导致死亡的治疗相关不良事件。Durvalumab 组 88.0% 的患者和对照组 83.2% 的患者接受了根治性膀胱切除术。

结论: 与单纯的新辅助化疗相比，围手术期durvalumab联合新辅助化疗可显著改善无事件生存率和总生存率。

Methods: In this phase III clinical trial (NIAGARA NCT03732677), patients with muscle-invasive bladder cancer were assigned in a 1:1 ratio to receive neoadjuvant durvalumab plus gemcitabine-cisplatin every 3 weeks for 4 cycles followed by radical cystectomy and adjuvant durvalumab every 4 weeks for 8 cycles (durvalumab group); or neoadjuvant gemcitabine-cisplatin followed by radical cystectomy alone (control group). Event-free survival was one of the two primary endpoints. Overall survival was a key secondary endpoint.

Results: A total of 533 patients were assigned to the durvalumab group and 530 to the control group. The estimated event-free survival rate at 24 months was 67.8% (95% confidence interval [CI], 63.6 to 71.7) in the durvalumab group and 59.8% (95% CI, 55.4 to 64.0) in the control group (hazard ratio for progression, recurrence, failure to undergo radical cystectomy, or death from any cause, 0.68; 95% CI, 0.56 to 0.82; P < .001 by stratified log-rank test). The estimated 24-month overall survival rate was 82.2% (95% CI, 78.7 to 85.2) in the durvalumab group and 75.2% (95% CI, 71.3 to 78.8) in the control group (hazard ratio for death, 0.75; 95% CI, 0.59 to 0.93; P = .01 by stratified log-rank test).

Treatment-related adverse events of grade 3 or 4 occurred in 40.6% of patients in the durvalumab group and 40.9% of patients in the control group; 0.6% of patients in each group had treatment-related adverse events leading to death. Radical cystectomy was performed in 88.0% of patients in the durvalumab group and 83.2% of patients in the control group.

Conclusion: Perioperative durvalumab combined with neoadjuvant chemotherapy significantly improved event-free survival and overall survival compared with neoadjuvant chemotherapy alone.

参考文献 Reference

Powles T et al. N Engl J Med 2024; 391:1773

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Nivolumab用于高风险肌层浸润性尿路上皮癌的辅助治疗：CheckMate 274 (11/30/2024)

Adjuvant nivolumab in high-risk muscle-invasive urothelial carcinoma: CheckMate 274

CheckMate 274 (NCT02632409)是一项 III 期随机双盲试验，比较辅助治疗 Nivolumab 与安慰剂对根治性切除后复发风险高的肌层浸润性尿路上皮癌的疗效。符合条件的患者要么之前接受过新辅助顺铂化疗（ypT2-ypT4a 或 ypN+），要么未接受过新辅助顺铂化疗且不符合或拒绝接受辅助顺铂化疗（pT3-pT4a 或 pN+），在过去 120 天内接受过根治性切除术。研究者报告了意向治疗人群中 36.1 个月的延长中位随访结果; 还首次报告了膀胱原发性肿瘤（肌层浸润性膀胱癌)患者的中期总生存期数据和探索性分析。

在意向治疗人群（风险比 [HR]，0.71 [95% CI，0.58 至 0.86]）和 PD-L1 ≥1%（HR，0.52 [95% CI，0.37 至 0.72]）患者中，均观察到 nivolumab 与安慰剂相比具有一致的无进展生存期获益。在意向治疗人群中，nivolumab 与安慰剂相比的总生存期 HR 为 0.76（95% CI，0.61 至 0.96），在 PD-L1 ≥1 人群中为 0.56（95% CI，0.36 至 0.86）。在两组患者中，非尿路上皮癌无复发生存率和无远处转移生存率均持续获益。对肌层浸润性膀胱癌患者的探索性分析也显示，无论 PD-L1 状态如何，疗效均持续获益。未报告新的安全信号。

总体而言，这些结果进一步支持辅助 nivolumab 作为根治性切除术后高风险肌层浸润性尿路上皮癌的标准治疗。

CheckMate 274 (NCT02632409) is a phase III, randomized, double-blind trial comparing adjuvant nivolumab versus placebo for muscle-invasive urothelial carcinoma at high risk of recurrence after radical resection. Eligible patients either had previously received neoadjuvant cisplatin chemotherapy (ypT2-ypT4a or ypN+) or had not received neoadjuvant cisplatin chemotherapy and were ineligible for or refused adjuvant cisplatin chemotherapy (pT3-pT4a or pN+) and had undergone radical resection within the past 120 days.

Investigators reported results with an extended median follow-up of 36.1 months in the intention-to-treat population; interim overall survival data and exploratory analyses were also reported for the first time for patients with bladder primary tumors (muscle-invasive bladder cancer).

A consistent progression-free survival benefit with nivolumab versus placebo was observed in both the intention-to-treat population (hazard ratio [HR], 0.71 [95% CI, 0.58 to 0.86]) and in patients with PD-L1 ≥1% (HR, 0.52 [95% CI, 0.37 to 0.72]). The HR for overall survival with nivolumab versus placebo was 0.76 (95% CI, 0.61 to 0.96) in the intention-to-treat population and 0.56 (95% CI, 0.36 to 0.86) in the PD-L1 ≥1 population. The benefit in non-urothelial cancer recurrence-free survival and distant metastasis-free survival was sustained in both groups. An exploratory analysis of patients with muscle-invasive bladder cancer also showed a sustained benefit regardless of PD-L1 status. No new safety signals were reported.

Overall, these results further support adjuvant nivolumab as standard of care for high-risk muscle-invasive urothelial carcinoma after curative resection.

参考文献 Reference

Galsky MD et al. J Clin Onc 2024; Oct 11. https://doi.org/10.1200/JCO.24.00

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KEYNOTE-522显示新辅助帕博利珠单抗加化疗延长高风险早期三阴性乳腺癌的总体生存 (11/24/2024)

KEYNOTE-522 shows neoadjuvant pembrolizumab plus chemotherapy prolongs overall survival in high-risk early-stage triple-negative breast cancer

方法: 符合条件的未经治疗, 无转移, 集中确认的三阴性乳腺癌 (T1c N1-2 期或 T2-4 N0-2 期) 患者按 2:1 的比例随机分配接受新辅助治疗派姆单抗 200 mg 每3星期或安慰剂，均给予 4 个周期的紫杉醇 + 卡铂，然后 4 个周期的阿霉素或表柔比星 + 环磷酰胺。手术后，患者接受 9 个周期的辅助治疗派姆单抗或安慰剂，或直至复发或出现不可接受的毒性。双重主要终点是病理性完全响应率和无事件生存率。总生存期是关键的次要终点。  

结果: 1,174 名患者随机接受派姆单抗 (n=784) 或安慰剂 (n=390)。在预先指定的数据截止时间 (2024 年 3 月 22 日)，中位随访期 (范围) 为 75.1 个月 (65.9-84.0)。派姆单抗组有 115 名患者 (14.7%) 死亡，安慰剂组有 85 名患者 (21.8%) 死亡；HR 为 0.66 (95% CI, 0.50-0.87; P=0.0015)，符合预先指定的显着性边界 0.00503。 5 年总生存率 (95% CI) 分别为 86.6% (84.0-88.8) vs 81.7% (77.5-85.2)。派姆单抗对总生存期的获益在预先指定的亚组中大致一致，包括通过 PD-L1 表达和淋巴结状态定义的亚组。派姆单抗组 5 年无事件生存率 (95% CI) 为 81.2% (78.3-83.8) vs 安慰剂组 72.2% (67.4-76.4) (HR 0.65 [95% CI, 0.51-0.83])。

派姆单抗组 ≥3 级治疗相关副作用发生率分别为 77.1% 和 73.3%（死亡率分别为 0.5% vs 0.3%）；任何等级的免疫介导不良事件发生率分别为 35.0% 和 13.1%。   

结论: 与单独进行新辅助化疗相比，在高风险早期三阴性乳腺癌患者中，新辅助派姆单抗 + 化疗后进行辅助派姆单抗治疗可显著改善总生存期，且具有临床意义。

Methods: Eligible patients with untreated, nonmetastatic, centrally confirmed triple-negative breast cancer (T1c N1-2 or T2-4 N0-2) were randomized 2:1 to receive neoadjuvant pembrolizumab 200 mg every 3 weeks or placebo, both given for 4 cycles of paclitaxel + carboplatin, followed by 4 cycles of doxorubicin or epirubicin + cyclophosphamide. After surgery, patients received 9 cycles of adjuvant pembrolizumab or placebo or until relapse or unacceptable toxicity. Dual primary endpoints were pathological complete response rate and event-free survival. Overall survival was a key secondary endpoint.

Results: 1,174 patients were randomized to receive pembrolizumab (n=784) or placebo (n=390). At the prespecified data cutoff (March 22, 2024), the median follow-up (range) was 75.1 months (65.9-84.0). Deaths had occurred in 115 patients (14.7%) in the pembrolizumab group and 85 patients (21.8%) in the placebo group; the HR was 0.66 (95% CI, 0.50-0.87; P=0.0015), meeting the prespecified significance margin of 0.00503. The 5-year overall survival rates (95% CI) were 86.6% (84.0-88.8) vs 81.7% (77.5-85.2), respectively. The benefit of pembrolizumab on overall survival was generally consistent across prespecified subgroups, including those defined by PD-L1 expression and lymph node status. The 5-year event-free survival rate (95% CI) was 81.2% (78.3-83.8) in the pembrolizumab group vs 72.2% (67.4-76.4) in the placebo group (HR 0.65 [95% CI, 0.51-0.83]).

The incidence of grade ≥3 treatment-related adverse events was 77.1% and 73.3% in the pembrolizumab group (mortality was 0.5% vs 0.3%, respectively); the incidence of any grade immune-mediated adverse events was 35.0% and 13.1%, respectively.

Conclusions: Neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab significantly improved overall survival compared with neoadjuvant chemotherapy alone in patients with high-risk early-stage triple-negative breast cancer, and this was clinically meaningful.

参考文献 Reference

Schmid P et al. Annals of Oncology 2024; 35 (suppl_2): 1-72

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FDA 加速批准 zanidatamab用于治疗不可切除或转移性 HER2 阳性胆道癌 (11/23/2024)

FDA grants accelerated approval to zanidatamab for unresectable or metastatic HER2+ biliary tract cancer

Zanidatamab-hrii (Ziihera.) 是一种双特异性 HER2 靶向抗体。2024 年 11 月 20 日，FDA加速批准它用于治疗之前接受过治疗的不可切除或转移性 HER2 阳性 (IHC 3+) 胆道癌，FDA 还批准了 VENTANA PATHWAY 抗 HER-2/neu (4B5) 兔单克隆原发抗体作为辅助诊断设备，以帮助识别可能适合使用 Ziihera 治疗的胆道癌患者。

 Zanidatamab的疗效和安全性经过一项开放标签多中心单组试验 (HERIZON-BTC-01, NCT04466891) ，试验对象为 62 名患有不可切除或转移性 HER2 阳性 的胆道癌患者。患者必须在晚期疾病环境中接受过至少一种含吉西他滨的治疗方案。 主要疗效结果指标是客观响应率和响应持续时间。客观响应率为 52% (95% CI: 39, 65)，中位响应持续时间为 14.9 个月 (95% CI: 7.4，无法估计)。

处方信息包含胚胎-胎儿毒性的黑框警告。至少 20% 接受 zanidatamab-hrii 治疗的患者报告的最常见不良反应是腹泻, 输液相关反应, 腹痛和疲劳。

Zanidatamab-hrii 的推荐剂量为 20 mg/kg，每 2 周静脉输注一次，直至病情进展或出现不可接受的毒性。

Zanidatamab-hrii (Ziihera.) is a bispecific HER2-targeted antibody. On November 20, 2024, the FDA granted accelerated approval for the treatment of previously treated unresectable or metastatic HER2-positive (IHC 3+) biliary tract cancer, and the FDA also approved VENTANA PATHWAY anti-HER-2/neu (4B5) rabbit monoclonal primary antibody as a companion diagnostic device to help identify patients with biliary tract cancer who may be suitable for treatment with Ziihera.

The efficacy and safety of zanidatamab were evaluated in an open-label, multicenter, single-arm trial (HERIZON-BTC-01, NCT04466891) in 62 patients with unresectable or metastatic HER2-positive biliary tract cancer. Patients must have received at least one prior gemcitabine-containing regimen in the advanced disease setting. The primary efficacy outcome measures were objective response rate and duration of response. The objective response rate was 52% (95% CI: 39, 65), and the median duration of response was 14.9 months (95% CI: 7.4, not estimable).

The prescribing information contains a boxed warning for embryo-fetal toxicity. The most common adverse reactions reported in at least 20% of patients treated with zanidatamab-hrii were diarrhea, infusion-related reactions, abdominal pain, and fatigue. The recommended dose of zanidatamab-hrii is 20 mg/kg, administered intravenously every 2 weeks until disease progression or unacceptable toxicity.

参考文献 Reference

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-zanidatamab-hrii-previously-treated-unresectable-or-metastatic-her2

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派姆單抗合併化療治療小細胞/神經內分泌膀胱癌和前列腺癌 (11/17/2024)

Pembrolizumab plus chemotherapy in small cell/neuroendocrine bladder and prostate cancers

小细胞神经内分泌癌在不同组织类型之间具有生物学相似性，包括对铂类化疗的短暂反应和疾病的快速进展。 这是一项Ib期临床试验（NCT03582475），在15 名III-IV 期小细胞膀胱癌（队列1）或小细胞/神经内分泌前列腺癌（队列2）患者中进行了派姆单抗联合铂类化疗的研究。整体响应率为43%，队列1两年总体存活率为86%（95% 信赖区间 [CI]：0.63, 1.00），队列2 为57%（95% CI：0.30,  1.00）。治疗耐受性良好，40% 的患者发生 3 级或更高级别的不良事件，但无死亡或因毒性而停止治疗。对连续周边血液样本的单细胞和 T 细胞受体定序揭示了与无进展生存相关的多种 T 细胞库的克隆扩增。

结果证明了这种治疗组合的良好疗效和安全性，并支持对该生物标记的未来研究。

Small cell neuroendocrine cancers have biological similarities across tissue types, including transient responses to platinum-based chemotherapy and rapid disease progression. This phase Ib clinical trial (NCT03582475) investigated pembrolizumab in combination with platinum-based chemotherapy in 15 patients with stage III-IV small cell bladder cancer (cohort 1) or small cell/neuroendocrine prostate cancer (cohort 2). The overall response rate was 43%. The two-year overall survival rate was 86% (95% confidence interval [CI]: 0.63, 1.00) in cohort 1 and 57% (95% CI: 0.30, 1.00) in cohort 2. Treatment was well tolerated, with 40% of patients experiencing grade 3 or higher adverse events, but no deaths or discontinuations due to toxicity. Single cell and T cell receptor sequencing of serial peripheral blood samples revealed clonal expansion of multiple T cell repertoires that were associated with progression-free survival.

The results demonstrate promising efficacy and safety of this treatment combination and support future investigation of this biomarker.

参考文献 Reference

Gu Y et al. Cell Reports Medicine 2024; Nov 12

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Retifanlimab 联合化疗可延长肛门鳞状细胞癌患者的无进展生存期 (11/16/2024)

Retifanlimab plus chemotherapy extends progression-free survival in patients with anal squamous cell carcinoma

 Retifanlimab 是一种针对 PD-1 的人源化单克隆抗体。 在 III 期 POD1UM-303/InterAACT2 试验中，无法手术的局部复发或转移性肛门鳞状细胞癌成年患者, 之前未接受过全身化疗，以1:1随机分配，每28 天周期接受 500 毫克静脉注射 retifanlimab 或安慰剂联合卡铂-紫杉醇治疗，最长 6 个月，随后单药治疗最长 1 年。病情进展后，允许接受安慰剂治疗的患者交叉接受 retifanlimab。 试验的主要终点是无进展生存期，次要终点包括总体生存期。次要目标包括客观响应率，响应持续时间，疾病控制率，安全性和药代动力学。

结果: 研究发现，在标准化疗中添加 retifanlimab 可使癌症进展或死亡风险在临床上显著降低 37%（风险比 [HR] = 0.63，95% 置信区间 [CI] = 0.47–0.84，P = .0006）。retifanlimab 联合化疗组患者的中位无进展生存期为 9.3 个月，而安慰剂联合化疗组患者的中位无进展生存期为 7.4 个月。 在中期分析中，与接受安慰剂联合化疗的患者相比，接受 retifanlimab 联合化疗的患者中位总生存期延长了约 6 个月（29.2 个月 vs 23.0 个月）。（HR = 0.70，95% CI = 0.49–1.01，P = .0273）。总生存期随访仍在进行中。 与安慰剂联合化疗组相比，接受 retifanlimab 联合化疗组患者的总体响应（56% vs 44%，95% CI = 48%–64% vs 36%–52%）和响应持续时间（14 个月 vs 7 个月，95% CI = 8.6–22.2 vs 5.6–9.3）均有所改善。 Retifanlimab 总体耐受性良好，安全性与其他化疗加检查点抑制剂方案一致。Retifanlimab 和化疗联合治疗组中最常见的治疗中出现的不良事件是贫血 (66.2%)、恶心 (56.5%) 和脱发 (51.3%)。

 结论 : 结果表明新研究达到了其主要终点，在未接受过系统治疗的患者中实现了统计学上显著具有临床意义的无进展生存期改善。

Retifanlimab is a humanized monoclonal antibody directed against PD-1. In the phase III POD1UM-303/InterAACT2 trial, adult patients with inoperable locally recurrent or metastatic anal squamous cell carcinoma who had not previously received systemic chemotherapy were randomized 1:1 to receive 500 mg Retifanlimab intravenously every 28 days or placebo plus carboplatin-paclitaxel for up to 6 months, followed by monotherapy for up to 1 year. After disease progression, patients receiving placebo were allowed to cross over to retifanlimab. The primary endpoint of the trial was progression-free survival, and secondary endpoints include overall survival, objective response rate, duration of response, disease control rate, safety and pharmacokinetics.

Resukts: The study found that adding retifanlimab to standard chemotherapy resulted in a clinically significant 37% reduction in the risk of cancer progression or death (hazard ratio [HR] = 0.63, 95% confidence interval [CI] = 0.47–0.84, P = .0006) . The median progression-free survival for patients in the retifanlimab plus chemotherapy group was 9.3 months, compared with 7.4 months for those in the placebo plus chemotherapy group. At an interim analysis, median overall survival was prolonged by approximately 6 months in patients who received retifanlimab plus chemotherapy compared with those who received placebo plus chemotherapy (29.2 months vs 23.0 months). (HR = 0.70, 95% CI = 0.49–1.01, P = .0273). Overall survival follow-up is ongoing. Overall response (56% vs 44%, 95% CI = 48%–64% vs 36%–52%) and duration of response (14 months vs 7 months, 95% CI = 8.6–22.2 vs 5.6–9.3).

Retifanlimab was generally well tolerated, with a safety profile consistent with other chemotherapy plus checkpoint inhibitor regimens. The most common treatment-emergent adverse events in the retifanlimab and chemotherapy combination group were anemia (66.2%), nausea (56.5%), and alopecia (51.3%).

Conclusion: The results show that the new study met its primary endpoint, achieving a statistically significant and clinically meaningful improvement in progression-free survival in patients who had not received prior systemic therapy.

参考文献 Reference

Rao S et Al. 2024 ESMO Symp Abstr LBA2

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新辅助免疫检查点抑制剂治疗肝细胞癌 (11/10/2024)

Neoadjuvant immune checkpoint inhibitors (ICI) treating hepatocellular carcinoma

方法: 在这项跨试验, 患者水平分析中，研究者对肝切除术前接受 ICI 治疗的肝细胞癌患者的数据进行了汇总分析，这是全球合作联盟 (NeoHCC) 的一部分，该联盟在美国、英国和台湾的 12 个三级转诊中心开展了五项 I 期和 II 期临床试验和标准化观察方案。符合条件的患者为成人（年龄≥18岁），在开始治疗前通过组织芯活检诊断为肝细胞癌，肝脏影像报告和数据系统评分为5分，或两者兼有，无肝外扩散或既往接受过ICI治疗。病理响应以切除的手术标本中非存活肿瘤的百分比来衡量，主要病理响应对应于至少70%的肿瘤消退，病理完全响应对应于100%的肿瘤消退。将病理响应与放射学总体反应相关联，并评估了与无复发生存期最佳关联的肿瘤消退阈值。  

结果: 截至2024年1月31日数据截止，111名患者被纳入研究，其中104名（94%）患者的病理响应数据可用。患者从 2017 年 10 月 5 日至 2023 年 11 月 15 日接受治疗，主要采用 ICI 联合治疗 (76 [69%])，中位治疗时间为 1.4 个月（IQR 0.7–2.9）。87 名（78%）患者为男性，24 名（22%）为女性。大多数患者患有潜在的病毒性慢性肝病 (73 [66%]) 和巴塞罗那诊所肝癌 A 期肝细胞癌 (61 [55%])，无门静脉血栓形成 (87 [78%])。 33 名 (32%) 患者出现主要病理响应，19 名 (18%) 患者出现病理完全响应。放射学总体响应与主要病理响应相关，

总共 31 名有放射学响应的患者中 23 名 (74%) 出现主要病理响应，而 10/73(14%)名无放射学响应，33 个主要病理响应中有 10 个（30%）不是放射学反应所预测的。经过中位随访期 27.2 个月（95% CI 22.3–32.1），整个队列的中位无复发生存期为 43.6 个月（95% CI 28.3–无法评估）。有显著病理响应的患者的无复发生存期明显长于无显著病理响应的患者（未达到 [95% CI 不可评估 – 不可评估] vs 28.3 个月 [12.8–43.8]；风险比 0.26 [0.10–0.66]；p =0.0024），有病理完全响应的患者的无复发生存期明显长于无病理完全响应的患者（NR [95% CI 不可评估 – 不可评估] vs 32.8 个月 [15.0–50.5]；0.19 [0.05–0.78]；p =0.010）。对复发、死亡或两者兼有风险的队列进行无偏递归划分，确定了 90% 的阈值作为病理肿瘤消退的最佳截止值，以预测无复发生存率的提高。   

解释: 新辅助 ICI 治疗后的肿瘤消退程度可以识别肝切除术后无复发生存率提高的患者。应在 3 期随机对照试验中验证至少 90% 的肿瘤消退阈值对无复发生存率的替代作用。

Methods: In this cross-trial, patient-level analysis, the researchers pooled data from patients with HCC who received ICI therapy before liver resection as part of a global collaborative consortium (NeoHCC) that included five phase I and II clinical trials and standardized observational protocols at 12 tertiary referral centers in the United States, United Kingdom, and Taiwan. Eligible patients were adults with a diagnosis of HCC by core biopsy before starting treatment, a Liver Imaging Reporting and Data System score of 5, or both, without extrahepatic spread or prior ICI therapy. Pathological response was measured as the percentage of nonviable tumor in the resected surgical specimen, with major pathological response corresponding to at least 70% tumor regression and pathological complete response corresponding to 100% tumor regression. Pathological response was correlated with radiographic overall response, and the threshold of tumor regression that best correlated with recurrence-free survival was assessed.

Results: As of data cutoff on January 31, 2024, 111 patients were enrolled in the study, of whom pathological response data were available for 104 (94%) patients. Patients were treated from October 5, 2017, to November 15, 2023, mainly with ICI combination therapy (76 [69%]), with a median treatment duration of 1 4 months (IQR 0 7–2 9). Eighty-seven (78%) patients were male and 24 (22%) were female. Most patients had underlying viral chronic liver disease (73 [66%]) and Barcelona Clinic Liver Cancer stage A hepatocellular carcinoma (61 [55%]), without portal vein thrombosis (87 [78%]).

Thirty-three (32%) patients had a major pathological response, and 19 (18%) had a pathological complete response. Radiographic overall response correlated with major pathological response, with 23 of 31 patients (74%) having a major pathological response, while 10 of 73 (14%) had no radiographic response, and 10 of 33 major pathological responses (30%) were not predicted by radiographic response. After a median follow-up of 27.2 months (95% CI 22.3–32.1), the median recurrence-free survival for the entire cohort was 43.6 months (95% CI 28.3–not evaluable). Patients with a major pathological response had significantly longer recurrence-free survival than those without a major pathological response (not reached [95% CI not evaluable – not evaluable] vs 28.3 months [12.8–43.8]; hazard ratio 0.26 [0.10–0.66]; p = 0.0024), and patients with a pathological complete response had significantly longer recurrence-free survival than those without a pathological complete response (NR [95% CI not evaluable – not evaluable] vs 32.8 months [15.0–50.5]; 0.19 [0.05–0.78]; p = 0.010). Unbiased recursive partitioning of the cohort into those at risk for recurrence, death, or both identified a threshold of 90% as the optimal cutoff for pathological tumor regression to predict improved recurrence-free survival.

Interpretation: The extent of tumor regression after neoadjuvant ICI therapy can identify patients with improved recurrence-free survival after hepatectomy. The surrogate effect of a tumor regression threshold of at least 90% on recurrence-free survival should be validated in phase 3 randomized controlled trials.

参考文献 Reference

D’Alessio A et al. Lancet Onc 2024; 25:1465

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Nivolumab+AVD 治疗晚期经典霍奇金淋巴瘤 (11/9/2024)

Nivolumab plus AVD in advanced-stage classic Hodgkin’s lymphoma

背景: 将 brentuximab vedotin 纳入晚期经典霍奇金淋巴瘤的治疗可改善预后。然而，brentuximab vedotin 会增加治疗毒性作用，复发仍然是一个挑战。程序性死亡 1 阻断对霍奇金淋巴瘤有效，包括对未接受过治疗的患者。

方法: 这是一项III期多中心, 开放标签, 随机临床试验（NCT03907488），试验对象为至少 12 岁,新诊断为 III 期或 IV 期霍奇金淋巴瘤的患者。患者被随机分配接受 brentuximab vedotin 与阿霉素, 长春花碱和达卡巴嗪 (BV+AVD) 或 nivolumab 与阿霉素, 春花碱和达卡巴嗪 (N+AVD) 治疗。预先指定的患者可以接受针对残留代谢活性病变的放射治疗。主要终点是无进展生存期，定义为从随机分组到首次观察到疾病进展或因任何原因死亡的时间。 

结果: 在接受随机分组的 994 名患者中，970 名被纳入意向治疗人群。在第二次计划中期分析中，中位随访时间为 12.1 个月，疗效阈值已超过，表明与 BV+AVD 相比，N+AVD 显著改善了无进展生存期（疾病进展或死亡的风险比为 0.48；99% 置信区间 [CI]，0.27 至 0.87；双侧 P =0.001）。对更长时间的随访分析, 中位随访时间 2.1 年（范围为 0 至 4.2 年），N+AVD 的 2 年无进展生存率为 92%（95% CI，89 至 94），而 BV+AVD 的 2 年无进展生存率为 83%（95% CI，79 至 86）（疾病进展或死亡的风险比为 0.45；95% CI，0.30 至 0.65）。总体而言，7 名患者接受了放射治疗。nivolumab 很少发生免疫相关不良事件；brentuximab vedotin 与更多治疗中断相关。

结论: 对于患有 III 期或 IV 期晚期经典霍奇金淋巴瘤的青少年和成人，N+AVD 比 BV+AVD 可延长无进展生存期，且副作用更少。

Background: Incorporation of brentuximab vedotin into the treatment of advanced classical Hodgkin lymphoma has improved outcomes. However, brentuximab vedotin is associated with increased toxicity, and relapse remains a challenge. Programmed death 1 blockade is effective in Hodgkin lymphoma, including in treatment-naïve patients.

Methods: This was a phase III multicenter, open-label, randomized clinical trial (NCT03907488) in patients at least 12 years of age with newly diagnosed stage III or IV Hodgkin lymphoma. Patients were randomly assigned to receive brentuximab vedotin with doxorubicin, vinblastine, and dacarbazine (BV+AVD) or nivolumab with doxorubicin, vinblastine, and dacarbazine (N+AVD). Prespecified patients could receive radiation therapy to target residual metabolically active lesions. The primary endpoint was progression-free survival, defined as the time from randomization to the first observation of disease progression or death from any cause.

Results: Of the 994 patients who underwent randomization, 970 were included in the intention-to-treat population. At the second planned interim analysis, with a median follow-up of 12.1 months, the efficacy threshold was crossed, showing that N+AVD significantly improved progression-free survival as compared with BV+AVD (hazard ratio for disease progression or death, 0.48; 99% confidence interval [CI], 0.27 to 0.87; two-sided P = .001). At longer follow-up, with a median follow-up of 2.1 years (range, 0 to 4.2 years), the 2-year progression-free survival rate was 92% (95% CI, 89 to 94) with N+AVD and 83% (95% CI, 79 to 86) with BV+AVD (hazard ratio for disease progression or death, 0.45; 95% CI, 0.30 to 0.65). Overall, 7 patients received radiation therapy. Immune-related adverse events were rare with nivolumab; brentuximab vedotin was associated with more treatment discontinuations.

Conclusions: For adolescents and adults with advanced stage III or IV classical Hodgkin lymphoma, N+AVD prolonged progression-free survival with fewer side effects than BV+AVD.

参考文献 Reference

Herrera AF et al. N Engl J Med 2024；391：1379

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帕博利珠单抗或安慰剂联合放化疗治疗新诊断的高风险局部晚期宫颈癌 (11/3/2024)

Pembrolizumab or placebo with chemoradiotherapy for newly diagnosed, high-risk, locally advanced cervical cancer

方法: 这是一项III期临床试验（ENGOT-cx11/GOG-3047/KEYNOTE-A18, NCT04221945），符合条件的新诊断, 高风险（FIGO 2014 IB2-IIB 期淋巴结阳性疾病或 III-IVA 期，无论淋巴结状态如何）, 局部晚期鳞状细胞癌, 腺癌或腺鳞状宫颈癌患者按 1:1 随机分配接受 5 个周期的派姆单抗（200 毫克）或安慰剂治疗，每 3 周一次，同时进行放化疗，然后接受 15 个周期的派姆单抗（400 毫克）或安慰剂治疗，每 6 周一次。主要终点是无进展生存期，以及总生存期，定义为从随机分组到因任何原因死亡的时间。安全性是次要终点。

结果: 2020 年 6 月 9 日至 2022 年 12 月 15 日期间，来自亚洲、澳大利亚、欧洲、北美和南美 30 个国家/地区的 176 个地点的 1,060 名患者被随机分配接受治疗，其中 529 名患者属于帕博利珠单抗-放化疗组，531 名患者属于安慰剂-放化疗组。在方案规定的第二次中期分析（数据截止时间为 2024 年 1 月 8 日）中，中位随访时间为 29.9 个月（IQR 23.3–34.3）。两组均未达到中位总生存期；帕博利珠单抗-放化疗组的 36 个月总生存率为 82.6%（95% CI 78.4–86.1），安慰剂-放化疗组为 74.8%（70.1–78.8）。死亡风险比为 0.67（95% CI 0.50–0.90；p=0.0040），符合方案规定的主要目标。

派姆单抗-放化疗组 528 名患者中有 413 名（78%）, 安慰剂-放化疗组 530 名患者中有 371 名（70%）出现 3 级或更高级别不良事件，其中最常见的不良事件为贫血, 白细胞计数减少和中性粒细胞计数减少。派姆单抗-放化疗组 528 名患者中有 206 名（39%）, 安慰剂-放化疗组 530 名患者中有 90 名（17%）出现潜在免疫介导不良事件。

解释: 帕博利珠单抗联合放化疗显著改善了局部晚期宫颈癌患者的总体生存率。这些数据与第一次中期分析的结果相结合，支持将这种免疫放化疗策略作为该人群的新治疗标准。

Methods: This was a phase III clinical trial (ENGOT-cx11/GOG-3047/KEYNOTE-A18, NCT04221945) in which eligible patients with newly diagnosed, high-risk (FIGO 2014 stage IB2-IIB node-positive disease or stage III-IVA regardless of nodal status), locally advanced squamous cell carcinoma, adenocarcinoma, or adenosquamous cervical cancer were randomized 1:1 to receive 5 cycles of pembrolizumab (200 mg) or placebo every 3 weeks with concurrent chemoradiation followed by 15 cycles of pembrolizumab (400 mg) or placebo every 6 weeks. The primary end points were progression-free survival and overall survival, defined as the time from randomization to death from any cause. Safety was a secondary end point.

Results: Between June 9, 2020, and Dec 15, 2022, 1,060 patients at 176 sites in 30 countries in Asia, Australia, Europe, North America, and South America were randomly assigned to treatment, with 529 patients in the pembrolizumab-chemoradiotherapy and 531 patients in the placebo-chemoradiotherapy. At the protocol-specified second interim analysis (data cutoff January 8, 2024), the median follow-up was 29.9 months (IQR 23 3–34 3). Median overall survival was not reached in either group; the 36-month overall survival rate was 82 6% (95% CI 78 4–86 1) in the pembrolizumab-chemoradiotherapy group and 74 8% (70 1–78 8) in the placebo-chemoradiotherapy group. The hazard ratio for death was 0.67 (95% CI 0.50–0.90; p=0.0040), meeting the protocol-specified primary objective.

Grade 3 or higher adverse events occurred in 413 (78%) of 528 patients in the pembrolizumab-chemoradiotherapy group and in 371 (70%) of 530 patients in the placebo-chemoradiotherapy group, with the most common adverse events being anemia, decreased white blood cell count, and decreased neutrophil count. Potential immune-mediated adverse events occurred in 206 (39%) of 528 patients in the pembrolizumab-chemoradiotherapy group and in 90 (17%) of 530 patients in the placebo-chemoradiotherapy group.

Interpretation: The addition of pembrolizumab to chemoradiotherapy significantly improved overall survival in patients with locally advanced cervical cancer. These data, combined with the results of the first interim analysis, support the use of this immuno-chemoradiotherapy strategy as a new standard of care for this population.

参考文献 Reference

Lorusso D et al. Lancet 2024; 404: 1321

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细胞周期蛋白依赖性激酶 4/6 抑制剂治疗伴有 GNAS 突变的腹膜粘液癌 (11/2/2024)

Novel therapy using CDK 4/6 inhibitor for peritoneal mucinous carcinomatosis with GNAS mutations

胃肠道粘液肿瘤的特点是易于转移到腹膜，导致腹膜粘液癌病 (PMC), 对细胞毒性化疗的反应较差。

方法: 该临床试验招募了 16 名 PMC 患者参加单组个性化癌症治疗。对于所有患者，使用下一代测序对肿瘤组织和/或循环肿瘤 DNA 进行基因组分析，并在可能的情况下评估 PD-L1 表达、肿瘤突变负荷和微卫星不稳定性状态。16 名患者中有 12 名在至少一线化疗中出现疾病进展。13 名患者的原发肿瘤为阑尾，2 名患者的原发肿瘤未知，1 名患者的原发肿瘤为胰腺。11 例被归类为低级别，5 例被归类为高级别。患者接受CDK4/6抑制剂 palbociclib 治疗

结果: 在 16 名患者中，观察到 13 名患者的癌胚抗原 (CEA) 减少，6 名患者的 CEA 下降 >50%。根据临床和改良的腹膜 RECIST 标准测量，50% 的可评估患者在接受 palbociclib 治疗 12 个月后病情稳定。在 17.6 个月的中位随访中，尚未达到中位生存期。使用体外临床前平台，CDK4/6 抑制的临床反应反映在具有 GNAS 突变和粘液组织学的肿瘤中。

结论: 使用 palbociclib 抑制 CDK4/6 对以 GNAS 突变为特征的 PMC 具有临床活性，优于之前报道的细胞毒性化疗, 是一种新的治疗策略。

Gastrointestinal mucinous tumors are characterized by a tendency to metastasize to the peritoneum, resulting in peritoneal mucinous carcinomatosis (PMC), which is poorly responsive to cytotoxic chemotherapy.

Methods: This clinical trial enrolled 16 patients with PMC in a single-arm personalized cancer therapy. For all patients, genomic analysis of tumor tissue and/or circulating tumor DNA was performed using next-generation sequencing, and PD-L1 expression, tumor mutational burden, and microsatellite instability status were assessed when possible. Twelve of the 16 patients had disease progression on at least one line of chemotherapy. The primary tumor was appendix in 13 patients, unknown in 2 patients, and pancreatic in 1 patient. Eleven cases were classified low grade and 5 cases were classified high grade. Patients were treated with the CDK4/6 inhibitor palbociclib

Results: Of the 16 patients, a decrease in carcinoembryonic antigen (CEA) was observed in 13 patients, and a decrease in CEA of >50% was observed in 6 patients. Fifty percent of evaluable patients had stable disease after 12 months of palbociclib treatment, as measured by clinical and modified peritoneal RECIST criteria. At a median follow-up of 17.6 months, median survival had not been reached. Using an in vitro preclinical platform, clinical responses to CDK4/6 inhibition were reflected in tumors with GNAS mutations and mucinous histology.

Conclusions: CDK4/6 inhibition with palbociclib is clinically active against PMCs with GNAS mutations. It outperforms previously reported cytotoxic chemotherapy, and is a novel therapeutic strategy.

参考文献 Reference

Weitz J et al. J Clin Onc 2024; https://doi.org/10.1200/JCO.24.0051

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Datopotamab–deruxtecan联合durvalumab治疗早期乳腺癌：I-SPY2.2试验 (10/27/2024)

Datopotamab–deruxtecan in combination with durvalumab in early state breast cancer, I-SPY2.2 trial

该报导描述了抗体-药物偶联物Datopotamab–deruxtecan (Dato-DXd) 与PD-1抑制剂durvalumab联合使用作为 I-SPY2.2 第 2 阶段新辅助序贯多重分配随机试验中高风险 II/III 期乳腺癌的第一个治疗序列的结果。

该试验包括三个治疗区块，最初患者随机分配到不同的实验药物（区块 A），然后是针对肿瘤亚型定制的紫杉烷类方案（区块 B），然后是阿霉素-环磷酰胺（区块 C）。基于磁共振成像肿瘤体积变化和核心活检的亚型特异性算法指导治疗重定向，包括对预测病理完全响应可能性较高的患者选择早期手术切除，这是切除时评估的主要终点。

有两种主要疗效分析：针对六种预先指定的 HER2 阴性亚型（由激素受体状态和/或反应预测亚型定义）。总共有 106 名患者在区块 A 中接受了 Dato-DXd/durvalumab 治疗。在免疫阳性亚型中，Dato-DXd/durvalumab 在区块 A 后超过了预先指定的成功阈值(总体观察到的病理完全响应率为 50%)（毕业）；在所有区块中，病理完全响应率相当于标准治疗的预期响应率 (79%)，但单独使用 Dato-DXd/durvalumab（区块 A）后有 54% 的患者达到了这一结果，未使用阿霉素 – 环磷酰胺（区块 A+B）后有 92% 的患者达到了这一结果。

在激素受体阴性/免疫阴性/DNA损伤修复缺陷阴性（全阴性）亚型中，完全治疗策略（A + B + C 区块）取得了良好的病理完全响应率（意向治疗人群中为 44%, 动态对照组为 16%）。

所有区块未观察到新的毒性。口腔炎是区块 A 中最常见的副作用。单独接受区块 A 治疗的患者均未出现肾上腺功能不全。Dato-DXd/durvalumab 是一种很有前途的治疗组合。

This report described results of the antibody-drug conjugate Datopotamab–deruxtecan (Dato-DXd) in combination with the PD-1 inhibitor durvalumab as the first treatment sequence in high-risk stage II/III breast cancer in the I-SPY2.2 phase 2 neoadjuvant sequential multiple assignment randomized trial.

The trial consisted of three treatment blocks, with patients initially randomized to different experimental drugs (Block A), followed by a taxane regimen tailored to tumor subtype (Block B), and then doxorubicin-cyclophosphamide (Block C). A subtype-specific algorithm based on tumor volume change on MRI and core biopsy guided treatment redirection, including the selection of early surgical resection for patients with a high predicted likelihood of pathological complete response, which was the primary endpoint assessed at the time of resection.

There were two primary efficacy analyses: for six prespecified HER2-negative subtypes (defined by hormone receptor status and/or response prediction subtype). A total of 106 patients were treated with Dato-DXd/durvalumab in Block A. In the immune-positive subtype, Dato-DXd/durvalumab exceeded the pre-specified success threshold after block A (graduation). In all blocks, the pathological complete response rate was equivalent to the expected response rate with standard treatment (79%), but this result was achieved in 54% of patients after Dato-DXd/durvalumab alone (block A) and 92% of patients without doxorubicin-cyclophosphamide (block A+B). In the hormone receptor-negative/immune-negative subtype/DNA damage repair deficiency-negative (all-negative) subtype, the complete treatment strategy (blocks A+B+C) achieved a good pathological complete response rate (44% in the intention-to-treat population vs 16% in the dynamic control group).

No new toxicities were observed in any block. Stomatitis was the most common side effect in block A. No patient treated with block A alone developed adrenal insufficiency. Dato-DXd/durvalumab is a promising treatment combination

参考文献 Reference

Shatsky RA et al. Nature Medicine 2024; Sept 14   

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Ifinatamab deruxtecan 用于广泛期小细胞肺癌 (10/25/2024)

Ifinatamab deruxtecan in extensive-stage small cell lung cancer

抗体-药物偶联物 ifinatamab deruxtecan (I-DXd) 在 II 期 IDeate-Lung01 研究的中期分析中显示出对广泛期小细胞肺癌 (SCLC) 患者具有临床意义的活性。I-DXd 是一种针对 B7 同源物 3 (B7-H3) 的抗体-药物偶联物，B7 同源物 3包括免疫检查点蛋白，例如 PD-L1。B7-H3 的高表达和持续表达已在 SCLC 的所有分子亚型中得到证实，并且与预后不良有关。  

在 IDeate-Lung01 的剂量优化部分，对之前接受过一至三种治疗方案的广泛期 SCLC 患者评估了两种剂量的 I-DXd（每 3 周静脉注射 8 mg/kg 和 12 mg/kg）。主要终点是客观响应率。次要终点包括响应持续时间, 无进展生存期, 总体生存期, 疾病控制率, 缓解时间和安全性。中期分析包括随机分配两种剂量的 88 名患者（42% 患有无症状稳定脑转移）。中位随访期约为 15 个月。

主要结果: 8 mg/kg 的确认响应率为 26.1%，12 mg/kg 的确认响应率基本翻倍至 54.8%。两种剂量的响应都很快，约为 1.4 个月。中位缓解持续时间分别为 7.9 个月和 4.2 个月。 8 mg/kg剂量的 I-DXd 使疾病控制率达到 80.4%，12 mg/kg剂量使疾病控制率达到 90.5%。在对 16 名基线时有脑病变的患者的分析中，8 mg/kg剂量组的颅内响应率为 66.7%，12 mg/kg剂量组的颅内响应率为 50.0%。 两组之间的中位无进展生存期和总生存期相似，但从数值上看，12 mg/kg剂量组更有利。8 mg/kg和 12 mg/kg组的中位无进展生存期分别为 4.2 个月和 5.5 个月，中位总生存期分别为 9.4 个月和 11.8 个月。

安全性和毒性: 各组间所有级别的治疗相关不良事件相似，约为 96% 至 97%，但 12 mg/kg 组发生 ≥ 3 级毒性更多（50.0% vs 43.5%），治疗中断也更多（15.7% vs 6.5%）。最常见的不良事件是胃肠道和血液学毒性。 9 名患者记录了经裁定的间质性肺病/肺炎，8 mg/kg 组发生率为 8.7%，12 mg/kg 组发生率为 11.9%。在这 9 例病例中，一例为 5 级，一例为 3 级；其他均为 1 级或 2 级。 12 mg/kg 剂量被选为 SCLC 单药治疗的最佳剂量。它将会在IDeate-Lung01的扩展部分和第三阶段IDeate-Lung02试验中进行进一步研究。

The antibody-drug conjugate ifinatamab deruxtecan (I-DXd) showed clinically meaningful activity in patients with extensive-stage small cell lung cancer (SCLC) in an interim analysis of the phase II IDeate-Lung01 study. I-DXd is an antibody-drug conjugate that targets B7 homolog 3 (B7-H3), which includes immune checkpoint proteins such as PD-L1. High and sustained expression of B7-H3 has been demonstrated in all molecular subtypes of SCLC and is associated with a poor prognosis.

In the dose optimization portion of IDeate-Lung01, two doses of I-DXd (8 mg/kg and 12 mg/kg intravenously every 3 weeks) were evaluated in patients with extensive-stage SCLC who had received one to three prior lines of therapy. The primary endpoint was objective response rate. Secondary endpoints included duration of response, progression-free survival, overall survival, disease control rate, duration of response, and safety. The interim analysis included 88 patients (42% had asymptomatic stable brain metastases) randomized to both doses. The median follow-up was approximately 15 months.

Main results: The confirmed response rate was 26.1% with 8 mg/kg, versus 54.8% with 12 mg/kg. Responses were rapid at both doses, approximately 1.4 months. The median duration of response was 7.9 months and 4.2 months, respectively. I-DXd achieved a disease control rate of 80.4% with the 8 mg/kg dose and 90.5% with the 12 mg/kg dose. In an analysis of 16 patients with brain lesions at baseline, the intracranial response rate was 66.7% with the 8 mg/kg dose and 50.0% with the 12 mg/kg dose. Median progression-free survival and overall survival were similar between the two groups, but numerically favored the 12 mg/kg dose. Median progression-free survival was 4.2 months and 5.5 months in the 8 mg/kg and 12 mg/kg groups, respectively, and median overall survival was 9.4 months and 11.8 months, respectively.

Safety and toxicity: Treatment-related adverse events of all grades were similar between groups, approximately 96% to 97%, but more grade ≥ 3 toxicities occurred in the 12 mg/kg group (50.0% vs 43.5%), as did more treatment discontinuations (15.7% vs 6.5%). The most common adverse events were gastrointestinal and hematologic toxicities. Adjudicated interstitial lung disease/pneumonitis was documented in 9 patients, with an incidence of 8.7% in the 8 mg/kg group and 11.9% in the 12 mg/kg group. Of these 9 cases, one was grade 5 and one was grade 3; the others were grade 1 or 2. The 12 mg/kg dose was selected as the optimal dose for monotherapy in SCLC. It will be further studied in the extension part of IDeate-Lung01 and the phase III IDeate-Lung02 trial.

参考文献 Reference

Rudin Cm et al. 2024 World Conference on Lung Cancer. Abstract OA04.03

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局部晚期直肠癌的治疗：ASCO 指南 (10/20/2024)

Management of locally advanced rectal cancer: ASCO guideline

局部晚期直肠癌患者治疗开始前准备和检查:

1.1. 应进行 MSI 或 MMR 状态评估。

1.2. 应进行高分辨率盆腔 MRI 检查，并采用专门的直肠序列，以评估复发风险因素并为手术计划提供信息。

1.3. 建议使用标准化综合 MRI 报告，其中包括原发肿瘤与肛缘, 括约肌复合体, 盆腔淋巴结和直肠系膜筋膜(MRF) 的关系，并包括对壁外血管侵犯 (EMVI) , 肿瘤沉积和淋巴结的评估。

治疗建议:

2.1. 对于低位直肠癌患者和/或局部和/或远处转移风险较高的患者，包括具有以下一个或多个风险因素的患者，应将总新辅助治疗 TNT, 即放化疗和化疗）) 作为初始治疗：T4, 壁外血管侵犯和/或 MRI 上发现的肿瘤沉积,  直肠系膜筋膜威胁或括约肌间平面威胁。  

声明： 临床淋巴结分期的准确性有限。因此，专家小组建议不要仅根据放射学淋巴结评估做出治疗决定。因此，临床医生和患者应讨论各种治疗方案相对于患者个体临床和 MRI 预后特征以及他们的价值观和偏好的潜在益处和危害风险。

2.2. 对于中上直肠癌患者，肿瘤壁外浸润深度 > 5 mm，符合 PROSPECT II/III 期试验标准，即 T3 N0 至 N1 期保肛手术候选者，且无直肠系膜筋膜威胁，可进行氟嘧啶和奥沙利铂为基础的新辅助化疗。对于肿瘤面积缩小 < 20% 的患者，可在新辅助化疗后选择性加用放化疗。  

复发风险较低的患者的其他选择包括新辅助长程放化疗或短程放疗。总新辅助治疗也可能是该组中某些患者的一种选择，具体取决于治疗目标，应考虑毒性特征, 新辅助治疗后确定完全缓解的可能性, 治疗持续时间和可行性。

3.1. 对于适合接受总新辅助治疗的患者，建议在放疗后进行化疗。

声明： 在 OPRA II 期 随机对照试验中，放化疗后接受化疗的患者 3 年无全直肠系膜切除术生存率较高，但与放化疗前接受化疗的患者相比，无病生存率无差异。对于远处转移风险较高的患者，可以讨论在放化疗前进行三联化疗的总新辅助治疗。对于患有合并症或年龄较大的患者，应考虑三联化疗和双联化疗可能发生的不良事件发生率较高，  

4.1. 如果治疗计划中包括放疗，对于局部晚期直肠癌患者，新辅助长程放化疗优于短程放疗。

说明： 此建议基于 RAPIDO III 期随机对照试验的长期结果，结果显示，与标准放化疗（6%）相比，总新辅助治疗短程放疗的 5 年局部区域失败率（10%）显著升高，而与放化疗相比，总新辅助治疗的疾病相关治疗失败率和远处转移率的降低在治疗后 5 年得以维持。

短程放疗也可能是一种可行的治疗选择。长程放化疗或短程放化疗的选择取决于患者情况，长程 放化疗可能更适合具有与 RAPIDO 试验所需特征相似的高风险特征的患者或考虑非手术治疗目标的患者。

5.1. 对于新辅助治疗后临床完全响应的患者，可以讨论非手术治疗作为全直肠系膜切除术的替代方案。

注释： 本综述中对非手术治疗的研究包括接受包括放疗在内的新辅助治疗的患者; 本综述未包括单独新辅助化疗后非手术治疗的研究。     

声明： 决策应包括讨论如果提供非手术治疗，功能结果改善的可能性, 手术风险, 监测要求以及永久性造口术风险的降低。 需要腹会阴切除术或结肠肛门吻合术的患者可能更倾向于这种方法。对于远端肿瘤患者，器官保留的好处包括避免超低吻合的全直肠系膜切除术，以及与近端肿瘤相比，更适合密切监测复发的位置。 在 OPRA 试验中，监测方案包括从评估治疗响应开始的 2 年内每 4 个月进行一次直肠指检和柔性乙状结肠镜检查，随后 3 年每 6 个月进行一次。前 2 年每 6 个月进行一次直肠 MRI，随后 3 年每年进行一次。反应评估和非手术治疗随访的影像学指导不在本指南的范围内。 为确定是否符合非手术治疗资格，应在完成任何总新辅助治疗方案后 8 ± 4 周进行首次完全响应评估 。完全响应者，不应存在溃疡。 直肠指检和直肠镜检查：未触及肿瘤物质，无残留肿瘤物质，无红斑溃疡或疤痕。 MRI：大幅缩小，无可观察到的残留肿瘤物质，或仅有残留纤维化，有时伴有因水肿导致的残留壁增厚，无可疑淋巴结。 内镜活检：不是强制性的或定义完全响应所必需的，不应进行活检，也不建议进行，特别是如果直肠指检, 直肠镜检查和 MRI 的 完全响应标准都得到满足。 

6.1. 建议对 MSI-H 或 dMMR 肿瘤进行免疫治疗。

声明： 建议 2.1 至 4.1 中概述的治疗方案适用于 MSI-H 或 dMMR 肿瘤且有免疫治疗禁忌症的患者。dMMR 肿瘤已被证明对放化疗敏感。

Preparation and examination before starting treatment for patients with locally advanced rectal cancer:

1.1. Patients should be assessed for MSI or MMR status

1.2. Patients should undergo high-resolution pelvic MRI with dedicated rectal sequence to assess for risk factors for recurrence and to provide information for surgical planning.

1.3. The use of a standardized synoptic MRI report is recommended that includes relation of the primary tumor to the anal verge, sphincter complex, pelvic nodes, and mesorectal fascia (MRF) and includes assessment of extramural vascular invasion (EMVI), tumor deposits, and lymph nodes.

Treatment suggestions:

2.1. Total neoadjuvant therapy (TNT: chemoradiation [CRT] and chemotherapy) should be offered as initial treatment for patients with low rectum locally advanced rectal cancer and/or patients who are at higher risk for local and/or distant metastases, including patients with one or more of the following risk factors: T4, EMVI, and/or tumor deposits identified on MRI, threatened MRF, or threatened intersphincteric plane.

Qualifying statements for Recommendation 2.1: Clinical lymph node staging has limited accuracy. Therefore, the Expert Panel recommends against making treatment decisions based solely on radiographic nodal assessment.

 While this patient population is defined by validated prognostic factors, randomized clinical trial (RCT) data are not available for specific prognostic subpopulations, therefore, clinicians and patients should discuss the potential benefits and risks of harm associated with various treatment options relative to patients’ individual clinical and MRI prognostic features, as well as their values and preferences.

2.2. Patients with locally advanced middle or upper rectal cancer and a tumor depth of extramural invasion of > 5 mm who meet the criteria for the PROSPECT phase II/III trial, ie, T3 N0 to N1 candidates for sphincter-sparing surgery without a threatened MRF, may be offered neoadjuvant fluoropyrimidine and oxaliplatin–based chemotherapy. Selective addition of chemoradiation therapy (CRT) may be offered following neoadjuvant chemotherapy to patients whose tumors decrease in area by < 20%.

Note for Recommendation 2.2: Recommendations for patients with a tumor depth of extramural invasion of ≤5 mm and no other risk factors will be addressed in an ASCO guideline on earlier-stage rectal cancer.

Qualifying statements for Recommendation 2.2: Other options for patients with lower risk of recurrence include neoadjuvant long-course CRT or short-course radiation (RT). TNT may also be an option for some patients in this group, depending on the goals of treatment, eg, complete response and potentially nonoperative management (NOM). Choice of treatment should be made with consideration to toxicity profile, likelihood of identifying a complete response following neoadjuvant therapy, duration of treatment, and feasibility.

3.1. For patients who are candidates for TNT, the recommended timing for chemotherapy is after radiation.

Qualifying Statements for Recommendation 3.1: In the OPRA phase II RCT, patients treated with chemotherapy after CRT had a higher rate of TME-free survival at 3 years, but no difference in disease-free survival compared to patients treated with chemotherapy before CRT.

 TNT with triplet chemotherapy before CRT may be discussed for patients at greater risk of distant metastases. Consideration of the higher rates of adverse events that may occur with triplet v doublet chemotherapy should be made for patients with comorbidities or older age, eg, in the PRODIGE 23 trial, eligibility to the trial was limited to patients under 76 years of age to improve the safety of FOLFIRINOX chemotherapy. Delivery of chemotherapy prior to CRT is an additional recommended option for TNT candidates, particularly in settings where the initiation of radiation therapy may be slower than the initiation of chemotherapy.

4.1. If radiation is included in the treatment plan, neoadjuvant long-course CRT is preferred over short-course RT for patients with locally advanced rectal cancer.

Note for Recommendation 4.1: This recommendation is based on longer-term results of the RAPIDO phase III RCT showing a significantly higher rate of 5-year locoregional failure with TNT with short-course RT (10%), compared to standard CRT (6%), while the reduction in the rate of disease-related treatment failure and distant metastases with TNT compared to CRT was maintained at 5 years post-treatment.

Qualifying statements for Recommendation 4.1: Short-course RT may also be a viable treatment option. The choice of long-course CRT or short-course RT is patient circumstance–driven, and long-course CRT may be more appropriate for patients with higher-risk features similar to those required for inclusion in the RAPIDO trial or for patients considering a goal of NOM.

5.1. NOM may be discussed as an alternative to TME for patients who have a clinical complete response (cCR) following neoadjuvant therapy.

Note for Recommendation 5.1: Studies of NOM in this review included patients who underwent neoadjuvant therapy that included radiation; no studies of NOM after neoadjuvant chemotherapy alone were included in this review.

Qualifying statements for Recommendation 5.1: Decision making should include a discussion of the potential for improved functional outcomes, surgical risk, surveillance requirements, and reduced risk of a permanent ostomy if NOM is offered.

 A preference for this approach may be greater among those patients who require an abdominoperineal resection (APR) or a coloanal anastomosis. The benefits of organ preservation among those with distal tumors include avoiding a TME with ultra-low anastomosis, and a location that is more amenable to close surveillance for regrowth, compared to more proximal tumors.

 In the OPRA trial, the surveillance protocol included digital rectal examination (DRE) and flexible sigmoidoscopy every 4 months for the first 2 years from the time of assessment of response, continuing every 6 months for the following 3 years. Rectal MRI was to be performed every 6 months for the first 2 years and yearly for the following 3 years.

 First assessment of complete response for the purpose of determining eligibility for NOM should be made at 8 ± 4 weeks following the completion of any TNT regimen

 A definition of cCR is provided. Note that this definition has been slightly modified from the original to indicate that when using cCR to inform eligibility for NOM, there should be no ulcer present. DRE and rectoscopy: No palpable tumor material present, no residual tumor material, and no erythematous ulcer or scar. MRI: substantial downsizing with no observable residual tumor material, or residual fibrosis only (with limited signal on diffusion-weighted imaging), sometimes associated with residual wall thickening owing to edema, no suspicious lymph nodes. Endoscopic biopsy: Not mandatory or required to define cCR, biopsy should not be performed and is not recommended, especially if the DRE, rectoscopy, and MRI criteria for cCR are all fulfilled.

6.1. Immunotherapy is recommended for tumors that are MSI-H or dMMR (evidence quality: low; strength of recommendation: strong).

Qualifying statement for Recommendation 6.1: The treatment options outlined in Recommendations 2.1 to 4.1 are recommended for patients with tumors that are MSI-H or dMMR and have contraindications to immunotherapy. dMMR tumors have been shown to be sensitive to CRT. Historically, fluorouracil-based chemotherapy has been less effective in patients with dMMR.

参考文献 Reference

Scott AJ et al. J Clin Onc 2024; https://doi.org/10.1200/JCO.24.01160

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FDA 批准 lazertinib与amivantamab-vmjw 联合用于非小细胞肺癌(NSCLC) (10/19/2024)

FDA approved lazertinib with amivantamab-vmjw for non-small lung cancer

2024 年 8 月 19 日，FDA批准lazertinib 与amivantamab 联合用于一线治疗局部晚期或转移性NSCLC，该癌症存在EGFR 外显子 19 缺失或外显子 21 L858R 置换突变。

疗效和安全性: MARIPOSA (NCT04487080) 是一项随机, 阳性对照, 多中心试验，纳入了 1,074 名外显子 19 缺失或外显子 21 L858R 置换突变阳性的局部晚期或转移性 NSCLC 患者，且未接受过针对晚期疾病的全身治疗。患者随机（2:2:1）接受lazertinib与amivantamab, 奥希替尼单药治疗或lazertinib单药治疗，直至病情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, 总生存期是关键的次要结果指标。

与奥希替尼相比，lazertinib与amivantamab在无进展生存期方面表现出统计学显著改善，风险比为 0.70（95% 置信区间 [CI]：0.58，0.85；p 值 = 0.0002）。lazertinib与amivantamab组的中位无进展生存期为 23.7 个月（95% CI：19.1，27.7），奥希替尼组的中位 PFS 为 16.6 个月（95% CI：14.8，18.5）。 虽然目前的分析中位总生存期结果尚不成熟，最终分析报告的死亡率为 55%。

最常见的不良反应 (≥20%) 是皮疹, 指甲毒性, 输液相关反应 (amivantamab),  肌肉骨骼疼痛, 水肿, 口腔炎, 静脉血栓栓塞, 感觉异常, 疲劳, 腹泻, 便秘, COVID-19 感染, 出血, 皮肤干燥, 食欲下降, 瘙痒, 恶心和眼部毒性。lazertinib与amivantamab联合使用时观察到静脉血栓栓塞事件的严重安全信号，治疗的前四个月应进行预防性抗凝治疗。 lazertinib的推荐剂量为每日一次口服 240 毫克，与阿米凡他单抗联合使用，可与食物一起或单独服用。阿米凡他单抗的推荐剂量基于基线体重。

编者注: lazertinib通过与 EGFR 激酶结构域的 ATP 结合位点的 Cys797 残基形成共价键，不可逆地抑制 EGFR。它阻断 EGFR 下游信号级联（包括 EGFR、AKT 和 ERK 的磷酸化），并促进 EGFR 突变肺癌细胞凋亡。 lazertinib针对 EGFR 的外显子 19 缺失和外显子 21 L858R 点突变形式，此外，它还显示出对 T790M 突变的疗效。

Amivantamab 是一种双特异性抗体，具有阻止 EGFR 和 MET 配体与其受体结合, 触发受体内化和降解, 和促进免疫细胞导向活性, 包括抗体依赖性细胞毒性。

On August 19, 2024, FDA approved lazertinib in combination with amivantamab for the first-line treatment of locally advanced or metastatic NSCLC with EGFR exon 19 deletion or exon 21 L858R substitution mutation.

Efficacy and Safety: MARIPOSA (NCT04487080) is a randomized, active-controlled, multicenter trial that enrolled 1,074 patients with locally advanced or metastatic NSCLC who were positive for exon 19 deletion or exon 21 L858R substitution mutation and had not received prior systemic therapy for advanced disease. Patients were randomized (2:2:1) to receive lazertinib with amivantamab, osimertinib monotherapy, or lazertinib monotherapy until disease progression or unacceptable toxicity. The primary efficacy outcome measure was progression-free survival;  overall survival was a key secondary outcome measure.

Lazertinib plus amivantamab demonstrated a statistically significant improvement in progression-free survival compared with osimertinib, with a hazard ratio of 0.70 (95% confidence interval [CI]: 0.58, 0.85; p-value = 0.0002). The median progression-free survival was 23.7 months (95% CI: 19.1, 27.7) in the lazertinib plus amivantamab arm and 16.6 months (95% CI: 14.8, 18.5) in the osimertinib arm. Although median overall survival results were not mature at the current analysis, the mortality rate reported at the final analysis was 55%.

The most common adverse reactions (≥20%) were rash, nail toxicity, infusion-related reactions (amivantamab), musculoskeletal pain, edema, stomatitis, venous thromboembolism, paresthesia, fatigue, diarrhea, constipation, COVID-19 infection, hemorrhage, dry skin, decreased appetite, pruritus, nausea, and ocular toxicity. Serious safety signals of venous thromboembolic events were observed when lazertinib was used in combination with amivantamab, and prophylactic anticoagulation should be instituted for the first four months of treatment. The recommended dose of lazertinib is 240 mg orally once daily, in combination with amivantamab, with or without food. The recommended dose of amivantamab is based on body weight.

Editor: Lazertinib irreversibly inhibits EGFR by forming a covalent bond with the Cys797 residue in the ATP binding site of the EGFR kinase domain. It blocks the EGFR downstream signaling cascade (including phosphorylation of EGFR, AKT, and ERK) and promotes apoptosis in EGFR mutant lung cancer cells. Lazertinib targets exon 19 deletion and exon 21 L858R point mutation forms of EGFR. In addition, it has shown efficacy against the T790M mutation.

Amivantamab is a bispecific antibody with the potential to block the binding of EGFR and MET ligands to their receptors, trigger receptor internalization and degradation and promote immune cell-directed activities, including antibody-dependent cellular cytotoxicity.

参考文献 Reference

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lazertinib-amivantamab-vmjw-non-small-lung-cancer

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新辅助免疫检查点抑制剂 (ICI) 联合化疗治疗早期乳腺癌: 荟萃分析 (10/13/2024)

Neoadjuvant immune checkpoint inhibitors (ICI) plus chemotherapy in breast cancer: A meta-Analysis

在这项涉及 5,114 名患者的荟萃分析中，新辅助 ICI 治疗与早期三阴性乳腺癌, 和PD-L1 阳性/激素受体阳性 (HR+) /HER2 阴性肿瘤的疗效结果改善相关，且安全性可接受。在三阴性乳腺癌中，对于病理完全缓解或残留疾病的患者，辅助(术后) ICI 没有观察到任何益处。 这些结果有利于新辅助治疗而不是辅助 ICI 治疗早期乳腺癌。

数据来源 于 2023 年 12 月 10 日搜索了 PubMed 数据库，评估早期乳腺癌（新）辅助 ICI 加化疗的随机临床试验。主要结果和测量结果是病理性完全响应率, 有和没有病理性完全响应患者的无事件生存期和不良事件。使用分层 Cox 比例风险回归模型估计风险比。

结果: 涉及 5,114 名患者的 9 项随机临床试验符合纳入标准（2097 名三阴性乳腺癌, 1,924 HR+/HER2 阴性, 和 1,115 名 HER2+ 肿瘤）。在三阴性乳腺癌,中，无论PD-L状态如何，添加 ICI 均与病理性完全响应率改善相关（绝对改善，>10%）。在 HR+/ERBB2- 肿瘤中，仅在PD-L1+人群中使用 ICI 与病理性完全响应改善相关（绝对改善，+12.2%），而在 HER2+ 肿瘤中未观察到任何益处。

在达到病理性完全响应的三阴性乳腺癌患者中，添加 ICI 与无事件生存期改善相关（风险比，0.65；95% CI，0.42-1.00），使用 ICI 的 5 年无事件生存率为 92.0%，而未使用 ICI 的 5 年无事件生存率为 88.0%。对于有残留疾病的患者，ICI 也显示出更好的无事件生存率（风险比为 0.77；95% CI，0.61-0.98），使用 ICI 的 5 年无事件生存率为 63.3%，不使用 ICI 的 5 年无事件生存率为 56.1%。辅助 ICI 在病理性完全响应或残留疾病患者中未显示数值改善（所有风险比 >1）。

在新辅助治疗期间，ICI 发生 3 级或更高级别免疫相关不良事件的发生率为 10.3%。

这些发现表明，新辅助 ICI 治疗可改善早期三阴性乳腺癌和 PD-L1+ HR+/HER2− 肿瘤的疗效结果，且安全性可接受；然而，辅助 ICI 没有观察到任何益处。

In this meta-analysis involving 5,114 patients, neoadjuvant ICI therapy was associated with improved efficacy outcomes in early-stage triple-negative breast cancer, and PD-L1-positive/hormone receptor-positive (HR+)/HER2-negative tumors, with an acceptable safety profile. In triple-negative breast cancer, no benefit was observed with adjuvant (postoperative) ICI for patients with pathological complete response or residual disease. These results favor neoadjuvant therapy over adjuvant ICI therapy for early breast cancer.

Data source: PubMed database was searched on December 10, 2023. Study evaluated randomized clinical trials evaluating (neo)adjuvant ICI plus chemotherapy for early breast cancer. The primary outcomes and measures were pathological complete response rate, event-free survival, and adverse events in patients with and without pathological complete response. Hazard ratios were estimated using stratified Cox proportional hazards regression models.

Results: Nine randomized clinical trials involving 5,114 patients met inclusion criteria (2,097 with triple-negative breast cancer, 1,924 HR+/HER2-negative, and 1,115 with HER2+ tumors). In triple-negative breast cancer, the addition of ICIs was associated with improved pathological complete response rates (absolute improvement, >10%) regardless of PD-L status. In HR+/ERBB2- tumors, ICI use was associated with improved pathological complete response only in the PD-L1+ population (absolute improvement, +12.2%), whereas no benefit was observed in HER2+ tumors.

Among patients with triple-negative breast cancer who achieved a pathological complete response, the addition of ICIs was associated with improved event-free survival (hazard ratio, 0.65; 95% CI, 0.42-1.00), with a 5-year event-free survival rate of 92.0% with ICIs versus 88.0% without ICIs. ICIs also showed better event-free survival for patients with residual disease (hazard ratio, 0.77; 95% CI, 0.61-0.98), with a 5-year event-free survival of 63.3% with ICIs and 56.1% without ICIs.

Adjuvant ICIs did not show numerical improvement in patients with pathological complete response or residual disease (all hazard ratios >1). During neoadjuvant therapy, the incidence of grade 3 or higher immune-related adverse events with ICIs was 10.3%.

These findings suggest that neoadjuvant ICI therapy may improve efficacy outcomes in early triple-negative breast cancer and PD-L1+ HR+/HER2− tumors with an acceptable safety profile. However, no benefit was observed with adjuvant ICIs.

参考文献 Reference

Villacampa G et al.  JAMA Onc 2024; DOI: 10.1001/jamaoncol.2024.3456

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T-DXd用于激素受体阳性 (HR+), HER2低或 HER2 超低转移性乳腺癌 (10/12/2024)

Trastuzumab deruxtecan (T-DXd) hormone receptor-positive (HR+), HER2-low or HER2-ultralow metastatic breast cancer: DESTINY-Breast06 (DB-06)

方法：这是一项III期临床试验（DESTINY-Breast, DB-06, NCT04494425），HER2 低（IHC 1+ 或 2+/FISH 阴性）或超低（膜染色 IHC 为 0）, HR+ 转移性乳腺癌患者按 1:1 随机分配接受 T-DXd 5.4 mg/kg 或医生选择的化疗。患者之前未接受转移性乳腺癌化疗治疗，接受过 ≥2 线 转移性乳腺癌内分泌治疗治疗，或如果疾病进展发生于辅助内分泌治疗 ≤24 个月或转移性乳腺癌 内分泌治疗治疗+CDK4/6抑制剂 ≤6 个月，则接受 1 线转移性乳腺癌内分泌治疗治疗。主要终点是 HER2 低患者的无进展生存期。关键次要终点是意向治疗中的无进展生存期和总体生存率。其他终点包括客观缓解率和安全性。   

结果：截至 2024 年 3 月 18 日，866 名患者（HER2 低，n =713；HER2 超低，n =153）被随机分配；90.4% 的患者之前接受过 CDK4/6抑制剂治疗。医生选择的化疗组患者选择卡培他滨 (59.8%), 白蛋白紫杉醇 (24.4%) 或紫杉醇 (15.8%)。T-DXd 显著改善了 HER2 低患者的无进展生存期，相比于医生选择的化疗（HR，0.62 [95% CI 0.51, 0.74]，P <0.0001；中位数，13.2 vs 8.1 个月）。 ITT 和 HER2-ultralow 结果与 HER2-low 一致。中位治疗持续时间为 11.0 个月（T-DXd）vs 5.6 个月（医生选择的化疗）。第一次中期分析时总体生存率尚不成熟。

药物相关不良事件发生率≥3 级为 40.6%（T-DXd）相比于 31.4%（医生选择的化疗）。间质性肺病/肺炎发生在 49 名（11.3%；3/4级0.7%，5级0.7% ）相比于 1 名（2级0.2% ）患者中。

结论：在 HER2-low 转移性乳腺癌 中，T-DXd 显示出与医生选择的化疗相比具有统计学意义和临床意义的无进展生存期优势。HER2-ultralow 结果与 HER2-low 一致。安全性与已知概况一致。DB-06 将 T-DXd 确立为 HER2-low 和 -ultralow, HR+ 转移性乳腺癌患者接受 ≥1 次内分泌治疗后的护理标准。

Methods: This was a phase III clinical trial (DESTINY-Breast, DB-06, NCT04494425) in which patients with HER2-low (IHC 1+ or 2+/ISH negative) or ultra-low (membrane staining IHC 0), HR+ metastatic breast cancer were randomized 1:1 to receive T-DXd 5.4 mg/kg or physician’s choice of chemotherapy. Patients had not received prior chemotherapy for metastatic breast cancer and had received ≥2 lines of endocrine therapy for metastatic breast cancer or 1 line of endocrine therapy for metastatic breast cancer if disease progression occurred on adjuvant endocrine therapy ≤ 24 months or endocrine therapy for metastatic breast cancer plus CDK4/6 inhibitor ≤6 months. The primary endpoint was progression-free survival in patients with HER2-low disease. Key secondary endpoints were progression-free survival and overall survival in the intention-to-treat setting. Other endpoints included objective response rate and safety.

Results: As of March 18, 2024, 866 patients (HER2-low, n = 713; HER2-ultralow, n = 153) were randomized; 90.4% of patients had received prior CDK4/6 inhibitor therapy. Patients in the physician’s choice chemotherapy group selected capecitabine (59.8%), nab-paclitaxel (24.4%), or paclitaxel (15.8%). T-DXd significantly improved progression-free survival in HER2-low patients compared with physician’s choice chemotherapy (HR, 0.62 [95% CI 0.51, 0.74], P < .0001; median, 13.2 vs 8.1 months). ITT and HER2-ultralow results were consistent with HER2-low. Median treatment duration was 11.0 months (T-DXd) vs 5.6 months (physician’s choice chemotherapy). Overall survival was not mature at the time of the first interim analysis.

The incidence of drug-related adverse events ≥ grade 3 was 40.6% (T-DXd) vs. 31.4% (chemotherapy of physician’s choice). Interstitial lung disease/pneumonitis occurred in 49 (11.3%; grade 3/4 0.7% ; grade 5 0.7%) vs. 1 (grade 2 0.2%) patients.

Conclusions: In HER2-low metastatic breast cancer, T-DXd demonstrated a statistically significant and clinically meaningful progression-free survival advantage over chemotherapy of physician’s choice. HER2-ultralow results were consistent with HER2-low. Safety profile was consistent with the known profile. DB-06 establishes T-DXd as the standard of care for patients with HER2-low and -ultralow, HR+ metastatic breast cancer after ≥1 prior endocrine therapy.

参考文献 Reference

Curigliano G et al. J Clin Onc 2024; 42: 17_suppl LBA1000

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完全新辅助治疗 (TNT) 联合非手术治疗治疗局部晚期直肠癌：NO-CUT 试验 (10/6/2024)

Total neoadjuvant treatment (TNT) with non-operative management for pMMR locally advanced rectal cancer: NO-CUT trial

背景: TNT 后进行直肠手术是 proficient mismatch repair (pMMR)局部晚期直肠癌的标准治疗方法。对于 TNT 后达到临床完全响应的患者，可以提出由密集随访组成的非手术治疗作为手术治疗的替代方案。NO-CUT 是一项针对 pMMR 局部晚期直肠癌患者的多中心单臂 II 期试验 (EudraCT 2017-003671-60)，旨在评估 a) 非手术治疗治疗是否危及远处无复发生存期；b) 可以通过肿瘤和血液样本中的多组学分析确定临床完全响应的预测生物标志物。

方法: 4 个癌症中心的 cT3-4N0/cTxN1-2 低/中位 pMMR 局部晚期直肠癌患者接受 TNT 治疗，包括 4 个 CAPOX 周期，随后进行 5 周放化疗。TNT 后，根据基于临床完全响应参数的协议算法，患者被分配到手术治疗或非手术治疗治疗队列。多组学相关性分析包括组织转录组特征（和 Guardant Reveal 的组织不可知循环肿瘤 DNA。   

结果: 从 2018 年到 2024 年，180 名患者接受了 TNT，164 名（91%）按照方案完成治疗，46 名（25.5%）被分配到非手术治疗队列。非手术治疗队列中的30 个月远处无复发生存期为 96.9%，手术治疗队列中为 74%（中位随访期分别为 26（18-36）个月和 10（9-19）个月）。15% 的非手术治疗治疗队列和 9% 的手术治疗队列分别出现局部再生长。截至 2024 年 4 月 1 日，已报告 12 例死亡（6.6%）（1 例不良事件、9 例肿瘤和 2 例其他原因相关）。完整的多组学相关性分析正在进行中。前 77 名患者的液体活检循环肿瘤 DNA 与临床完全响应和远处无复发生存期相关。

结论: NO-CUT 试验的主要终点已达到，研究发现这种 TNT 方法导致非手术治疗率为 25.5%，30个月远处无复发生存期为 96.9%。

Background: TNT followed by rectal surgery is the standard of care for locally advanced rectal cancer with proficient mismatch repair (pMMR). For patients who achieve a clinical complete response after TNT, nonsurgical management consisting of intensive follow-up can be proposed as an alternative to surgical treatment. NO-CUT is a multicenter, single-arm, phase II trial (EudraCT 2017-003671-60) in patients with locally advanced rectal cancer with pMMR, designed to evaluate a) whether nonsurgical treatment compromises distant recurrence-free survival; and b) predictive biomarkers of clinical complete response can be identified by multiomic analysis in tumor and blood samples.

Methods: Patients with low/intermediate pMMR locally advanced rectal cancer with cT3-4N0/cTxN1-2 were treated with TNT consisting of 4 cycles of CAPOX followed by 5 weeks of chemoradiotherapy at 4 cancer centers. After TNT, patients were assigned to either surgical or nonsurgical treatment cohorts according to a protocol algorithm based on clinical complete response parameters. Multiomics correlation analysis included tissue transcriptome signatures and tissue-agnostic circulating tumor DNA from Guardant Reveal.

Results: From 2018 to 2024, 180 patients underwent TNT, 164 (91%) completed treatment per protocol, and 46 (25.5%) were assigned to the non-surgical treatment cohort. The 30-month distant recurrence-free survival was 96.9% in the non-surgical treatment cohort and 74% in the surgical treatment cohort (median follow-up, 26 (18-36) months and 10 (9-19) months, respectively). Local regrowth occurred in 15% of the non-surgical treatment cohort and 9% of the surgical treatment cohort, respectively. As of April 1, 2024, 12 deaths (6.6%) have been reported (1 adverse event, 9 tumor, and 2 other causes related). Full multiomics correlation analysis is ongoing. Liquid biopsy circulating tumor DNA in the first 77 patients was associated with clinical complete response and distant recurrence-free survival.

Conclusions: The primary endpoint of the NO-CUT trial was met, and the study found that this TNT approach resulted in a non-surgical cure rate of 25.5% and a 30-month distant recurrence-free survival of 96.9%.

参考文献 Reference

Amatu A. et al. ESMO Ann Onc 2024; 35: 2_suppl S431

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FDA 批准新辅助/辅助 nivolumab 用于可切除非小细胞肺癌 CHECKMATE-77T (10/5/2024)

FDA approves neoadjuvant/adjuvant nivolumab for resectable non-small cell lung cancer CHECKMATE-77T

2024 年 10 月 3 日，FDA批准 nivolumab联合铂类双药化疗作为新辅助治疗，术后再以单药 nivolumab 作为辅助治疗，用于可切除（肿瘤 ≥4 cm 和/或淋巴结阳性）非小细胞肺癌 (NSCLC) 且无EGFR 突变或ALK 重排的成人患者。

CHECKMATE-77T (NCT04025879) 评估了疗效，这是一项随机, 双盲, 安慰剂对照的多中心试验，纳入了 461 名未经治疗且可切除的 NSCLC 患者（IIA 期至 IIIB 期）。患者随机（1:1）接受 nivolumab 或安慰剂治疗，联合铂类化疗，每 3 周一次，最多 4 个周期（新辅助治疗），术后继续每 4 周接受单药 nivolumab 或安慰剂治疗，最多 13 个周期（辅助治疗）。 主要疗效结果指标是无事件生存期 (EFS)。 nivolumab 组的中位 EFS 未达到（95% CI：28.9，不可估计 [NE]），而化疗组的中位 EFS 为 18.4 个月（95% CI：13.6，28.1）（风险比 0.58 [95% CI：0.43，0.78]；p 值 0.00025）。在预先指定的中期分析中，未正式检验总生存期的统计学意义。 不良反应与其他 nivolumab 联合化疗临床试验中发生的不良反应相似。

在接受新辅助 nivolumab 治疗的患者中，5.3% 因不良反应而无法接受手术，而安慰剂组为 3.5%。此外，在接受新辅助治疗和手术的 nivolumab 组中，4.5% 的患者因不良反应而推迟手术，而安慰剂组中这一比例为 3.9%。

建议的 nivolumab 剂量为每 3 周 360 毫克（新辅助治疗）和每 4 周 480 毫克（辅助治疗）。如果在同一天给药，nivolumab 应在化疗之前给药。

On October 3, 2024, FDA approved nivolumab in combination with platinum-based doublet chemotherapy as neoadjuvant therapy, followed by nivolumab alone as adjuvant therapy, for adult patients with resectable (tumor ≥4 cm and/or node-positive) non-small cell lung cancer (NSCLC) without EGFR mutations or ALK rearrangements.

Efficacy was evaluated in CHECKMATE-77T (NCT04025879), a randomized, double-blind, placebo-controlled, multicenter trial that enrolled 461 patients with previously untreated, resectable NSCLC (stage IIA to IIIB). Patients were randomized (1:1) to receive nivolumab or placebo in combination with platinum-based chemotherapy every 3 weeks for up to 4 cycles (neoadjuvant therapy) and continued to receive postoperatively nivolumab alone or placebo every 4 weeks for up to 13 cycles (adjuvant therapy). The primary efficacy outcome measure was event-free survival (EFS). Median EFS was not reached in the nivolumab group (95% CI: 28.9, not estimable [NE]) compared with 18.4 months in the chemotherapy group (95% CI: 13.6, 28.1) (hazard ratio 0.58 [95% CI: 0.43, 0.78]; p-value 0.00025). Statistical significance for overall survival was not formally tested at the prespecified interim analysis. Adverse reactions were similar to those seen in other nivolumab-chemotherapy clinical trials.

Among patients who received neoadjuvant nivolumab, 5.3% were unable to undergo surgery due to adverse reactions, compared with 3.5% in the placebo group. In addition, among patients who received neoadjuvant therapy and surgery, 4.5% of patients in the nivolumab group had surgery delayed due to adverse reactions, compared with 3.9% in the placebo group.

The recommended dose of nivolumab is 360 mg every 3 weeks (neoadjuvant therapy) and 480 mg every 4 weeks (adjuvant therapy). Nivolumab should be given before chemotherapy if given on the same day.

参考文献 Reference

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-neoadjuvantadjuvant-nivolumab-resectable-non-small-cell-lung-cancer

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FDA 批准 amivantamab-vmjw 联合化疗用于治疗 EGFR 外显子 19 缺失或 L858R 突变的非小细胞肺癌 (9/29/2224)

FDA approves amivantamab-vmjw in combination with chemotherapy for non-small cell lung cancer with EGFR exon 19 deletion or L858R mutation

2024 年 9 月 19 日，FDA批准 amivantamab-vmjw 联合卡铂和pemetrexed (培美曲塞)用于治疗EGFR外显子 19 缺失或外显子 21 L858R 置换突变的局部晚期或转移性非小细胞肺癌 (NSCLC)，且在接受 EGFR 酪氨酸激酶抑制剂治疗期间/后病情出现进展。

MARIPOSA-2 (NCT04988295) 是一项随机, 开放标签, 多中心试验，试验对象为 657 名局部晚期或转移性 NSCLC 患者，这些患者存在 EGFR 外显子 19 缺失或外显子 21 L858R 替代突变，且在接受奥希替尼治疗时或之后病情出现进展。患者按 1:2:2 的比例随机接受amivantamab与卡铂和培美曲塞 (amivantamab + CP),卡铂和培美曲塞(CP)或amivantamab 作为另一种联合方案的一部分。 主要疗效结果指标是无进展生存期，由盲法独立中央审查评估。总体响应率和总体生存期是关键的次要结果指标。

Amivantamab + CP 组的中位无进展生存期为 6.3 个月（95% CI：5.6, 8.4），CP 组的中位中位无进展生存期为 4.2 个月（95% CI：4.0, 4.4）（风险比 0.48 [95% CI：0.36, 0.64]，p 值 <0.0001）。amivantamab + CP 组的确认总体响应率为 53%（95% CI：44, 62），CP 组的确认总体响应率为 29%（95% CI：23, 35）（p 值 <0.0001）。 在预先指定的 OS 第二次中期分析中，最终分析需要 85% 的死亡病例，OS 没有统计学上显着差异。分层总体生存期风险比为 0.73（95% CI：0.54, 0.99）。  

最常见的不良反应（≥20%）是皮疹, 输液相关反应, 疲劳, 指甲毒性, 恶心, 便秘, 水肿, 口腔炎, 食欲下降, 肌肉骨骼疼痛, 呕吐和 COVID-19 感染。 推荐的 amivantamab-vmjw 剂量基于基线体重。有关具体剂量信息，请参阅处方信息。

编者注:

作用机制: Amivantamab 是一种针对 EGFR 和 MET 的全人源双特异性抗体。其作用机制包括配体阻断, 受体降解和免疫细胞导向活性，例如抗体依赖性细胞毒性和吞噬作用。

剂量:

< 80 公斤

第 1 周第 1 天：350 毫克静脉注射 x 1 剂

第 1 周第 2 天：700 毫克静脉注射 x 1 剂

第 2-5 周：1,050 毫克静脉注射，每周一次

第 6 周：无剂量

第 7 周及之后：1,050 毫克静脉注射，每 2 周一次

≥80 公斤:

第 1 周第 1 天：350 毫克静脉注射 x 1 剂

第 1 周第 2 天：1,050 毫克静脉注射 x 1 剂

第 2-5 周：1,400 毫克静脉注射，每周一次

第 6 周：无剂量

第 7 周及之后：1,400 毫克静脉注射，每 2 周一次

On September 19, 2024, FDA approved amivantamab-vmjw in combination with carboplatin and pemetrexed for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR exon 19 deletion or exon 21 L858R substitution mutations, who have progressed during or after treatment with an EGFR tyrosine kinase inhibitor.

MARIPOSA-2 (NCT04988295) is a randomized, open-label, multicenter trial of 657 patients with locally advanced or metastatic NSCLC who have EGFR exon 19 deletion or exon 21 L858R substitution mutations and have progressed on or after treatment with osimertinib. Patients were randomized in a 1:2:2 ratio to receive amivantamab with carboplatin and pemetrexed (amivantamab + CP), carboplatin and pemetrexed (CP), or amivantamab alone as part of another combination regimen. The primary efficacy outcome measure was progression-free survival, assessed by blinded independent central review. Overall response rate and overall survival (OS) were key secondary outcome measures.

The median progression-free survival was 6.3 months (95% CI: 5.6, 8.4) in the amivantamab + CP group and 4.2 months (95% CI: 4.0, 4.4) in the CP group (hazard ratio 0.48 [95% CI: 0.36, 0.64], p-value <0.0001). The confirmed overall response rate was 53% (95% CI: 44, 62) in the amivantamab + CP group and 29% (95% CI: 23, 35) in the CP group (p-value <0.0001). At the pre-specified second interim analysis for OS, where 85% of deaths were required for the final analysis, there was no statistically significant difference in OS. The stratified OS hazard ratio was 0.73 (95% CI: 0.54, 0.99).

The most common adverse reactions (≥20%) were rash, infusion-related reactions, fatigue, nail toxicity, nausea, constipation, edema, stomatitis, decreased appetite, musculoskeletal pain, vomiting, and COVID-19 infection.

Editor’s Note:

Mechanism of Action: Amivantamab is a fully human bispecific antibody targeting EGFR and MET. Its mechanism of action includes ligand blockade, receptor degradation, and immune cell-directed activities such as antibody-dependent cellular cytotoxicity and phagocytosis.

Dosage:

< 80 kg

Week 1 Day 1: 350 mg IV x 1 dose

Week 1 Day 2: 700 mg IV x 1 dose

Weeks 2-5: 1,050 mg IV once weekly

Week 6: No dose

Weeks 7 and thereafter: 1,050 mg IV once every 2 weeks

≥ 80 kg:

Week 1 Day 1: 350 mg IV x 1 dose

Week 1 Day 2: 1,050 mg IV x 1 dose

Weeks 2-5: 1,400 mg IV once weekly

Week 6: No dose

Weeks 7 and thereafter: 1,400 mg IV once every 2 weeks

参考文献 Reference

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-amivantamab-vmjw-carboplatin-and-pemetrexed-non-small-cell-lung-cancer-egfr-exon-19

Cho BC et al. Clin Lung Cancer 2023; 24: 89

https://reference.medscape.com/drug/rybrevant-amivantamab-4000216

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Atezolizumab, venetoclax 和 obinutuzumab 联合治疗 Richter 转化型弥漫性大 B 细胞淋巴瘤 (DLBCL) (9/28/2024)

Atezolizumab, venetoclax, and obinutuzumab combination in Richter transformation diffuse large B-cell lymphoma (MOLTO)

方法: 这是一项前瞻性, 开放标签, 多中心, 单组, 研究者发起的 II 期研究(MOLTO, NCT04082897)，在意大利和瑞士的 15 家医院进行。符合条件的患者必须确诊为慢性淋巴细胞白血病或小淋巴细胞淋巴瘤，且活检证实已转化为 DLBCL；之前未接受过 DLBCL- Richter转化型治疗(可以接受过慢性淋巴细胞白血病治疗)。不允许之前使用三联疗法中的任何一种药物进行治疗。患者接受了 35 个周期, 每个周期 21 天的静脉注射obinutuzumab（第 1 天 100 mg, 第 2 天 900 mg, 第 1 周期第 8 天和第 15 天 1000 mg；第 2-8 周期第 1 天 1000 mg）和静脉注射atezolizumab（第 1 周期第 2 天 1200 mg, 第 2-18 周期第 1 天 1200 mg），以及持续口服venetoclax（根据慢性淋巴细胞白血病治疗方案，从第 1 周期第 15 天开始逐渐增加剂量为 20 mg/天，然后从第 3 周期第 1 天开始逐渐增加剂量为 400 mg/天，直至第 35 周期第 21 天）。主要终点是意向治疗人群在第 6 周期第 21 天的总体响应率。总体响应率为 67% 或更高才具有临床活性，拒绝了响应率为 40% 或更低的零假设。

结果: 2019 年 10 月 9 日至 2022 年 10 月 19 日期间，共招募了 28 名患者（12 名 [43%] 男性患者和 16 名 [57%] 女性患者）。中位随访时间为 16.8 个月（IQR 7.8–32.0）。在第 6 个周期，28 名患者中有 19 名出现响应，总体响应率为 67.9%（95% CI 47.6–84.1）。 28 名患者中有 17 名 (61%；95% CI 40.6–78.5) 报告了 3 级或更严重的治疗引起的不良事件，其中最常见的是中性粒细胞减少症（28 名患者中有 11 名 [39%；21.5–59.4]）。8 名 (29%；14.2–48.7) 患者报告了严重的治疗引起的不良事件，最常见的是感染（28 名患者中有 5 名 [18%；6.1–36.9]）。研究期间有 2 例 (7%) 患者死于不良事件：一例死于败血症，一例死于真菌性肺炎，研究人员认为这些事件与治疗没有直接关系。6 名 (21.4%) 患者发生了免疫相关不良事件，但均未导致停药。未观察到肿瘤溶解综合征。  

解释: Atezolizumab, venetoclax 和 Obinutuzumab 三联疗法被证明有效且安全，这种无化疗方案可能成为 DLBCL- Richter转化型患者的新一线治疗方法。

Methods: This was a prospective, open-label, multicenter, single-arm, investigator-initiated phase II study (MOLTO, NCT04082897) conducted in 15 hospitals in Italy and Switzerland. Eligible patients must  have a confirmed diagnosis of chronic lymphocytic leukemia or small lymphocytic lymphoma with biopsy-proven transformation to DLBCL; no previous treatment for DLBCL- Richter transformation (previous treatment for chronic lymphocytic leukemia was acceptable). Previous treatment with any of the drugs in the triplet therapy was not allowed. Patients received 35 cycles of 21-day intravenous obinutuzumab (100 mg on day 1, 900 mg on day 2, 1000 mg on days 8 and 15 of cycle 1; 1000 mg on day 1 of cycles 2-8) and intravenous atezolizumab (1200 mg on day 2 of cycle 1, 1200 mg on day 1 of cycles 2-18), as well as continuous oral venetoclax (according to the chronic lymphocytic leukemia treatment protocol, starting at 20 mg/day on day 15 of cycle 1, then gradually increasing to 400 mg/day starting on day 1 of cycle 3 until day 21 of cycle 35). The primary endpoint was the overall response rate on day 21 of cycle 6 in the intention-to-treat population. An overall response rate of 67% or higher was considered clinically active, rejecting the null hypothesis of a response rate of 40% or lower.

Results: Between Oct 9, 2019, and Oct 19, 2022, 28 patients (12 [43%] males and 16 [57%] females) were enrolled. The median follow-up was 16.8 months (IQR 7.8–32.0). At cycle 6, 19 of 28 patients responded, for an overall response rate of 67.9% (95% CI 47.6–84.1). Seventeen of 28 patients (61%; 95% CI 40.6–78.5) reported grade 3 or higher treatment-emergent adverse events, the most common of which was neutropenia (11 of 28 patients [39%; 21.5–59.4]). Eight patients (29%; 14.2–48.7) reported serious treatment-emergent adverse events, the most common of which was infection (five of 28 patients [18%; 6.1–36.9]). Two patients (7%) died during the study due to adverse events: one from sepsis and one from fungal pneumonia, which were not considered directly related to treatment by the investigators. Six patients (21.4%) had immune-related adverse events, none of which led to discontinuation of treatment. Tumor lysis syndrome was not observed.

Interpretation: The triple combination of atezolizumab, venetoclax, and obinutuzumab was shown to be effective and safe, and this chemotherapy-free regimen may become a new first-line treatment for patients with DLBCL-Richter transformation.

参考文献 Reference

Tedeschi A et al. Lancet Onc 2024; Sept 10.

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FDA 批准ribociclib与芳香酶抑制剂联合用于治疗早期高风险乳腺癌 (9/22/2024)

FDA approves ribociclib with an aromatase inhibitor for early high-risk breast cancer

2024 年 9 月 17 日，FDA批准ribociclib与芳香酶抑制剂，用于辅助治疗激素受体阳性, HER2阴性且复发风险较高的 II 期和 III 期乳腺癌。

疗效和安全性: NATALEE (NCT03701334) 是一项随机, 开放标签, 多中心试验，对 5101 名激素受体阳性, HER2 阴性早期乳腺癌患者进行了疗效评估。试验包括1) 任何淋巴结受累（不包括微观淋巴结受累）的患者，2) 淋巴结阴性，肿瘤 > 5 厘米，3) 肿瘤为 2 至 5 厘米，且为 2 级（且基因组风险高或 Ki67 ≥ 20%）或 3 级。 参与者随机（1:1）接受ribociclib（400 毫克）+ 芳香酶抑制剂或单独接受芳香酶抑制剂；患者可以根据指示接受goserelin。主要疗效结果指标是无浸润性疾病生存期, 其定义为以下情况的首次发生：局部或区域性浸润性乳腺复发, 远处复发, 任何原因导致的死亡, 对侧浸润性乳腺癌或继发性原发性非乳腺浸润性癌症。

在中期分析中，意向治疗患者群体的无浸润性疾病生存期有统计学显著改善。最终分析显示，ribociclib + 芳香酶抑制剂组 36 个月时的无浸润性疾病生存期为 90.7%（95% CI：89.3, 91.8）, 芳香酶抑制剂组为 87.6%（95% CI：86.1, 88.9）, 风险比为 0.749（95% CI：0.628, 0.892）。在无浸润性疾病生存期最终分析时，总生存期尚未成熟。  

NATALEE 试验中观察到的不良反应与 ribociclib 与芳香酶抑制剂联合使用的当前安全性特征一致。在辅助治疗中，建议的ribociclib剂量为口服400毫克（两片200毫克薄膜包衣片），每天一次，连续21天，然后停药7天，治疗周期为28天。

On September 17, 2024, FDA approved ribociclib with an aromatase inhibitor for the adjuvant treatment of hormone receptor-positive, HER2-negative stage II and III breast cancer at high risk of recurrence.

Efficacy and Safety: NATALEE (NCT03701334) was a randomized, open-label, multicenter trial evaluating efficacy in 5,101 patients with hormone receptor-positive, HER2-negative early-stage breast cancer. The trial included patients with 1) any lymph node involvement (excluding microscopic lymph node involvement), 2) node-negative with tumors > 5 cm, and 3) tumors 2 to 5 cm and grade 2 (and high genomic risk or Ki67 ≥ 20%) or grade 3. Participants were randomized (1:1) to receive ribociclib (400 mg) + an aromatase inhibitor or an aromatase inhibitor alone; patients could receive goserelin as indicated. The primary efficacy outcome measure was invasive disease-free survival, defined as the first occurrence of the following: local or regional invasive breast recurrence, distant recurrence, death from any cause, contralateral invasive breast cancer, or secondary primary non-breast invasive cancer.

At the interim analysis, there was a statistically significant improvement in invasive disease-free survival in the intention-to-treat population. The final analysis showed invasive disease-free survival at 36 months was 90.7% (95% CI: 89.3, 91.8) in the ribociclib + aromatase inhibitor group and 87.6% (95% CI: 86.1, 88.9) in the aromatase inhibitor group, with a hazard ratio of 0.749 (95% CI: 0.628, 0.892). Overall survival was not mature at the time of the final analysis of invasive disease-free survival.

Adverse reactions observed in the NATALEE trial are consistent with the current safety profile of ribociclib in combination with aromatase inhibitors.

In adjuvant therapy, the recommended dose of ribociclib is 400 mg (two 200 mg film-coated tablets) taken orally once daily for 21 days, followed by 7 days off, for a treatment cycle of 28 days.

参考文献 Reference

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ribociclib-aromatase-inhibitor-and-ribociclib-and-letrozole-co-pack-early-high-risk-0

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晚期胃肠道癌多药治疗方案中省略 5-FU 推注 (9/21/2024)

Omission of bolus 5-FU from multidrug regimes for advanced GI cancers

这是一项大型回顾性队列研究，研究人员分析了 2011 年 1 月至 2022 年 5 月期间美国约280 家癌症诊所中 11,765 名被诊断为晚期结直肠癌, 胃食管癌和胰腺癌的患者的治疗结果。仅当患者接受 NCCN 指南推荐的用于治疗转移性/晚期胃肠道癌症的一线治疗的 FOLFOX, FOLFIRI 或 FOLFIRINOX 时，才纳入研究。然后, 确定了患者在接受多药 5-FU 化疗（包括和不包括 5-FU 推注成分）后的安全性和生存率。 研究人员发现，在 13.7% 未接受 5-FU 推注成分作为治疗方案一部分的患者中，总生存率没有下降。然而，这些患者的血细胞减少症（包括中性粒细胞减少症或血小板减少症）显著减少。

结论: 这项研究表明在晚期胃肠道癌症中，不需要将 5-FU 推注与 FOLFOX/FOLFIRI/FOLFIRINOX 方案一起使用。

This is a large retrospective cohort study in which researchers analyzed treatment outcomes for 11,765 patients diagnosed with advanced colorectal, gastroesophageal, and pancreatic cancers seen in approximately 280 cancer clinics in the United States between January 2011 and May 2022. Patients were included in the study only if they were receiving FOLFOX, FOLFIRI, or FOLFIRINOX as recommended by the NCCN guidelines for first-line treatment of metastatic/advanced gastrointestinal cancers. The safety and survival of patients after receiving multi-agent 5-FU chemotherapy with and without a 5-FU bolus component were determined.

It was found that overall survival was not reduced in the 13.7% of patients who did not receive a 5-FU bolus component as part of their treatment regimen. However, these patients experienced significantly fewer cytopenias, including neutropenia or thrombocytopenia.

Conclusions: This study suggests that bolus 5-FU is not necessary with the FOLFOX/FOLFIRI/FOLFIRINOX regimen in advanced gastrointestinal cancers.

参考文献 Reference

Peng C et al. JNCCN 2024; DOI: https://doi.org/10.6004/jnccn.2024.7029

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新辅助 Durvalumab (D) + 定向抗体-药物偶联物 + 化疗用于可切除非小细胞肺癌 (9/15/2024)

Neoadjuvant durvalumab + directed antibody-drug conjugate + chemotherapy in resectable NSCLC (Neocoast-2 trial)

方法：这是一项开放标签、多中心, II期 NeoCOAST-2 多臂平台研究 (NCT05061550)。未经治疗, 可切除的 IIA-IIIB 期 NSCLC 患者根据 PD-L1 表达情况分层（<1% vs ≥1%），并随机分配至第 1 组：新辅助 D + 铂双药化疗 + oleclumab（抗 CD73 单抗），第 2 组：D + 铂双药化疗 + monalizumab（抗 NKG2A单抗），或第 4 组：D + 单药铂类化疗 + Dato-DXd（TROP2 定向抗体-药物偶联物）。手术前给予 4 个周期3星期一次的新辅助治疗，然后以 D + 奥利珠单抗（第 1 组）或莫那珠单抗（第 2 组）或单独治疗（第 4 组）进行辅助治疗，直至疾病进展或长达 1 年。主要终点是病理性完全病理响应率, 安全性和耐受性。关键次要终点包括研究者评估的无事件生存期,  手术可行性, 主要病理响应率和客观响应率。   

结果：截至 2024 年 6 月 17 日，202 名患者被随机分配（第 1 组，n =76；第 2 组，n =72；第 4 组，n =54）。各组之间的基线特征平衡。在接受或不适合手术的患者中，第 1, 2 和 4 组中分别有 59/64 (92.2%), 58/63 (92.1%) 和 46/48 (95.8%) 名患者接受了手术。在改良意向治疗人群中，第 1, 2 和 4 组的病理性完全响应率分别为 20%, 26.7% 和 34.1%，而主要病理响应率分别为 45%、53.3% 和 65.9%。总体而言，无论 PD-L1 状态如何，第 4 组的病理性完全响应率和主要病理响应率在数值上都更高。

第 1 组中 95.9% 的患者, 第 2 组中 91.5% 的患者和第 4 组中 96.3% 的患者发生了治疗相关不良事件。≥3 级 TRAE 的发生率分别为 33.8%、38.0% 和 18.5%。

结论：对于早期可切除 NSCLC 患者，第 4 组的病理性完全响应 率最高。所有组的治疗均提高了主要病理响应率，并且安全性和手术率与目前批准的新辅助和围手术期免疫治疗方案相当。这是第一项全球II期平台研究，显示抗体-药物偶联物在新辅助 NSCLC 治疗中具有令人鼓舞的疗效和可控的安全性。

Methods: This is an open-label, multicentre, phase (Ph) 2 NeoCOAST-2 multi-arm platform study (NCT05061550). Patients with untreated, resectable stage IIA-IIIB NSCLC were stratified by PD-L1 expression (<1% vs ≥1%) and randomized to group 1: neoadjuvant D + platinum doublet chemotherapy + oleclumab (anti-CD73 mAb), group 2: D + platinum doublet chemotherapy + monalizumab (anti-NKG2A mAb), or group 4: D + single-agent platinum chemotherapy + Dato-DXd (TROP2-directed antibody-drug conjugate). Four cycles of 3-weekly neoadjuvant therapy were given before surgery, followed by adjuvant therapy with D + oleclumab (group 1) or monalizumab (group 2) or alone (group 4) until disease progression or up to 1 year. Primary endpoints were pathological complete response rate, safety, and tolerability. Key secondary endpoints included investigator-assessed event-free survival, surgical feasibility, major pathological response rate, and objective response rate.

Results: As of June 17, 2024, 202 patients were randomized (Group 1, n =76; Group 2, n =72; Group 4, n =54). Baseline characteristics were balanced between groups. Among patients who were eligible or not suitable for surgery, 59/64 (92.2%), 58/63 (92.1%), and 46/48 (95.8%) patients in Groups 1, 2, and 4 underwent surgery, respectively. In the modified intention-to-treat population, the pathological complete response rates were 20%, 26.7%, and 34.1%, and the major pathological response rates were 45%, 53.3%, and 65.9%, respectively, in Groups 1, 2, and 4. Overall, group 4 had numerically higher pathological complete response and major pathological response rates, regardless of PD-L1 status.

Treatment-related adverse events occurred in 95.9% of patients in group 1, 91.5% in group 2, and 96.3% in group 4. The incidence of grade ≥3 TRAEs was 33.8%, 38.0%, and 18.5%, respectively.

Conclusions: Group 4 had the highest pathological complete response rate for patients with early-stage resectable NSCLC. Treatment in all groups improved major pathological response rates with a safety profile and surgical rates comparable to currently approved neoadjuvant and perioperative immunotherapy regimens. This is the first global phase II platform study showing encouraging efficacy and manageable safety of antibody-drug conjugates in neoadjuvant NSCLC.

参考文献 Reference

Cascone T et al. 2024 World Conference Lung Cancer 2024; abstr 02.07

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帕博利珠单抗联合化疗治疗酪氨酸激酶抑制剂耐药,  EGFR 突变, 转移性非小细胞肺癌 (9/13/2024)

Pembrolizumab in combination with chemotherapy for TKI‒resistant, EGFR–mutant, metastatic NSCLC

目的:研究者报告了随机, 双盲, III 期 KEYNOTE-789 研究的结果，该研究使用培美曲塞和铂类化疗联合或不联合帕博利珠单抗治疗 TKI 耐药, EGFR 突变, 转移性非鳞状 NSCLC（NCT03515837）。

方法: 经病理学确诊的 IV 期非鳞状 NSCLC 病人, 患者 DEL19 或 L858R EGFR 突变，EGFR-TKI 治疗后病情进展，随机按 1:1 分为 35 个周期的派姆单抗 200 mg 或安慰剂，每 3 周一次，加上 4 个周期的培美曲塞和卡铂或顺铂，每 3 周一次，然后维持培美曲塞。两个主要终点是无进展生存期和总生存期。最终无进展生存期测试在第二次中期分析 (数据截止时间为 2021 年 12 月 3 日) 时完成；总生存期在最终分析 (数据截止时间为 2023 年 1 月 17 日) 时进行测试。   

结果: 492 名患者被随机分配接受派姆单抗联合化疗 (n = 245) 或安慰剂联合化疗 (n = 247)。在第二次中期分析 时，派姆单抗联合化疗的中位无进展生存期为 5.6 个月，而安慰剂联合化疗为 5.5 个月（风险比 [HR]，0.80 [95% CI，0.65 至 0.97]；P = .0122）。在最终分析时，中位总生存期分别为 15.9 个月和 14.7 个月（HR，0.84 [95% CI，0.69 至 1.02]；P = .0362）。43.7% 的派姆单抗联合化疗患者发生了 ≥3 级治疗相关不良事件，而安慰剂联合化疗患者为 38.6%。  

结论: 在 KEYNOTE-789 试验中，对于 TKI 耐药, EGFR 突变, 转移性非鳞状 NSCLC 患者，化疗中添加派姆单抗与安慰剂加化疗相比，并未显著延长无进展生存期或总生存期。

Purpose: Researchers reported results from the randomized, double-blind, phase III KEYNOTE-789 study of pemetrexed and platinum chemotherapy with or without pembrolizumab in TKI-resistant, EGFR-mutated, metastatic nonsquamous NSCLC (NCT03515837).

Methods: Patients with pathologically confirmed stage IV nonsquamous NSCLC, recorded DEL19 or L858R EGFR mutations, and disease progression after EGFR-TKI therapy were randomized 1:1 to 35 cycles of pembrolizumab 200 mg or placebo every 3 weeks, plus 4 cycles of pemetrexed and carboplatin or cisplatin every 3 weeks, followed by maintenance pemetrexed. The two primary endpoints were progression-free survival and overall survival. Final progression-free survival testing was completed at the second interim analysis (data cutoff, December 3, 2021); overall survival was tested at the final analysis (data cutoff, January 17, 2023).

Results: 492 patients were randomly assigned to receive pembrolizumab plus chemotherapy (n = 245) or placebo plus chemotherapy (n = 247). At the second interim analysis, median progression-free survival was 5.6 months with pembrolizumab plus chemotherapy and 5.5 months for placebo plus chemotherapy (hazard ratio [HR], 0.80 [95% CI, 0.65 to 0.97]; P = .0122). At the final analysis, median overall survival was 15.9 months and 14.7 months, respectively (HR, 0.84 [95% CI, 0.69 to 1.02]; P = .0362). Grade ≥3 treatment-related adverse events occurred in 43.7% of patients who received pembrolizumab plus chemotherapy and in 38.6% of those who received placebo plus chemotherapy.

Conclusions: In the KEYNOTE-789 trial, the addition of pembrolizumab to chemotherapy did not significantly prolong progression-free survival or overall survival compared with placebo plus chemotherapy in patients with TKI-resistant, EGFR-mutated, metastatic nonsquamous NSCLC.

参考文献 Reference

Yang J C-H et al. J Clin Onc 2024; https://doi.org/10.1200/JCO.23.027

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劳拉替尼与克唑替尼在晚期 ALK 阳性非小细胞肺癌中的疗效对比： CROWN 研究的 5 年结果 (9/8/2024)

Lorlatinib versus Crizotinib in advanced ALK-positive NSCLC: 5-year outcomes from the CROWN study

在 III 期 CROWN 研究中，劳拉替尼与克唑替尼相比，改善了未经治疗的晚期 ALK 阳性非小细胞肺癌 (NSCLC) 患者的无进展生存期和颅内活动。

方法: 296 名 ALK 阳性 NSCLC 患者按 1:1 的比例随机分配接受劳拉替尼 100 mg 每日一次 (n = 149) 或克唑替尼 250 mg 每日两次 (n = 147)。

结果: 无进展生存期的中位随访时间分别为 60.2 个月和 55.1 个月，劳拉替尼组未达到中位无进展生存期（NR [95% CI，64.3 至 NR]），克唑替尼组为 9.1 个月（95% CI，7.4 至 10.9）（风险比 [HR]，0.19 [95% CI，0.13 至 0.27]）；5 年无进展生存期分别为 60%（95% CI，51 至 68）和 8%（95% CI，3 至 14）。劳拉替尼治疗组颅内进展中位时间为未达到（95% CI，未达到至未达到），克唑替尼治疗组颅内进展中位时间为 16.4 个月（95% CI，12.7 至 21.9）（HR，0.06 [95% CI，0.03 至 0.12]）。安全性与之前的分析一致。在劳拉替尼治疗结束时收集的循环肿瘤 DNA 中未检测到新出现的 ALK 耐药突变。

结论: 经过 5 年的随访，劳拉替尼组尚未达到中位未达到，相当于迄今为止报道的晚期 NSCLC 和所有转移性实体瘤中任何单药分子靶向治疗的最长无进展生存期。这些结果加上延长的颅内疗效和没有新的安全信号，代表了晚期 ALK 阳性 NSCLC 患者前所未有的结果。

In the phase III CROWN study, lorlatinib improved progression-free survival and intracranial activity compared with crizotinib in patients with previously untreated advanced ALK-positive non-small cell lung cancer (NSCLC).

Methods: 296 patients with ALK-positive NSCLC were randomized 1:1 to receive lorlatinib 100 mg once daily (n = 149) or crizotinib 250 mg twice daily (n = 147).

Results: With a median follow-up of 60.2 months, the median progression-free survival was not reached (NR [95% CI, 64.3 to NR]) with lorlatinib and 9.1 months (95% CI, 7.4 to 10.9) with crizotinib (hazard ratio [HR], 0.19 [95% CI, 0.13 to 0.27]); the 5-year progression-free survival was 60% (95% CI, 51 to 68) and 8% (95% CI, 3 to 14), respectively. The median time to intracranial progression was not reached (95% CI, not reached to not reached) with lorlatinib and 16.4 months (95% CI, 12.7 to 21.9) with crizotinib (HR, 0.06 [95% CI, 0.03 to 0.12]). Safety was consistent with previous analyses. No new ALK resistance mutations were detected in circulating tumor DNA collected at the end of lorlatinib treatment. Conclusions: After 5 years of follow-up, the median progression-free-survival has not reached with lorlatinib, corresponding to the longest progression-free survival reported to date for any single-agent molecular targeted therapy in advanced NSCLC and all metastatic solid tumors. These results, combined with the prolonged intracranial efficacy and the absence of new safety signals, represent unprecedented outcomes for patients with advanced ALK-positive NSCLC. 

参考文献 Reference

Solomon BJ et al. J Clin Onc 2024: https://doi.org/10.1200/JCO.24.00581

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Sacituzumab Govitecan 治疗乳腺癌脑转移和复发性胶质母细胞瘤患者 (9/7/2024)

Sacituzumab Govitecan in patients with breast cancer brain metastases and recurrent glioblastoma

Sacituzumab Govitecan (SG) 是一种抗体-药物偶联物，已证明对 TROP-2 表达上皮癌患者有效。在颅内乳腺癌异种移植模型中，SG 抑制了肿瘤生长并提高了小鼠存活率。

研究者进行了一项前瞻性0 期机会窗口试验 (NCT03995706)，以检查接受开颅手术治疗乳腺癌脑转移 (BCBM) 或复发性胶质母细胞瘤 (rGBM) 患者的 SG 肿瘤内浓度和颅内活性。一共招募了 25 名年龄 ≥ 18 岁, 确诊为 BCBM 和 rGBM 的患者，在切除术前一天接受单次静脉注射 10 mg/kg SG，并在恢复后 21 天周期的第 1 天和第 8 天继续给药。

在术后组织中，BCBM 的中位总 SN-38 为 249.8 ng/g，rGBM 的中位总 SN-38 为 104.5 ng/g，从而达到了主要终点。生物标志物分析表明有效载荷通过直接释放到目标部位，而缺氧变化不会导致间接释放。BCBM 和 rGBM 组的无进展生存期分别为 8 个月和 2 个月。次要终点总生存期为 BCBM 队列 35.2 个月，rGBM 9.5 个月。非计划探索性终点响应率分别为 BCBM 38% 和 29%。在 100% 的 BCBM 肿瘤和 78% 的 rGBM 肿瘤中观察到 Trop-2 表达的探索性终点。 

≥3 级副作用包括中性粒细胞减少症 (28%), 低钾血症 (8%),  癫痫发作 (8%), 血栓栓塞事件 (8%), 尿路感染 (8%) 和下肢肌无力 (8%)。

总之，SG 被发现耐受性良好，能够充分渗透到颅内肿瘤中，并在中枢神经系统内具有良好的初步活性。

Sacituzumab Govitecan (SG) is an antibody-drug conjugate that has demonstrated efficacy in patients with TROP-2-expressing epithelial cancers. In an intracranial breast cancer xenograft model, SG inhibited tumor growth and improved mouse survival.

Researchers conducted a prospective phase 0 window-of-opportunity trial (NCT03995706) to examine SG intratumoral concentrations and intracranial activity in patients undergoing craniotomy for breast cancer brain metastases (BCBM) or recurrent glioblastoma (rGBM). A total of 25 patients aged ≥ 18 years with confirmed BCBM and rGBM were enrolled and received a single intravenous injection of 10 mg/kg SG one day before resection and continued on days 1 and 8 of a 21-day cycle after recovery.

In postoperative tissue, median total SN-38 was 249.8 ng/g for BCBM and 104.5 ng/g for rGBM, thus meeting the primary endpoint. Biomarker analysis indicated that the payload was delivered to the target site via direct release, without indirect release due to hypoxic changes. Progression-free survival was 8 months and 2 months in the BCBM and rGBM groups, respectively. The secondary endpoint of overall survival was 35.2 months for the BCBM cohort and 9.5 months for rGBM. Unplanned exploratory endpoint response rates were 38% and 29% for BCBM, respectively. The exploratory endpoint of Trop-2 expression was observed in 100% of BCBM tumors and 78% of rGBM tumors.

Grade ≥3 adverse events included neutropenia (28%), hypokalemia (8%), seizures (8%), thromboembolic events (8%), urinary tract infections (8%), and lower extremity weakness (8%).

In conclusion, SG was found to be well tolerated, to penetrate adequately into intracranial tumors, and to have good initial activity within the CNS.

参考文献 Reference

Balinda HU et al. Nature Communications 2024;15:6707

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NX-5948 , 一种首次应用人类BTK 降解剂在难治性慢性淋巴细胞白血病患者中的应用 (9/1/2024)

First in human BTK degrader, NX-5948 in refractory CLL patients

NX-5948 是一种口服布鲁顿酪氨酸激酶 (BTK) 降解剂，在正在进行的 1a/b 期临床试验中，该试验针对复发或难治性 B 细胞恶性肿瘤患者，包括慢性淋巴细胞白血病 (CLL) 和非霍奇金淋巴瘤 (NHL)。欧洲血液学协会大会上展示的数据包括第 1a 阶段剂量递增研究中所有患者的安全性结果，无论诊断如何（n =79），以及复发或难治性慢性淋巴细胞白血病患者的疗效结果（n =31）。患者每日口服一次 NX-5948，剂量范围从 50 毫克到 600 毫克。NX-5948 在所有剂量下均具有良好的耐受性，最常见的治疗不良事件是紫癜/挫伤, 血小板减少和中性粒细胞减少。

在可评估疗效的 CLL 患者（n =26）中，NX-5948 治疗在所有测试剂量中均获得了 69.2% 的客观响应率 (ORR)，早在第一次扫描（8 周）时就观察到响应，并且许多患者的响应随着治疗时间的延长而加深。截至 4 月 17 日数据截止，所有响应仍持续。这群 CLL 患者是一群接受过大量治疗的人群，他们接受过中位数为四种先前治疗（范围 = 2-14）的治疗，包括先前共价 BTK 抑制剂（96.8%）, 先前 BCL2 抑制剂（90.3%）和先前非共价 BTK 抑制剂（25.8%）。在基线时，大量患者具有与 BTK 抑制剂耐药相关的突变，包括 BTK（43.3%）和 PLC2G（20.0%）的突变。不良预后特征很常见，包括 TP53 突变 (46.7%), 两名患者 (6.5%) 有中枢神经系统受累。无论先前接受过何种治疗、基线突变或 CNS 受累，所有人群均观察到响应。   

有一位CLL患者并受 CNS 受累, 在接受过三种先前疗法（包括 BTK 抑制剂治疗）后进入研究。在每天接受 100 毫克、随后 300 毫克 NX-5948 治疗后，患者表现出加深的响应，在 36 周内接近完全响应标准，并在 24 周内消除脑脊液中的恶性细胞。另一名患者曾接受过 11 种先前疗法，包括所有可用的 BTK 抑制剂（依鲁替尼, 阿卡替尼, 赞布替尼和吡托替尼）。每天服用 200 毫克 NX-5948 后，患者在第 8 周时获得响应，并且随着时间的推移，响应程度不断加深，并且持续了超过 6 个月的随访。

研究者将在一系列 CLL 亚群中扩大试验的 1b 期部分，为 2025 年启动关键的注册指导临床评估做准备。

NX-5948 is an oral Bruton’s tyrosine kinase (BTK) degrader. It is being tested in phase Ia/b clinical trial in patients with relapsed or refractory B-cell malignancies, including chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL). Data presented at the European Association of Hematology Meeting included safety results for all patients in the phase 1a dose-escalation study, regardless of diagnosis (n =79), and efficacy results for patients with relapsed or refractory CLL (n =31). Patients received NX-5948 orally once daily at doses ranging from 50 mg to 600 mg. NX-5948 was well tolerated at all doses, with the most common treatment-related adverse events being purpura/contusion, thrombocytopenia, and neutropenia.

In efficacy-evaluable CLL patients (n = 26), NX-5948 treatment resulted in an objective response rate (ORR) of 69.2% across all doses tested, with responses observed as early as the first scan (week 8) and responses deepening with treatment duration in many patients. All responses were ongoing as of the April 17 data cutoff. This cohort of CLL patients was a heavily pre-treated population, having received a median of four prior lines of therapy (range = 2-14), including prior covalent BTK inhibitors (96.8%), prior BCL2 inhibitors (90.3%), and prior non-covalent BTK inhibitors (25.8%). At baseline, a significant number of patients had mutations associated with BTK inhibitor resistance, including mutations in BTK (43.3%) and PLC2G (20.0%). Poor prognostic features were common, including TP53 mutations (46.7%), and two patients (6.5%) had CNS involvement. Responses were observed in all populations regardless of prior therapy, baseline mutations, or CNS involvement. One patient with CLL and CNS involvement entered the study after three prior lines of therapy, including a BTK inhibitor. After receiving 100 mg followed by 300 mg of NX-5948 daily, the patient demonstrated a deepening response, approaching complete response criteria at 36 weeks with elimination of malignant cells in the cerebrospinal fluid at 24 weeks. The other patient had received 11 prior lines of therapy, including all available BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib, and pirtobrutinib). Patients who took 200 mg of NX-5948 daily achieved responses at week 8, with responses increasing over time and sustained over 6 months of follow-up.

Investigators will expand the phase 1b portion of the trial across a range of CLL subpopulations in preparation for the launch of a pivotal registration-directed clinical evaluation in 2025.

参考文献 Reference

Linton K. Eur Hemat Asso Meeting 2024; abstr S155

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血液中白细胞介素 6 的水平可预测 2 型糖尿病患者中与肥胖相关癌症风险 (8/31/2024)

Circulating levels of interleukin-6 predict risk of obesity-related cancers in those with recently diagnosed type 2 diabetes

背景: 2 型糖尿病患者更容易患上肥胖相关癌症（包括乳腺癌,  肾细胞癌, 子宫内膜癌, 直肠癌, 胰腺癌, 甲状腺癌和卵巢癌）和多发性骨髓瘤。 研究表明，肥胖和 2 型糖尿病中普遍存在的慢性低度炎症可能在这两种疾病的癌症发展中发挥重要作用。促炎细胞因子是加剧炎症的免疫系统蛋白。

研究方法和结果: 在这项研究中，研究人员检查了促炎细胞因子水平的差异是否有助于预测 6,466 名最近被诊断患有 2 型糖尿病的患者的肥胖相关癌症风险，这些患者的中位年龄为 60.9 岁。40.5% 的患者为女性。 研究人员测量了基线时促炎细胞因子白细胞介素 (IL)-6、肿瘤坏死因子 (TNF)-alpha 和高敏 C 反应蛋白的水平。IL-6 和 TNF-alpha 是由脂肪组织释放的，在 2 型糖尿病患者中通常含量较高。根据 IL-6 水平将参与者分为三类：IL-6 水平低于 0.94 pg/mL 的为最低三分之一，IL-6 水平在 0.94 至 1.58 pg/mL 之间的为中间三分之一，IL-6 水平高于 1.58 pg/mL 的为最高三分之一。

经过 8.8 年的随访，研究人员发现其中 327 名患者患上了肥胖相关癌症。基线时 IL-6 水平越高，患肥胖相关癌症的风险就越大。当根据年龄, 性别, 糖尿病持续时间, 饮酒量, 腰围, 体力活动, HbA1C, 甘油三酯水平, 降脂药物的使用和糖尿病药物的使用对结果进行调整后，与水平​​最低的患者相比，水平最高组患者患肥胖相关癌症的风险高出 51%。 此外，与 IL-6 相比，TNF-alpha 和高敏 C 反应蛋白与肥胖相关癌症的关联性较弱。吸烟状况的因素不会改变结果。当研究人员将基线 IL-6 水平添加到已知会增加肥胖相关癌症风险的其他因素中时，预测患者是否会患上肥胖相关癌症的能力会显著增加。相比之下，加入 TNF-alpha 或高敏 C 反应蛋白并没有改善预测模型。

结论: 较高的 IL-6 水平可能与新诊断为 2 型糖尿病患者的肥胖相关癌症的发展有关。血液测试可以识别出患癌症风险较高的人。

Background: People with type 2 diabetes are more likely to develop obesity-related cancers (including breast, renal cell, endometrial, colorectal, pancreatic, thyroid, and ovarian cancers) and multiple myeloma. Studies suggest that chronic, low-grade inflammation, which is common in obesity and type 2 diabetes, may play an important role in the development of cancer in both diseases. Proinflammatory cytokines are immune system proteins that exacerbate inflammation.

Methods and results: In this study, researchers examined whether differences in proinflammatory cytokine levels could help predict obesity-related cancer risk in 6,466 patients who had recently been diagnosed with type 2 diabetes and had a median age of 60.9 years. 40.5% of the patients were women. Researchers measured levels of the proinflammatory cytokines interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, and high-sensitivity C-reactive protein at baseline. IL-6 and TNF-alpha are released by fat tissue and are often higher in people with type 2 diabetes. Participants were divided into three categories based on IL-6 levels: the lowest third with IL-6 levels below 0.94 pg/mL, the middle third with IL-6 levels between 0.94 and 1.58 pg/mL, and the highest third with IL-6 levels above 1.58 pg/mL.

After 8.8 years of follow-up, the researchers found that 327 of the patients developed obesity-related cancers. The higher the IL-6 level at baseline, the greater the risk of obesity-related cancer. When the results were adjusted for age, sex, duration of diabetes, alcohol consumption, waist circumference, physical activity, HbA1C, triglyceride levels, use of lipid-lowering medications, and use of diabetes medications, patients in the highest group of IJ-6 had a 51% higher risk of obesity-related cancer compared with those in the lowest group. In addition, TNF-alpha and high-sensitivity C-reactive protein were less strongly associated with obesity-related cancers than IL-6.

Factoring in smoking status did not change the results. When researchers added baseline IL-6 levels to other factors known to increase the risk of obesity-related cancers, the ability to predict whether a patient would develop obesity-related cancer increased significantly. In contrast, adding TNF-alpha or high-sensitivity C-reactive protein did not improve the prediction model.

Conclusion: Higher IL-6 levels may be associated with the development of obesity-related cancers in people newly diagnosed with type 2 diabetes. Blood tests may be employed to identify people at higher risk of developing cancer.

参考文献 Reference

Bennetsen M et al. 60th Eur Asso for the Study of Diabetes Ann Meeting 2024; abstr 1026

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CAR-T 细胞与复发性高级别脑癌 (8/25/2024)

CAR-T cell therapy in recurrent high-grade glioma 

研究者报告了一项已完成的 I 期试验(NCT02208362)，该试验评估了 65 名复发性高级别胶质瘤患者中 IL-13Rα2 靶向 CAR-T 细胞的效果，这些患者大多数是复发性胶质母细胞瘤 (rGBM)。主要目标是安全性和可行性、最大耐受剂量/最大可行剂量和推荐的 II 期剂量计划。次要目标包括总体生存率, 疾病反应、细胞因子动力学和肿瘤免疫背景生物标志物。这项试验旨在评估三种局部区域 T 细胞给药途径[肿瘤内 (ICT), 脑室内 (ICV) 和 ICT/ICV]和两个制造平台，最终在第 5 组中采用 ICT/ICV 输送和优化的制造平台。

局部区域 CAR-T 细胞给药可行且耐受性良好，且由于所有组均未出现剂量限制性毒性，因此未确定最大耐受剂量。可能的治疗相关 3 级以上毒性包括 1 例 3 级脑病和 1 例 3 级共济失调。第 5 组的临床最大可行剂量为每个输注周期 200 × 10⁶ CAR-T 细胞；但是，由于制造可行性，其他组未测试或未达到此剂量。将根据本次试验的数据在未来的研究中完善推荐的 2 期剂量。

一共50% (29/58) 的患者病情稳定或更好，在停止方案后的额外 CAR-T 周期后出现两次部分响应、一次完全响应和第二次完全响应。对于 rGBM，所有患者的中位总生存期为 7.7 个月，第 5 组的中位总生存期为 10.2 个月。中枢神经系统炎症细胞因子（包括 IFNγ、CXCL9 和 CXCL10）的增加与 CAR-T 细胞给药和生物活性有关。治疗前肿瘤内 CD3 T 细胞水平与生存率呈正相关。

这些发现表明，局部区域 IL-13Rα2 靶向 CAR-T 疗法是安全的，并且在部分患者中具有良好的临床活性。

Researchers reported a completed phase I trial (NCT02208362) evaluating IL-13Rα2-targeted CAR-T cells in 65 patients with recurrent high-grade glioma, most of whom had recurrent glioblastoma (rGBM). The primary objectives were safety and feasibility, maximum tolerated dose/maximum feasible dose, and recommended phase II dose schedule. Secondary objectives included overall survival, disease response, cytokine dynamics, and tumor immune background biomarkers. The trial was designed to evaluate three locoregional T cell administration routes [intratumoral (ICT), intraventricular (ICV), and ICT/ICV] and two manufacturing platforms, culminating in cohort 5, which utilized ICT/ICV delivery and an optimized manufacturing process.

Locoregional CAR-T cell administration was feasible and well tolerated, and no maximum tolerated dose was determined because no dose-limiting toxicities were seen in all groups. Possible treatment-related grade ≥3 toxicities included 1 case of grade 3 encephalopathy and 1 case of grade 3 ataxia. The clinically feasible maximum dose for group 5 was 200 × 10⁶ CAR-T cells per infusion cycle; however, this dose was not tested or reached in other groups due to manufacturing feasibility. The recommended phase 2 dose will be refined in future studies based on data from this trial.

A total of 50% (29/58) of patients had stable disease or better, with two partial responses, one complete response, and a second complete response after additional CAR-T cycles after stopping the regimen. For rGBM, the median overall survival was 7.7 months for all patients and 10.2 months for group 5. Increases in CNS inflammatory cytokines, including IFNγ, CXCL9, and CXCL10, were associated with CAR-T cell administration and biological activity. Pretreatment intratumoral CD3 T cell levels positively correlated with survival.

These findings suggest that locoregional IL-13Rα2-targeted CAR-T therapy is safe and has good clinical activity in some patients.

参考文献 Reference

Brown CE. Nature Medicine 2024; 30:1001

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Belantamab Mafodotin,  泊马度胺和地塞米松在多发性骨髓瘤中的应用 (8/24/2024)

Belantamab mafodotin, pomalidomide, and dexamethasone in multiple myeloma

方法: 在这项 3 期随机开放标签试验中（NCT04484623），研究者比较了 belantamab mafodotin, 泊马度胺和地塞米松 (BPd) 相比于泊马度胺, 硼替佐米 (bortezomib) 和地塞米松 (PVd) 的疗效，这些患者接受过来那度胺治疗和至少一线治疗后出现复发或难治性骨髓瘤。主要终点是无进展生存期。还评估了疾病反应和安全性。

结果: 共有 302 名患者接受随机分组；155 名患者被分配到 BPd 组，147 名患者被分配到 PVd 组。中位随访时间为 21.8 个月（范围，<0.1 至 39.2），BPd 组的 12 个月估计无进展生存率为 71%（95% 置信区间 [CI]，63 至 78），而 PVd 组为 51%（95% CI，42 至 60）（疾病进展或死亡的风险比，0.52；95% CI，0.37 至 0.73；P <0.001）。总体生存数据尚不成熟。BPd 组对治疗有反应（部分反应或更好）的患者百分比为 77%（95% CI，70 至 84），PVd 组为 72%（95% CI，64 至 79）；分别有 40%（95% CI，32 至 48）和 16%（95% CI，11 至 23）的患者获得完全缓解或更好。

BPd 组 94% 的患者和 PVd 组 76% 的患者发生了 3 级或更高级别的不良事件。接受 BPd 治疗的患者中有 89%（43% 为 3 级或 4 级）和接受 PVd 治疗的患者中有 30%（2% 为 3 级或 4 级）发生了眼部事件；BPd 组的眼部事件通过调整 belantamab mafodotin 剂量进行管理。BPd 组有 9% 的患者因眼部事件而停止治疗，而 PVd 组没有患者停止治疗。

结论: 对于接受来那度胺治疗的复发或难治性骨髓瘤患者，BPd 在无进展生存期以及更深, 更持久的反应方面比 PVd 具有显著更大的益处。眼部事件很常见，但可以通过调整 belantamab mafodotin 剂量来控制。

Methods: In this phase 3, randomized, open-label trial (NCT04484623), researchers compared belantamab mafodotin, pomalidomide, and dexamethasone (BPd) with pomalidomide, bortezomib, and dexamethasone (PVd) in patients with relapsed or refractory myeloma who had received lenalidomide and at least one line of therapy. The primary endpoint was progression-free survival. Disease response and safety were also assessed.

Results: A total of 302 patients underwent randomization; 155 were assigned to the BPd group and 147 to the PVd group. With a median follow-up of 21.8 months (range, <0.1 to 39.2), the estimated 12-month progression-free survival rate was 71% (95% confidence interval [CI], 63 to 78) in the BPd group vs. 51% (95% CI, 42 to 60) in the PVd group (hazard ratio for disease progression or death, 0.52; 95% CI, 0.37 to 0.73; P < .001). Overall survival data were immature. The percentage of patients who had a response to treatment (partial response or better) was 77% (95% CI, 70 to 84) in the BPd group and 72% (95% CI, 64 to 79) in the PVd group; 40% (95% CI, 32 to 48) and 16% (95% CI, 11 to 23), respectively, had a complete response or better.

Grade 3 or higher adverse events occurred in 94% of patients in the BPd group and in 76% of patients in the PVd group. Ocular events occurred in 89% of patients treated with BPd (43% grade 3 or 4) and in 30% of patients treated with PVd (2% grade 3 or 4); ocular events in the BPd group were managed with dose adjustments of belantamab mafodotin. Ocular events led to treatment discontinuation in 9% of patients in the BPd group and in none of the patients in the PVd group.

Conclusions: BPd provided significantly greater benefits than PVd in terms of progression-free survival and deeper, more durable responses in patients with relapsed or refractory myeloma receiving lenalidomide. Ocular events were common but manageable with dose adjustments of belantamab mafodotin.

参考文献 Reference

M Athanasios et al. N Engl J Med 2024;391:408

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食管腺癌患者围手术期化疗 (FLOT) 优于新辅助放化疗 (CROSS) (8/18/2024)

Perioperative chemotherapy (FLOT protocol) is better than neoadjuvant chemoradiation (CROSS protocol) in esophageal cancer (ESOPEC trial)

ESOPEC (NCT02509286) 是一项多中心前瞻性随机试验，比较了新辅助 CROSS（41.4Gy 加卡铂/紫杉醇）后进行手术与围手术期 FLOT（5-FU/亚叶酸钙/奥沙利铂/多西他赛）和手术对局部晚期食管腺癌的治愈性治疗。

方法：cT1 cN+ cM0 或 cT2-4a cNany cM0 可切除局部晚期食管腺癌患者符合条件。主要终点是总生存期。 使用按研究地点分层的 Cox 回归估计治疗对总生存期的影响，包括 N 分期 (N0, N+) 和年龄作为协变量。

结果：2016 年 2 月至 2020 年 4 月期间，来自德国 25 个研究中心的 438 名患者被随机分配到两个治疗组（221 名 FLOT；217 名 CROSS）。两组的基线特征均衡。403 名患者（207 名 FLOT；196 名 CROSS）开始接受新辅助治疗。371 名患者（191 名 FLOT；180 名 CROSS）接受了手术。351 名患者（180 名 FLOT；171 名 CROSS）实现了 R0 切除。术后 90 天死亡率为 4.3%（3.2% FLOT；5.6% CROSS）。

经过中位随访期 55 个月，218 名患者死亡（97 名 FLOT 患者；121 名 CROSS 患者）。FLOT 组的中位总生存期为 66 个月（95% CI 36 – 无法估计），CROSS 组的中位总生存期为 37 个月（95% CI 28 – 43）。FLOT 组的 3 年总生存期率为 57.4%（95% CI 50.1 – 64.0%），CROSS 组的 3 年总生存期率为 50.7%（95% CI 43.5 – 57.5%）（HR 0.70，95% CI 0.53-0.92，p=0.012）。在 359 名具有肿瘤消退状态的患者中，FLOT 中有 35 名（19.3%，95%-CI 13.9 – 25.9%）实现了病理完全响应，CROSS 中有 24 名（13.5%，95%-CI 8.8 – 19.4%）实现了病理完全响应。 

结论：与新辅助 CROSS 相比，围手术期 FLOT 提高了可切除局部晚期食管腺癌的生存率。

ESOPEC (NCT02509286) is a multicenter prospective randomized trial comparing neoadjuvant CROSS (41.4Gy plus carboplatin/paclitaxel) followed by surgery versus perioperative FLOT (5-FU/leucovorin/oxaliplatin/docetaxel) and surgery for curative treatment of locally advanced esophageal adenocarcinoma.

Methods: Patients with cT1 cN+ cM0 or cT2-4a cNany cM0 resectable locally advanced esophageal adenocarcinoma were eligible. The primary endpoint was overall survival. The effect of treatment on overall survival was estimated using Cox regression stratified by study site, including N stage (N0, N+) and age as covariates.

Results: Between February 2016 and April 2020, 438 patients from 25 centers in Germany were randomized to two treatment groups (221 FLOT; 217 CROSS). Baseline characteristics were balanced between the two groups. 403 patients (207 FLOT; 196 CROSS) started neoadjuvant therapy. 371 patients (191 FLOT; 180 CROSS) underwent surgery. R0 resection was achieved in 351 patients (180 FLOT; 171 CROSS). The 90-day postoperative mortality rate was 4.3% (3.2% FLOT; 5.6% CROSS).

After a median follow-up of 55 months, 218 patients died (97 FLOT patients; 121 CROSS patients). The median overall survival was 66 months (95% CI 36 – not estimable) in the FLOT group and 37 months (95% CI 28 – 43) in the CROSS group. The 3-year overall survival rate was 57.4% (95% CI 50.1 – 64.0%) in the FLOT group and 50.7% (95% CI 43.5 – 57.5%) in the CROSS group (HR 0.70, 95% CI 0.53-0.92, p=0.012). Among 359 patients with tumor regression status, 35 (19.3%, 95%-CI 13.9 – 25.9%) in the FLOT group and 24 (13.5%, 95%-CI 8.8 – 19.4%) in the CROSS group achieved a pathological complete response.

Conclusion: Perioperative FLOT improved survival in resectable locally advanced esophageal adenocarcinoma compared with neoadjuvant CROSS.

参考文献 Reference

Hoepenner J et al. J Clin Onc 2024;42: 17_suppl LBA1

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FDA 批准 durvalumab 用于可切除非小细胞肺癌的新辅助/辅助治疗 (8/17/2024)

FDA approves neoadjuvant/adjuvant durvalumab for resectable non-small cell lung cancer

2024 年 8 月 15 日，FDA批准 durvalumab联合含铂化疗作为新辅助治疗，随后以单药 durvalumab 作为术后辅助治疗，用于可切除（肿瘤≥ 4 cm 和/或淋巴结阳性）非小细胞肺癌且无EGFR突变或ALK重排的成人患者。

AEGEAN (NCT03800134) 是一项随机, 双盲, 安慰剂对照的多中心试验，试验对象为 802 名未接受过治疗且可切除的鳞状或非鳞状非小细胞肺癌患者（IIA 期至 IIIB 期。患者随机（1:1）接受 durvalumab 或安慰剂治疗，以铂类为基础的化疗，每 3 周一次，最多 4 个术前周期，术前后继续单药 durvalumab 或安慰剂治疗，每 4 周一次，最多 12 个周期。 主要疗效结果指标是无事件生存期和病理完全缓解。 Durvalumab 组的中位无事件生存期未达到（95% CI：31.9，无法估计），安慰剂组的中位无事件生存期为 25.9 个月（95% CI：18.9，无法估计）（风险比 0.68 [95% CI：0.53，0.88]；p = 0.0039）。Durvalumab 和安慰剂组的病理完全缓解率分别为 17%（95% CI：13，21）和 4.3%（95% CI：2.5，7）。在预先指定的中期分析时，总生存期尚未正式检验。

最常见的不良反应（≥ 20%）是贫血, 恶心, 便秘, 疲劳,肌肉骨骼疼痛和皮疹。在接受新辅助治疗的 durvalumab 患者中，1.7% 的患者因不良反应无法接受手术，而安慰剂组为 1%。 对于体重≥ 30 公斤的患者，建议的 durvalumab 剂量为每 3 周（新辅助治疗）和每 4 周（辅助治疗）1,500 毫克。对于体重 < 30 公斤的患者，建议的 durvalumab 剂量为 20 毫克/公斤。如果在同一天给药，则应在化疗之前给药。 

On August 15, 2024, FDA approved durvalumab in combination with platinum-containing chemotherapy as neoadjuvant therapy, followed by durvalumab alone as postoperative adjuvant therapy, for adult patients with resectable (tumor ≥ 4 cm and/or lymph node-positive) non-small cell lung cancer without EGFR mutation or ALK rearrangement. The AEGEAN (NCT03800134) was a randomized, double-blind, placebo-controlled, multicenter trial in 802 patients with previously untreated, resectable squamous or nonsquamous NSCLC (stage IIA to IIIB). Patients were randomized (1:1) to receive durvalumab or placebo with platinum-based chemotherapy every 3 weeks for up to 4 cycles preoperatively and continued with single-agent durvalumab or placebo every 4 weeks for up to 12 cycles preoperatively. The primary efficacy outcome measures were event-free survival and pathological complete response.

The median event-free survival was not reached in the durvalumab group (95% CI: 31.9, not estimable) and was 25.9 months (95% CI: 18.9, not estimable) in the placebo group (hazard ratio 0.68 [95% CI: 0.53, 0.88]; p = 0.0039). Pathological complete response rates were 17% (95% CI: 13, 21) and 4.3% (95% CI: 2.5, 7) in the durvalumab and placebo groups, respectively. Overall survival was not formally tested at the time of the prespecified interim analysis.

The most common adverse reactions (≥ 20%) were anemia, nausea, constipation, fatigue, musculoskeletal pain, and rash. Among patients receiving neoadjuvant durvalumab, 1.7% of patients were unable to undergo surgery due to adverse reactions compared with 1% of patients receiving placebo.

For patients weighing ≥ 30 kg, the recommended durvalumab dose is 1,500 mg every 3 weeks (neoadjuvant therapy) and every 4 weeks (adjuvant therapy). For patients weighing < 30 kg, the recommended durvalumab dose is 20 mg/kg. If given on the same day, it should be given before chemotherapy.

参考文献 Reference

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-neoadjuvantadjuvant-durvalumab-resectable-non-small-cell-lung-cancer

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新辅助化疗 ± Nivolumab治疗雌激素受体+/HER2- 乳腺癌 (8/11/2024)

Neoadjuvant chemotherapy ± nivolumab for ER+/HER2- breast cancer( CheckMate 7FL)

背景： CheckMate 7FL (CM 7FL；NCT04109066) 是一项前瞻性, III 期, 随机, 多中心, 双盲试验，研究 nivolumab 联合新辅助化疗对高风险,雌激素受体阳性 (ER+)/HER2− 乳腺癌患者的效果。

方法： 该研究招募了新诊断的患者，T1c-2 N1-2 期或 T3-4 N0-2 期，2 级（ER 1-10%）或 3 级（ER ≥ 1%）。患者按 1:1 随机分配至联合新辅助化疗和nivolumab 360 mg 每3星期/nivolumab 240 mg 每2星期（A组）或新辅助化疗 + 安慰剂（B组）。主要终为病理完全响应率(pCR）和残留癌症负担 (RCB) 0-1。

结果： 总体而言，筛选了 830 名患者，521 名患者随机分组，517 名患者接受治疗，主要疗效人群 (n = 510) 包括随机分组患者。A 组和 B 组中 PD-L1+ (CPS)患病率平衡。 在 PD-L1 表达增加的肿瘤患者中，nivolumab效应更大，在CPS ≥ 1 的A组相对于B 组的pCR为40.4% 相对于 23.8%；95% CI，2.8 至 29.4; CPS ≥ 10 的患者的 pCR为 65.7% 相对于 33.3%；95% CI，7.3 至 52.3; CPS ≥ 20 的患者的 pCR为78.9% 相对于 26.7%；95% CI，18.6 至 72.4。相比之下，主要疗效人群的pCR为24.5% 相对于 13.8%；95% CI，3.9 至 17.4。A 组和 B 组之间的RCB 0–1未加权率差异（∆RCB 0–1 率）呈现出类似的趋势，在 CPS ≥ 1 中观察到 17.0%，在 CPS ≥ 10 中观察到 34.4%，在 CPS ≥ 20 中观察到 52.3%。

结论： PD-L1 表达越高，pCR 和 RCB 0–1 率越高，这表明 PD-L1+, 高风险, ER+/HER2− 乳腺癌患者通过在新辅助化疗中添加nivolumab可显著增加 pCR 率。

附注: 另一项类似的试验是 KEYNOTE 756（请参阅最近进展 2024 年 3 月 24 日）

Background: CheckMate 7FL (CM 7FL; NCT04109066) was a prospective, phase III, randomized, multicenter, double-blind trial investigating the effect of nivolumab combined with neoadjuvant chemotherapy in patients with high-risk, estrogen receptor-positive (ER+)/HER2− breast cancer.

Methods: The study enrolled patients with newly diagnosed, stage T1c-2 N1-2 or T3-4 N0-2, grade 2 (ER 1-10%) or grade 3 (ER ≥ 1%) disease. Patients were randomized 1:1 to neoadjuvant chemotherapy combined with nivolumab 360 mg every 3 weeks/nivolumab 240 mg every 2 weeks (group A) or neoadjuvant chemotherapy plus placebo (group B). The primary endpoints were pathological complete response rate (pCR) and residual cancer burden (RCB) 0-1.

Results: Overall, 830 patients were screened, 521 were randomized, and 517 were treated, with the primary efficacy population (n = 510) including randomized patients. The prevalence of PD-L1+ (CPS) was balanced between groups A and B. The nivolumab effect was greater in patients with tumors with increased PD-L1 expression, with a pCR of 40.4% vs 23.8% in group A vs B with CPS ≥ 1; 95% CI, 2.8 to 29.4; 65.7% vs 33.3% in patients with CPS ≥ 10; 95% CI, 7.3 to 52.3; and 78.9% vs 26.7% in patients with CPS ≥ 20; 95% CI, 18.6 to 72.4. In contrast, the pCR in the primary efficacy population was 24.5% vs. 13.8%; 95% CI, 3.9 to 17.4. Unweighted rate differences between arms A and B for RCB 0–1 between groups A and B showed a similar trend, with 17.0% observed in CPS ≥ 1, 34.4% in CPS ≥ 10, and 52.3% in CPS ≥ 20.

Conclusions: Higher PD-L1 expression was associated with higher pCR and RCB 0–1 rates, suggesting that patients with PD-L1+, high-risk, ER+/HER2− breast cancer can have significantly increased pCR rate by adding nivolumab to neoadjuvant chemotherapy.

P.S. Another similar trial is KEYNOTE 756 (please see Recent Progress 3/24/2024)

参考文献 Reference

Loi S. et al. Cancer Res 2024; 84 (9_Suppl): GS01-01.

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FDA 批准vorasidenib用于治疗具有易感 IDH1 或 IDH2 突变的 2 级星形细胞瘤或少突胶质细胞瘤 (8/10/2024)

FDA approves vorasidenib for grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation

2024 年 8 月 6 日，FDA批准vorasidenib (Voranigo)，一种异柠檬酸脱氢酶-1 (IDH1) 和异柠檬酸脱氢酶-2 (IDH2) 抑制剂，用于成人和 12 岁及以上患有具有易感 IDH1 或 IDH2 突变的 2 级星形细胞瘤或少突胶质细胞瘤，在手术（包括活检、部分全切除或大体全切除）后使用。 这是 FDA 首次批准针对具有易感 IDH1 或 IDH2 突变的 2 级星形细胞瘤或少突胶质细胞瘤患者的全身治疗。  

疗效和安全性: 在一项随机, 多中心, 双盲, 安慰剂对照试验 INDIGO (NCT04164901) 中，对 331 名 2 级星形细胞瘤或少突胶质细胞瘤患者进行了疗效评估，这些患者在手术后发生了易感 IDH1 或 IDH2 突变。患者按 1:1 的比例随机接受vorasidenib 40 毫克口服，每日一次或安慰剂口服，直至病情进展或出现不可接受的毒性。IDH1 或 IDH2 突变状态由 Life Technologies Corporation Oncomine Dx Target 试验前瞻性确定。在记录到放射学疾病进展后，允许随机接受安慰剂治疗的患者转用vorasidenib。接受过化疗或放疗等抗癌治疗的患者被排除在外。 主要疗效结果指标是无进展生存期。另一项疗效结果指标是下次干预时间。无进展生存期的风险比为 0.39 (95% CI: 0.27, 0.56)，p 值 <0.0001。Vorasidenib 组的下次干预中位时间未达到，安慰剂组的下次干预中位时间为 17.8 个月 (HR =0.26; 95% CI: [0.15, 0.43], p <0.0001)。   

最常见 (≥15%) 的不良反应是疲劳, 头痛, COVID-19 感染, 肌肉骨骼疼痛, 腹泻, 恶心和癫痫发作。最常见的 3 级或 4 级实验室异常（>2%）是丙氨酸氨基转移酶升高、天冬氨酸氨基转移酶升高、GGT 升高和中性粒细胞减少。 建议成人患者服用vorasidenib的剂量为每天口服一次 40 毫克，直至病情进展或出现不可接受的毒性。建议 12 岁及以上的儿科患者服用vorasidenib的剂量基于体重： 体重 ≥ 40 公斤的患者：每天口服一次 40 毫克。 体重 < 40 公斤的患者：每天口服一次 20 毫克。

On August 6, 2024, the FDA approved vorasidenib (Voranigo), an isocitrate dehydrogenase-1 (IDH1) and isocitrate dehydrogenase-2 (IDH2) inhibitor, for use in adults and children 12 years and older with grade 2 astrocytoma or oligodendroglioma with susceptible IDH1 or IDH2 mutations following surgery (including biopsy, sub-total resection, or gross total resection). This is the first FDA-approved systemic treatment for patients with grade 2 astrocytoma or oligodendroglioma with susceptible IDH1 or IDH2 mutations.

Efficacy and Safety: Efficacy was evaluated in 331 patients with grade 2 astrocytoma or oligodendroglioma with susceptible IDH1 or IDH2 mutations following surgery in a randomized, multicenter, double-blind, placebo-controlled trial, INDIGO (NCT04164901). Patients were randomized 1:1 to receive vorasidenib 40 mg orally once daily or placebo orally until disease progression or unacceptable toxicity. IDH1 or IDH2 mutation status was prospectively determined by the Life Technologies Corporation Oncomine Dx Target Test. Patients randomized to placebo were allowed to cross over to vorasidenib after documented radiographic disease progression. Patients who had received prior anticancer treatment, including chemotherapy or radiotherapy, were excluded. The primary efficacy outcome was progression-free survival. Another efficacy outcome measure was time to next intervention.

The hazard ratio for progression-free survival was 0.39 (95% CI: 0.27, 0.56), with a p-value of <0.0001. The median time to next intervention was not reached in the vorasidenib group and was 17.8 months in the placebo group (HR =0.26; 95% CI: [0.15, 0.43], p <0.0001). The most common adverse reactions (≥15%) were fatigue, headache, COVID-19 infection, musculoskeletal pain, diarrhea, nausea, and seizure. The most common grade 3 or 4 laboratory abnormalities (>2%) were increased alanine aminotransferase, increased aspartate aminotransferase, increased GGT, and neutropenia. The recommended dose of vorasidenib for adult patients is 40 mg orally once daily until disease progression or unacceptable toxicity. The recommended dose of vorasidenib for pediatric patients 12 years and older is based on weight: Patients weighing ≥ 40 kg: 40 mg orally once daily. Patients weighing < 40 kg: 20 mg orally once daily.

参考文献 Reference

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-vorasidenib-grade-2-astrocytoma-or-oligodendroglioma-susceptible-idh1-or-idh2-mutation

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Glofitamab 联合吉西他滨和奥沙利铂 (Gemox) 治疗复发/难治性弥漫性大 B 细胞淋巴瘤 (8/4/2024)

Glofitamab in combination with gemcitabine/oxaliplatin (Gemox) in relapsed or refractory diffuse large B-cell lymphoma (DLBCL)

背景： Glofitamab (GLOFIT)是一种 CD20:CD3 双特异性抗体， 该试验旨在研究 Glofit-GemOx 与利妥昔单抗-GemOx 在接受过 ≥1 线治疗后复发/难治性弥漫性大 B 细胞淋巴瘤(DLBCL)患者中的疗效和安全性结果。

方法： 这是一项全球随机 III 期临床试验（STARGLO），患者按 2:1 的比例随机分配接受 Glofit-GemOx （8 个周期，外加 4 个周期的 glofitamab 单药治疗 ） 或 利妥昔单抗- GemOx （8 个周期 ） 治疗，并根据既往治疗次数 （1 vs ≥ 2 ） 和对上次治疗的耐药性进行分层。 在奥比妥珠单抗(obinutuzumab)预先治疗后，在第 1 周期中以每周递增剂量 ( 2.5/10mg ) 的方式给予Glofitamab，然后从第 2 周期第 1 天开始，每 21 天给予 30mg 目标剂量。在接受过 1 次先前治疗后入组的患者，根据年龄 ≥ 70 岁, 器官 功能障碍, ECOG 体能状态 ≥ 2, 患者拒绝接受自体干细胞移植或其他研究者评估的合并症，被认为不适合接受自体干细胞移植。 主要终点是总体生存率。 次要终点包括无进展生存率和完全响应率。

结果： 共计 274 名 DLBCL 患者入组 （Glofit-GemOx，n=183；利妥昔单抗-GemOx，n=91 ） ，其中 172 名（ 62.8% ）患者接受过 1 次治疗，102 名（ 37.2% ）患者接受过 ≥ 2 次治疗。总体而言，153 名（ 55.8% ）患者患有原发性难治性疾病，166 名（ 60.6% ）患者对上次治疗有耐药性。 在初步分析中（截止日期为 2023 年 3 月 29 日），Glofit-GemOx 与利妥昔单抗-GemOx 相比具有显著的总体生存率优势（风险比 [HR] 0.59，95% 置信区间 [CI]：0.40 – 0.89；p=0.011 ）。中位随访时间为 11.3 个月，Glofit-GemOx 未达到中位总体生存率（95% CI：13.8 – 无法评估）而利妥昔单抗-GemOx 为 9 个月（95% CI：7.3 – 14.4 ）。在无进展生存率（HR 0.37，95% CI：0.25 – 0.55；p <0.0001 ） 和完全响应率 （50.3 vs 22.0%；95% CI：16.3 – 40.3，p <0.0001 ） 中也观察到了 Glofit-GemOx 的显著优势。所有患者完成治疗后进行了随访分析,  截止日期为 2024 年 2 月 16 日；中位随访时间为 20.7 个月 。 Glofit-GemOx 继续表现出优于利妥昔单抗-GemOx 的中位总体生存率 25.5 vs 12.9 个月； HR 0.62，95% CI：0.43 – 0.88), 中位无进展生存率 13.8 vs 3.6 个月； HR 0.40，95% CI：0.28 – 0.57 ) 和完全响应率 58.5 vs 25.3% )。

Glofit-GemOx 的不良事件发生率高于利妥昔单抗-GemOx，包括 3-4 级 (69.4% vs 36.4%), 5 级不良事件 (8.3% vs 4.5%；主要由 COVID-19 不良事件不平衡引起) 和严重不良事件 (54.4% vs 17.0%；主要由细胞因子释放综合征, CRS引起)。调整暴露差异后，两组的不良事件发生率相似。在接受 glofitamab 治疗的患者中， CRS 是最常见的不良事件（1级：31.4%，2级：10.5%，3级：2.3% ） ，并且有 4 名患者（ 2.3 % ）报告了与免疫效应细胞相关神经毒性综合征一致的事件，所有这些事件均与 CRS 同时发生。

结论： 对于不适合接受自体干细胞移植的治疗复发/难治性 DLBCL 患者，Glofit-GemOx 在总体生存率, 无进展生存率和完全响应率方面表现出统计学上显著且临床上有意义的优势，而利妥昔单抗-GemOx 则不然。Glofitamab 是首个在随机 III 期试验中表现出 DLBCL 生存优势的 CD20:CD3 双特异性抗体。

Background: Glofitamab (GLOFIT) is a CD20:CD3 bispecific antibody. This trial was designed to investigate the efficacy and safety of Glofit-GemOx versus rituximab-GemOx in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) after ≥1 line of therapy.

Methods: This was a global, randomized, phase III clinical trial (STARGLO) in which patients were randomly assigned in a 2:1 ratio to receive Glofit-GemOx (8 cycles plus 4 cycles of glofitamab monotherapy) or rituximab-GemOx (8 cycles) and stratified by the number of previous therapies (1 vs ≥ 2) and resistance to the last therapy. After pre-treatment with obinutuzumab, Glofitamab was given in weekly escalating doses (2.5/10 mg) in cycle 1, followed by a target dose of 30 mg every 21 days starting on day 1 of cycle 2. Patients enrolling after one prior therapy were considered ineligible for autologous stem cell transplantation based on age ≥ 70 years, organ dysfunction, ECOG performance status ≥ 2, patient refusal to undergo autologous stem cell transplantation, or other comorbidities assessed by the investigator. The primary endpoint was overall survival. Secondary endpoints included progression-free survival and complete response rate.

Results: A total of 274 patients with DLBCL were enrolled (Glofit-GemOx, n=183; rituximab-GemOx, n=91), of whom 172 (62.8%) had received 1 prior therapy and 102 (37.2%) had received ≥ 2 prior therapies. Overall, 153 (55.8%) patients had primary refractory disease and 166 (60.6%) were resistant to the last therapy. In the primary analysis (cutoff date March 29, 2023), Glofit-GemOx had a significant overall survival advantage compared with rituximab-GemOx (hazard ratio [HR] 0.59, 95% confidence interval [CI]: 0.40 – 0.89; p =0.011). With a median follow-up of 11.3 months, the median overall survival rate was not reached for Glofit-GemOx (95% CI: 13.8 – not evaluable) and 9 months for rituximab-GemOx (95% CI: 7.3 – 14.4). A significant advantage for Glofit-GemOx was also observed in progression-free survival (HR 0.37, 95% CI: 0.25 – 0.55; p < 0.0001) and complete response rate (50.3 vs 22.0%; 95% CI: 16.3 – 40.3, p < 0.0001). Follow-up analysis was performed after all patients completed treatment, with a cutoff date of February 16, 2024; median follow-up time of 20.7 months. Glofit-GemOx continued to demonstrate superiority over rituximab-GemOx with median overall survival (25.5 vs 12.9 months; HR 0.62, 95% CI: 0.43 – 0.88), median progression-free survival (13.8 vs 3.6 months; HR 0.40, 95% CI: 0.28 – 0.57) and complete response rate (58.5 vs 25.3%).

Glofit-GemOx had a higher incidence of adverse events than rituximab-GemOx, including grade 3-4 (69.4% vs 36.4%), grade 5 adverse events (8.3% vs 4.5%; mainly caused by imbalance of COVID-19 adverse events) and serious adverse events (54.4% vs 17.0%; mainly caused by cytokine release syndrome, CRS). After adjusting for differences in exposure, the incidence of adverse events was similar between the two groups. CRS was the most common adverse event in patients treated with glofitamab (grade 1: 31.4%, grade 2: 10.5%, grade 3: 2.3%), and 4 patients (2.3%) reported events consistent with immune effector cell-related neurotoxicity syndrome, all of which occurred concurrently with CRS.

Conclusions: For patients with relapsed/refractory DLBCL who were not eligible for autologous stem cell transplantation, Glofit-GemOx demonstrated statistically significant and clinically meaningful advantages in overall survival, progression-free survival, and complete response rate compared with rituximab-GemOx. Glofitamab is the first CD20:CD3 bispecific antibody to demonstrate a survival advantage in DLBCL in a randomized phase III trial.

参考文献 Reference

Abramson J et al. Eur Hemat Asso 2024 Congress Anstr LB3438

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Unesbulin 联合达卡巴嗪治疗局部复发,转移性, 或难治性平滑肌肉瘤 (8/3/2024)

Phase Ib study of Unesbulin plus dacarbazine for locally recurrent, metastatic or refractory leiomyosarcoma

目的: 这项多中心, 单组, 开放标签, Ib 期研究旨在确定推荐的 II 期剂量并评估 unesbulin 联合达卡巴嗪 (DTIC) 对晚期平滑肌肉瘤患者的安全性和初步疗效。

患者和方法: 患有局部晚期, 不可切除或转移性, 复发或难治性平滑肌肉瘤的成年受试者每周口服两次递增剂量的 unesbulin，同时每 21 天静脉注射一次 DTIC 1,000 mg/m²。采用事件发生时间持续重新评估法，根据前两个 21 天治疗周期中评估的剂量限制性毒性确定推荐的 II 期剂量。所有研究剂量的 unesbulin（200 mg 至 400 mg）均与 DTIC 联合使用。招募了一个扩展队列，以评估 unesbulin 在推荐的 II 期剂量时的安全性和有效性。  

结果: 每周两次口服 300 mg 的 Unesbulin 与每 21 天一次静脉注射 1,000 mg/m² 的 DTIC 联合使用被确定为推荐的 II 期剂量。根据 27 名被认为可评估剂量限制性毒性的受试者的数据，400 毫克 unesbulin 组的毒性较高，四名受试者中有三名 (75%) 出现剂量限制性毒性，而 200 毫克组四名受试者中有一名 (25%) 出现剂量限制性毒性，300 毫克组 19 名受试者中有三名 (15.8%) 出现剂量限制性毒性。最常见的剂量限制性毒性和治疗相关的 3 级和 4 级不良事件是血小板减少症和中性粒细胞减少症。在推荐的 II 期剂量中，七名可评估疗效的受试者获得部分响应，客观响应率为 24.1%; 疾病控制率为55.2%。

结论: 每周两次 300 毫克的 Unesbulin 加上每 21 天一次 1,000 毫克/米² 的 DTIC 被确定为推荐的 II 期剂量，在接受大量治疗的晚期平滑肌肉瘤人群中显示出良好的效益风险状况。

附: Unesbulin 靶向肿瘤细胞和癌症干细胞表达的 BMI1，诱导 BMI1 过度磷酸化，导致其降解。使表达 BMI1 的肿瘤细胞增殖减少。

Objective: This multicenter, single-arm, open-label, phase Ib study was designed to determine the recommended phase II dose and evaluate the safety and preliminary efficacy of unesbulin in combination with dacarbazine (DTIC) in patients with advanced leiomyosarcoma.

Patients and methods: Adult patients with locally advanced, unresectable or metastatic, recurrent, or refractory leiomyosarcoma received escalating doses of oral unesbulin twice weekly and concurrently with DTIC 1,000 mg/m2 intravenously every 21 days. The recommended phase II dose was determined based on dose-limiting toxicities assessed during the first two 21-day treatment cycles using a time-to-event continuous reassessment method. All study doses of unesbulin (200 mg to 400 mg) were given in combination with DTIC. An expansion cohort was enrolled to evaluate the safety and efficacy of unesbulin at the recommended phase II dose.

Results: Unesbulin 300 mg orally twice weekly in combination with DTIC 1,000 mg/m² intravenously every 21 days was determined to be the recommended phase II dose. Based on data from 27 subjects considered evaluable for dose-limiting toxicity, toxicity was higher in the 400 mg unesbulin group, with three of four subjects (75%) experiencing dose-limiting toxicity, compared with one of four subjects (25%) in the 200 mg group and three of 19 subjects (15.8%) in the 300 mg group. The most common dose-limiting toxicities and treatment-related grade 3 and 4 adverse events were thrombocytopenia and neutropenia. At the recommended phase II dose, seven subjects evaluable for efficacy achieved partial responses, with an objective response rate of 24.1%; the disease control rate was 55.2%.

Conclusion: Unesbulin 300 mg twice weekly plus DTIC 1,000 mg/m² every 21 days was determined to be the recommended phase II dose, showing a favorable benefit-risk profile in a heavily pretreated advanced leiomyosarcoma population.

P.S.: Unesbulin targets BMI1 expressed by tumor cells and cancer stem cells, inducing hyperphosphorylation of BMI1, leading to its degradation. Proliferation of tumor cells expressing BMI1 was reduced.

参考文献 Reference

Van Tine BA et al. J Clin Onc 2024; 42: https://doi.org/10.1200/JCO.23.0168.

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纹身是恶性淋巴瘤的危险因素? (7/29/2024)

Is tattoo a risk factor for malignant lymphoma?

背景: 纹身的流行度在过去几十年中急剧上升。纹身墨水通常含有致癌化学物质，例如初级芳香胺、多环芳烃和金属。纹身过程会引发免疫反应，导致纹身墨水从注射部位移位。纹身颜料沉积在淋巴结中已得到证实，但其长期健康影响仍未得到探索。研究者使用覆盖全人口的瑞典国家权威登记册来研究纹身暴露与整体恶性淋巴瘤以及淋巴瘤亚型之间的关联。

方法: 研究者进行了一项病例对照研究，确定了 2007 年至 2017 年期间在瑞典国家癌症登记册中 20-60 岁人群中诊断出的所有恶性淋巴瘤病例。使用发病率密度抽样，从总人口登记册中为每个病例随机抽取三个年龄和性别匹配的对照。研究者在 2021 年通过问卷调查评估了暴露情况，并从登记册中检索了有关潜在混杂因素的数据。研究者使用多变量逻辑回归来估计纹身个体中恶性淋巴瘤的发病率 (IRR)。  

结果: 研究人群包括 11,905 人，病例组 (n = 1398) 的响应率为 54%，对照组 (n = 4193) 的响应率为 47%。纹身患病率为病例组 21%，对照组 18%。纹身个体的总体淋巴瘤调整风险较高 (IRR = 1.21；95% CI 0.99–1.48)。第一次纹身与指数年之间相隔不到两年的个体患淋巴瘤的风险最高 (IRR = 1.81；95% CI 1.03–3.20)。随着暴露时间延长（三至十年），风险降低，但对于在指数年之前 ≥11 年首次纹身的个体，风险再次增加（IRR = 1.19；95% CI 0.94–1.50）。研究者没有发现纹身体表总面积越大风险就越大的证据。与纹身暴露相关的风险似乎最高的是弥漫性大 B 细胞淋巴瘤（IRR 1.30；95% CI 0.99–1.71）和滤泡性淋巴瘤（IRR 1.29；95% CI 0.92–1.82）。

解释: 研究结果表明，纹身暴露与恶性淋巴瘤风险增加有关。需要更多的流行病学研究来确定因果关系。

Background: The popularity of tattoos has increased dramatically over the past few decades. Tattoo inks often contain carcinogenic chemicals such as primary aromatic amines, polycyclic aromatic hydrocarbons, and metals. The tattooing process triggers an immune response that results in displacement of tattoo ink from the injection site. Deposition of tattoo pigment in lymph nodes is well established, but its long-term health effects remain unexplored. The researchers used population-wide authoritative national registries in Sweden to investigate the association between tattoo exposure and overall malignant lymphoma as well as lymphoma subtypes.

Methods: The researchers conducted a case-control study and identified all cases of malignant lymphoma diagnosed between 2007 and 2017 in the Swedish National Cancer Register among people aged 20-60  years. Using incidence density sampling, three age- and sex-matched controls were randomly selected for each case from the general population register. The researchers assessed exposure using a questionnaire in 2021 and retrieved data on potential confounders from the register. The researchers used multivariable logistic  regression to estimate the incidence rate ratio (IRR) of malignant lymphoma in tattooed individuals.

Results: The study population included 11,905 individuals, with a response rate of 54% for cases (n = 1398) and 47% for controls (n = 4193). The prevalence of tattoos was 21% for cases and 18% for controls. Individuals with tattoos had a higher overall adjusted risk of lymphoma (IRR = 1.21; 95% CI 0.99–1.48). The risk of lymphoma was highest in individuals with less than 2 years between their first tattoo and the index year (IRR = 1.81; 95% CI 1.03–3.20). The risk decreased with longer exposure (three to ten years), but increased again for individuals with their first tattoo ≥11 years before the index year (IRR = 1.19; 95% CI 0.94–1.50). The researchers found no evidence of an increased risk with greater total body surface area tattooed. The risks associated with tattoo exposure appeared to be highest for diffuse large B-cell lymphoma (IRR 1.30; 95% CI 0.99–1.71) and follicular lymphoma (IRR 1.29; 95% CI 0.92–1.82).

Interpretation: The findings suggest that tattoo exposure is associated with an increased risk of malignant lymphoma. Additional epidemiological studies are needed to establish causal  relationships.

参考文献 Reference

Nielsen C et al. eClin Med 2024; 72:102649

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复发性弥漫性大 B 细胞淋巴瘤的联合靶向治疗 (7/21/2024)

Combination targeted therapy in relapsed diffuse large B-cell lymphoma

方法: 研究者对弥漫性大 B 细胞淋巴瘤 (DLBCL） 患者，研究了venetoclax, ibrutinib, 泼尼松、奥比妥珠单抗和来那度胺 (ViPOR) 方案。在包括 DLBCL 和惰性淋巴瘤患者的 1b 期研究中，评估了维奈克拉的四种剂量水平，以确定推荐的 2 期剂量，其他四种药物的剂量固定。对生发中心 B 细胞 (GCB) 和非 GCB DLBCL 患者进行了 II 期扩展研究。 ViPOR 每 21 天给药一次，共 6 个周期。

结果: 这是一项单中心Ib/II期临床试验（NCT03223610），在研究的 1b 期中，涉及 20 名患者（10 名患有DLBCL），发生了 3 级颅内出血的单剂量限制性毒性作用，该结果确定 800 毫克剂量的venetoclax是推荐的 II 期剂量。第 II 期包括 40 名患有 DLBCL 的患者。在所有患者中观察到的毒性作用包括 3 级或 4 级中性粒细胞减少症（24% 的周期）, 血小板减少症（23%）, 贫血（7%）和发热性中性粒细胞减少症（1%）。在 48 名可评估的 DLBCL 患者中，54% 的患者出现客观响应，38% 的患者出现完全响应；完全响应仅发生在非 GCB DLBCL 和 MYC 和 BCL2 或 BCL6（或两者）重排的高级别 B 细胞淋巴瘤患者中。在 ViPOR 治疗结束时，33% 的患者循环肿瘤 DNA 检测不到。中位随访期为 40 个月，2 年无进展生存率和总生存率分别为 34%（95% 置信区间 [CI]，21 至 47）和 36%（95% CI，23 至 49）。   

结论: ViPOR 治疗与特定分子 DLBCL 亚型患者的持久响应相关，并且主要与可逆性不良事件相关。

Methods: We studied venetoclax, ibrutinib, prednisone, obinutuzumab, and lenalidomide (ViPOR) in patients with diffuse large B-cell lymphoma (DLBCL). Four dose levels of venetoclax were evaluated in a phase 1b study including patients with DLBCL and indolent lymphomas to determine the recommended phase 2 dose, and the doses of the other four drugs were fixed. A phase II extension study was conducted in patients with germinal center B-cell (GCB) and non-GCB DLBCL. ViPOR was administered every 21 days for 6 cycles.

Results: This was a single-center clinical trial (NCT03223610) involving 20 patients (10 with DLBCL) in the phase 1b of the study. A single dose-limiting toxic effect of grade 3 intracranial hemorrhage occurred. The result determined that the 800-mg dose of venetoclax was the recommended phase II dose. Phase II included 40 patients with DLBCL. Toxic effects observed in all patients included grade 3 or 4 neutropenia (24% of cycles), thrombocytopenia (23%), anemia (7%), and febrile neutropenia (1%). Of the 48 evaluable patients with DLBCL, 54% had an objective response and 38% had a complete response; complete responses occurred only in patients with non-GCB DLBCL and high-grade B-cell lymphoma with rearrangements of MYC and BCL2 or BCL6 (or both). At the end of ViPOR treatment, circulating tumor DNA was undetectable in 33% of patients. With a median follow-up of 40 months, the 2-year progression-free survival and overall survival rates were 34% (95% [CI], 21 to 47) and 36% (95% CI, 23 to 49), respectively.

Conclusions: Treatment with ViPOR was associated with durable responses in patients with specific molecular DLBCL subtypes and was associated with mainly reversible adverse events.

参考文献 Reference

Melani C et al. N Engl J Med 2024; 390:2143

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A-BRAVE 试验：一项使用avelumab治疗新辅助化疗后残留疾病或高风险早期三阴性乳腺癌的 III 期试验 (7/20/2024)

A-BRAVE trial: A phase III randomized trial with avelumab in early triple-negative breast cancer with residual disease after neoadjuvant chemotherapy or at high risk

方法： 这是一项 III 期, 多中心, 随机研究，比较了抗 PD-L1 avelumab治疗 1 年与观察治疗, 对复发风险较高的三阴性乳腺癌患者的影响。患者在完成包括手术和新辅助/辅助化疗在内的标准治愈性治疗后入组。高风险定义为：A) 新辅助化疗后有侵袭性残留疾病（乳腺和/或淋巴结）; B) 初次手术后 > pN2/任何 pT, pN1/pT2 或 pN0/pT3。患者被随机分配（1:1）接受avelumab 10 mg/kg 静脉注射，每 2 周一次，持续 1 年或观察。共同主要终点是总人群和 A 组的无病生存期。需要 474 名患者才能在总人群中检测到 3 年无病生存率从 60% 提高到 73.6%（HR 0.6；90% 功效，单侧检验，α 2%）。需要 172 个无病生存期事件才能执行事件驱动分析。假设 A 组中有 70-80% 的患者入组，则在该亚组中分配的 α 处检测到 HR 0.6 的预期功效为 70-79%。总生存期是次要终点。   

结果： 从 2016 年 6 月到 2020 年 10 月，从 64 个意大利中心和 6 个英国中心随机分配了 477 名患者。11 名患者（3 名avelumab，8 名对照）在随机分组后立即撤回同意，并被排除在进一步分析之外。 378 名患者进入 A 组（83%），其中 99 名（57 名avelumab组，42 名对照组）在参加试验前接受了手术后进一步化疗。中位随访期为 3 年，总人群无病生存率分别为 68.3% (61.9-73.8) 和 63.4% (56.8-69.3) (HR 0.85, 0.61-1.11, P= 0.193); A 组无病生存率分别为 66.9% (59.8-73.1) 和 61.0%( 53.6-67.6) (HR 0.81, 0.58-1.11,  P= 0.194) 。

总人群总生存率分别为 85.2% (79.9-89.2) 和 78.2%(72.2-83.1) (HR 0.66, 0.44-0.98,  P= 0.041); A 组无病生存率分别为 83.1% (77.1-87.8) 和 76.6%( 69.6-82.1) (HR 0.67, 0.44-1.03,  P= 0.06) 。

结论： 一年辅助avelumab组与对照组相比，并未显著改善高风险三阴性乳腺癌患者的无病生存期。但与对照组相比，avelumab组的次要总生存期显著改善。

Methods: This was a phase III, multicenter, randomized study comparing 1 year of anti-PD-L1 avelumab versus observation in patients with triple-negative breast cancer at high risk of recurrence. Patients were enrolled after completing standard curative therapy including surgery and neoadjuvant/adjuvant chemotherapy. High risk was defined as: A) invasive residual disease (breast and/or lymph nodes) after neoadjuvant chemotherapy; B) > pN2/any pT, pN1/pT2, or pN0/pT3 after primary surgery. Patients were randomized (1:1) to receive avelumab 10 mg/kg IV every 2 weeks for 1 year or observation. The co-primary endpoints were disease-free survival in the overall population and in arm A. 474 patients were needed to detect an improvement in 3-year disease-free survival from 60% to 73.6% in the overall population (HR 0.6; 90% power, one-sided test, alpha 2%). 172 disease-free survival events were required to perform event-driven analysis. Assuming 70-80% of patients were enrolled in group A, the expected power to detect a HR of 0.6 at the assigned α in this subgroup was 70-79%. Overall survival was a secondary endpoint.

Results: From June 2016 to October 2020, 477 patients were randomized from 64 Italian and 6 UK centers. Eleven patients (3 avelumab, 8 control) withdrew consent immediately after randomization and were excluded from further analysis. 378 patients entered group A (83%), of whom 99 (57 avelumab, 42 control) received further chemotherapy after surgery before trial entry. The median follow-up period was 3 years, and the disease-free survival rates of the overall population were 68.3% (61.9-73.8) and 63.4% (56.8-69.3) (HR 0.85, 0.61-1.11, P= 0.193) respectively; the disease-free survival rates of group A were 66.9% (59.8-73.1) and 61.0% (53.6-67.6) (HR 0.81, 0.58-1.11, P= 0.194).

The overall survival rates of the total population were 85.2% (79.9-89.2) and 78.2% (72.2-83.1) (HR 0.66, 0.44-0.98, P= 0.041); the overall survival rates in group A were 83.1% (77.1-87.8) and 76.6% (69.6-82.1) (HR 0.67, 0.44-1.03, P= 0.06).

Conclusion: One-year adjuvant avelumab group did not significantly improve the disease-free survival of patients with high-risk triple-negative breast cancer compared with the control group. However, the secondary overall survival of the avelumab group was significantly improved compared with the control group.

参考文献 Reference

Conte PF et al. J Clin Oncol 2024; 42 (suppl 17; abstr LBA500)

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使用胰高血糖素样肽 1 受体激动剂与 2 型糖尿病患者的 13 种肥胖相关癌症 (7/14/2024)

Glucagon-like peptide 1(GLP-1)  receptor agonists and 13 obesity-associated cancers in patients with type 2 diabetes

方法:研究人员利用全国多中心电子健康记录数据库，确定了 1,651,452 名 2 型糖尿病患者（平均年龄 = 59.8 岁），这些患者之前没有被诊断出肥胖相关癌症，并在 2005 年 3 月至 2018 年 11 月期间给于处方 GLP-1 受体激动剂、胰岛素或二甲双胍。数据分析于 2024 年 4 月进行。

结果: 与胰岛素相比，使用 GLP-1 受体激动剂治疗似乎降低了 2 型糖尿病患者患上特定肥胖相关癌症的风险。 可显著降低罹患 13 种已确定的肥胖相关癌症中的 10 种的风险，即胆囊癌（风险比 [HR] = 0.35）, 脑膜瘤（HR = 0.37）, 胰腺癌（HR = 0.41）, 肝细胞癌（HR = 0.47）, 卵巢癌（HR = 0.52）, 结直肠癌（HR = 0.54）, 多发性骨髓瘤（HR = 0.59）, 食道癌（HR = 0.60）, 子宫内膜癌（HR = 0.74）和肾癌（HR = 0.76）。接受 GLP-1 受体激动剂治疗的患者患胃癌的风险比为 0.73（统计学上不显著）。GLP-1 受体激动剂治疗似乎与绝经后乳腺癌或甲状腺癌的发病风险降低无关。

与二甲双胍相比，GLP-1 受体激动剂治疗与任何癌症发病风险降低无关；相反，它显示肾癌风险增加（HR = 1.54）。

研究人员总结: GLP-1 受体激动剂对肥胖相关癌症的潜在癌症预防作用值得进一步的长期研究。

Methods: Using a nationwide multicenter electronic health record database, researchers identified 1,651,452 patients with type 2 diabetes (mean age = 59.8 years) who had no been previously diagnosed with obesity-related cancer and were prescribed GLP-1 receptor agonists, insulin, or metformin between March 2005 and November 2018. Data analysis was performed in April 2024.

Results: Treatment with GLP-1 receptor agonists appeared to reduce the risk of specific obesity-related cancers in patients with type 2 diabetes compared with insulin. Significantly reduced risk for 10 of 13 established obesity-related cancers: gallbladder cancer (hazard ratio [HR] = 0.35), meningioma (HR = 0.37), pancreatic cancer (HR = 0.41), hepatocellular carcinoma (HR = 0.47), ovarian cancer (HR = 0.52), colorectal cancer (HR = 0.54), multiple myeloma (HR = 0.59), esophageal cancer (HR = 0.60), endometrial cancer (HR = 0.74), and kidney cancer (HR = 0.76). The hazard ratio for gastric cancer in patients treated with GLP-1 receptor agonists was 0.73 (not statistically significant). GLP-1 receptor agonist therapy did not appear to be associated with a reduced risk of postmenopausal breast or thyroid cancer.

Compared with metformin, GLP-1 receptor agonist therapy was not associated with a reduced risk of any cancer; instead, it showed an increased risk of kidney cancer (HR = 1.54).

The researchers conclude: The potential cancer preventive effects of GLP-1 receptor agonists against obesity-related cancers warrant further long-term investigation.

参考文献 Reference

Wang L et al. JAMA Network Open 2024; 7: e2421305

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树突状细胞的免疫疗法应用于胰腺癌切除后 (7/13/2024)

Dendritic cell-based immunotherapy in patients with resected pancreatic cancer

本研究的主要目的是确定基于树突状细胞的免疫疗法在预防疾病复发方面的功效。

方法: 这是一项单中心, 开放标签,单组,联合 I/II 期试验。主要终点是 2 年无复发生存率( ≥ 60% 被定义为具有临床意义的改善)。该试验纳入了切除后并完成标准护理治疗且在横断面成像上未出现复发疾病的胰腺癌患者。患者接受自体树突状细胞治疗，该树突状细胞用同种异体间皮瘤肿瘤细胞裂解物脉冲处理，该裂解物包含胰腺导管腺癌中也表达的抗原。  

结果: 38 名患者被纳入主要终点分析（47% 为男性，53% 为女性）。中位年龄为 62 岁（IQR，55-68）。28 名患者（74%）接受了五次树突状细胞疫苗接种并完成了研究方案。三名患者（8%）接受了四次疫苗接种，七名患者（16%）接受了三次疫苗接种。经过中位 25.5 个月的随访，26 名患者（68%）未出现疾病复发。估计的 2 年无复发生存率为 64%。疫苗接种导致循环活化 CD4+ T 细胞富集，并在体外检测到治疗诱导的免疫反应。对切​​除的单发性肺转移瘤进行 T 细胞受体测序分析显示疫苗特异性 T 细胞涌入。

结论: 该研究达到了主要终点:胰腺癌患者在胰腺切除术后接受标准护理治疗和辅助性树突状细胞免疫治疗其2 年无复发生存率 ≥ 60%。这些结果值得进行未来的随机试验。

The primary objective of this study was to determine the efficacy of dendritic cell-based immunotherapy in preventing disease relapse.

Methods: This was a single-center, open-label, single-arm, combined phase I/II trial. The primary endpoint was 2-year relapse-free survival (≥ 60% defined as a clinically meaningful improvement). The trial enrolled patients with pancreatic cancer who had undergone resection and completed standard-of-care therapy and who had no recurrent disease on cross-sectional imaging. Patients were treated with autologous dendritic cells pulsed with allogeneic mesothelioma tumor cell lysate containing antigens also expressed in pancreatic ductal adenocarcinoma.

Results: Thirty-eight patients were included in the primary endpoint analysis (47% male, 53% female). The median age was 62 years (IQR, 55-68). Twenty-eight patients (74%) received five dendritic cell vaccinations and completed the study protocol. Three patients (8%) received four vaccinations, and seven patients (16%) received three vaccinations. After a median follow-up of 25.5 months, 26 patients (68%) remained disease-free. The estimated 2-year relapse-free survival was 64%. Vaccination resulted in enrichment of circulating activated CD4+ T cells, and treatment-induced immune responses were detected in vitro. T-cell receptor sequencing analysis of resected solitary lung metastases showed vaccine-specific T-cell influx.

Conclusions: The study met its primary endpoint: 2-year relapse-free survival was ≥ 60% in patients with pancreatic cancer who received standard of care therapy and adjuvant dendritic cell immunotherapy after pancreatectomy. These results warrant future randomized trials.

参考文献 Reference

van’t Land FR et al. J Cln Onc 2024; https://doi.org/10.1200/JCO.23.0258

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围手术期 mFOLFIRINOX 治疗可切除胰腺癌非随机对照试验 (7/7/2024)

Results from a phase II study of perioperative mFOLFIRINOX for resectable pancreatic cancer

方法：这项针对可切除胰腺导管腺癌的开放标签, 单臂, II 期非随机对照试验于 2014 年 4 月 3 日至 2021 年 8 月 16 日在一家癌症医院进行。在诊断时进行胰腺方案计算机断层扫描以评估手术候选资格。患者在手术前接受 6 个周期的术前新辅助 mFOLFIRINOX 治疗，并接受 6 个周期的术后辅助 mFOLFIRINOX 治疗。收集全血并处理成储存血浆以分析循环肿瘤 DNA (ctDNA) 水平。评估肿瘤的治疗反应和角蛋白 17 (K17) 表达。主要终点是 12 个月无进展生存率。其他终点包括总生存期, ctDNA 水平、肿瘤分子特征和 K17 肿瘤水平。使用 Kaplan-Meier 估计量总结生存曲线。

结果: 46 名接受 mFOLFIRINOX 治疗的患者中，31 名 (67%) 为男性，中位年龄 (范围) 为 65 (46-80) 岁。共有 37 名 (80%) 完成了 6 个术前周期，33 名 (72%) 接受了手术。共有 27 名患者 (59%) 按照方案接受了切除术（25 名患有 R0 疾病，2 名患有 R1 疾病）；6 名患者在探查过程中被确诊为转移性或不可切除疾病。10 名患者接受了方案外手术。

12 个月无进展生存率为 67% (90% CI, 56.9-100)；中位无进展生存期 和总生存期分别为 16.6 个月 (95% CI, 13.3-40.6) 和 37.2 个月 (95% CI, 17.5-未达到)。接受 6 个周期的 mFOLFIRINOX 治疗后，22 名患者中有 16 名 (73%) 检测到基线 ctDNA 水平，17 名患者中有 3 名 (18%) 检测到基线 ctDNA 水平。与未检测到 ctDNA 水平的患者相比，术后 4 周检测到 ctDNA 水平的患者无进展生存率 (风险比 [HR]，34.0；95% CI，2.6-4758.6；P = .006) 和总生存期 (HR，11.7；95% CI，1.5-129.9；P = .02) 较差。K17 表达高的患者无进展生存率 (HR，2.7；95% CI，0.7-10.9；P = .09) 和总生存期 (HR，3.2；95% CI，0.8-13.6；P = .07) 较差，但差异不显著。  

结论和相关性:这项非随机对照试验达到了其主要终点，围手术期 mFOLFIRINOX 值得在随机临床试验中进一步评估。术后 ctDNA 阳性与复发密切相关。K17 和 ctDNA 是有前途的生物标记物，需要在未来的前瞻性研究中进行进一步验证。

Methods: This open-label, single-arm, phase II nonrandomized controlled trial for resectable pancreatic ductal adenocarcinoma was conducted at a single cancer hospital from April 3, 2014, to August 16, 2021. Pancreatic protocol computed tomography was performed at diagnosis to assess surgical candidacy. Patients received 6 cycles of neoadjuvant mFOLFIRINOX before surgery and 6 cycles of adjuvant mFOLFIRINOX. Whole blood was collected and processed into stored plasma for analysis of circulating tumor DNA (ctDNA) levels. Tumor treatment response and keratin 17 (K17) expression were assessed. The primary endpoint was 12-month progression-free survival. Other endpoints included overall survival, ctDNA levels, tumor molecular characteristics, and K17 tumor levels. Survival curves were summarized using Kaplan-Meier estimators.

Results: Of the 46 patients treated with mFOLFIRINOX, 31 (67%) were male, with a median age (range) of 65 (46-80) years. A total of 37 patients (80%) completed 6 preoperative cycles, and 33 (72%) underwent surgery. A total of 27 patients (59%) underwent per-protocol resection (25 with R0 disease and 2 with R1 disease); 6 patients were diagnosed with metastatic or unresectable disease during exploration. Ten patients underwent off-protocol surgery. The 12-month progression-free survival rate was 67% (90% CI, 56.9-100); median progression-free survival and overall survival were 16.6 months (95% CI, 13.3-40.6) and 37.2 months (95% CI, 17.5-not reached), respectively. After 6 cycles of mFOLFIRINOX, baseline ctDNA levels were detectable in 16 of 22 patients (73%) and in 3 of 17 patients (18%). Patients with detectable ctDNA levels 4 weeks after surgery had worse progression-free survival (hazard ratio [HR], 34.0; 95% CI, 2.6-4758.6; P = .006) and overall survival (HR, 11.7; 95% CI, 1.5-129.9; P = .02) compared with those without detectable ctDNA levels. Patients with high K17 expression had worse progression-free survival (HR, 2.7; 95% CI, 0.7-10.9; P = .09) and overall survival (HR, 3.2; 95% CI, 0.8-13.6; P = .07), but the differences were not significant.

Conclusions and relevance: This nonrandomized controlled trial met its primary endpoint, and perioperative mFOLFIRINOX deserves further evaluation in randomized clinical trials. Postoperative ctDNA positivity was strongly associated with recurrence. K17 and ctDNA are promising biomarkers that need to be further validated in future prospective studies.

参考文献 Reference

Cecchini M et al， JAMA Oncol 2024: June 20. doi:10.1001/jamaoncol.2024.1575

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三联疗法 nivolumab, relatlimab 和 ipilimumab在晚期黑色素瘤中的疗效和安全性(7/6/2024)

Efficacy and safety of triplet nivolumab, relatlimab, and ipilimumab in advanced melanoma

背景： nivolumab （NIVO,抗 PD-1 抗体）被批准作为单一疗法，并与 relatlimab （RELA, 抗 LAG-3 抗体）或 ipilimumab （IPI, 抗 CTLA-4 抗体）联合用于治疗晚期黑色素瘤患者。RELATIVITY-048 (NCT03459222) 是一项 I/II 期非随机试验，旨在评估包括 NIVO + RELA + IPI 在内的免疫肿瘤学三联疗法对特定实体瘤患者的疗效。

方法： 晚期黑色素瘤患者接受一线每4星期1次 NIVO 480 毫克 + 每4星期1次RELA 160 毫克 + 每8星期1次IPI 1 毫克/公斤治疗，直至病情进展或出现不可接受的毒性。如果在入组前 6 个月以上完成，则允许接受包括三联疗法药物在内的先前新辅助/辅助治疗。脑转移得到控制的患者可以入组。主要终点是安全性和每位研究者的确认客观响应率, 疾病控制率和中位响应持续时间。次要终点是每位研究者的无进展生存期。探索性终点包括总生存期。

结果： 总共有 46 名患者接受了治疗。中位随访时间为 44.1 个月（范围：0.4–53.5）。中位年龄为 61.0 岁，8.7% 患有皮肤肢端黑色素瘤，50.0% 为 BRAF 阳性，7​​3.9% 为 LAG-3 阳性（≥ 1%），26.1% 为肿瘤细胞 PD-L1 阳性（≥ 1%），6.5% 接受过先前的辅助治疗。中位治疗持续时间为 5.0 个月（范围：0.0–49.0）。NIVO + RELA + IPI 的确认客观响应率为 58.7%，48 个月总生存率为 69.1%。

共44 名患者 (95.7%) 和 18 名患者 (39.1%) 分别发生了任何级别和 3/4 级治疗相关不良事件。19 名患者 (41.3%) 因任何级别的治疗相关不良事件而停止治疗。2 名患者因治疗相关不良事件 死亡 (4.3%；直肠出血和呼吸困难 [n = 1]，免疫介导性肌炎 [n = 1])。   

结论： 在 RELATIVITY-048 中，NIVO + RELA + IPI 显示出良好的疗效，确认的客观响应率为 58.7%，48 个月总生存率率为 69.1%。该三联疗法没有新的安全信号，安全性与免疫肿瘤疗法组合基本一致。鉴于样本量较小，需要进行更多研究来确认该三联疗法的疗效和安全性。

Background: Nivolumab (NIVO, anti-PD-1 antibody) is approved as monotherapy and in combination with relatlimab (RELA, anti-LAG-3 antibody) or ipilimumab (IPI, anti-CTLA-4 antibody) for the treatment of patients with advanced melanoma. RELATIVITY-048 (NCT03459222) is a phase I/II non-randomized trial designed to evaluate the efficacy of immuno-oncology triplet therapy including NIVO + RELA + IPI in patients with selected solid tumors.

Methods: Patients with advanced melanoma received first-line treatment with NIVO 480 mg every 4 weeks + RELA 160 mg every 4 weeks + IPI 1 mg/kg every 8 weeks until disease progression or unacceptable toxicity. Prior neoadjuvant/adjuvant therapy including triplet therapy drugs was allowed if completed more than 6 months before enrollment. Patients with controlled brain metastases were eligible for enrollment. The primary endpoints were safety and confirmed objective response rate per investigator, disease control rate, and median duration of response. Secondary endpoints were progression-free survival per investigator. Exploratory endpoints included overall survival.

Results: A total of 46 patients were treated. The median follow-up was 44.1 months (range: 0.4–53.5). The median age was 61.0 years, 8.7% had cutaneous acral melanoma, 50.0% were BRAF-positive, 73.9% were LAG-3-positive (≥ 1%), 26.1% were PD-L1-positive (≥ 1%), and 6.5% had received prior adjuvant therapy. The median duration of treatment was 5.0 months (range: 0.0–49.0). The confirmed objective response rate of NIVO + RELA + IPI was 58.7%, and the 48-month overall survival rate was 69.1%.

Any-grade and grade 3/4 treatment-related adverse events occurred in 44 patients (95.7%) and 18 patients (39.1%), respectively. Treatment was discontinued due to any-grade treatment-related adverse events in 19 patients (41.3%). Two patients died due to treatment-related adverse events (4.3%; rectal bleeding and dyspnea [n = 1], immune-mediated myositis [n = 1]).

Conclusions: In RELATIVITY-048, NIVO + RELA + IPI showed excellent efficacy, with a confirmed objective response rate of 58.7% and a 48-month overall survival rate of 69.1%. There were no new safety signals for this triplet, and the safety profile was generally consistent with immuno-oncology combinations. Given the small sample size, additional studies are needed to confirm the efficacy and safety of this triplet immunotherapy.  

参考文献 Reference

Ascierto PA et al. J Clin Oncol 2024; 42 (suppl 16; abstr 9504)

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Armored huCART19-IL18 用于 CD19 CAR T 细胞治疗后进展的复发/难治性淋巴瘤 (6/30/24)

Armored huCART19-IL18 in relapsed/refractory lymphomas that progressed after anti-CD19 CAR T cells

背景：HuCART19-IL18是一种第 4 代 4-1BB 抗 CD19 构建体，具有分泌促炎细胞因子 IL-18 的能力。

方法： 这是首次使用 huCART19-IL18 治疗 CD19+ B 细胞恶性肿瘤 (NCT04684563) 的人体试验。采用 3 天快速制造以限制 T 细胞耗竭。患者必须在 CD19 CAR T 细胞治疗后进展的复发/难治性非霍奇金淋巴瘤。在淋巴细胞清除化疗后，huCART19-IL18+ 细胞的剂量水平介于 3×10⁶ 和 3×10⁸ 之间，以单次静脉输注方式给药。首次评估响应在 3 个月时进行。   

结果： 截至 2024 年 1 月 20 日，21 名患有 CD19+ 非霍奇金淋巴瘤患者输注了 huCART19-IL18。患者特征包括中位年龄 64 岁 (47-74)，76% 为男性，9 (43%) 例弥漫性大B细胞淋巴瘤，6 (29%) 例滤泡性淋巴瘤，3 (14%) 例套细胞淋巴瘤，2 (10%) 例t-滤泡性淋巴瘤，1 (5%) 例高级别 B 细胞淋巴瘤。既往接受过治疗患者的中位数量为 7 (4-14)，其中 20 (95%) 例患者对既往抗 CD19 CAR T 细胞治疗复发/难治。由于 4/6 (67%) 例剂量水平5 患者无法达到目标剂量，因此无法制造剂量水平5 (3×10⁸)。18 (86%) 例患者接受了(HuCART19-IL18前的)桥接治疗。 3 名患者接受剂量水平1（3×10⁶），4 名患者接受剂量水平2（7×10⁶），1 名患者接受未定义剂量（2.8×10⁷），6 名患者接受剂量水平3（3×10⁷），5 名患者接受剂量水平4（7×10⁷），2 名患者接受剂量水平5（3×10⁸）。21 名可进行安全性评估的患者中未发生与研究相关的死亡。15 名 (71%) 患者发生细胞因子释放综合征：8 名 (38%) 患者为1级，4 名 (19%) 患者为2级，3 名 (14%) 患者为3级。3 名 (14%) 患者发生 ICANS：2 名 (10%) 患者为1级，1 名 (5%) 患者为2级。至少可能与 huCART19-IL18 相关的最常见的3级不良事件包括疲劳（38%）、低血压（29%）和低纤维蛋白原（23%）。 20 名患者可评估疗效，中位随访期为 15 个月 (3-31)。3 个月总响应率为 80% (90% CI: 60-93%)，完全响应率为 50% (90% CI: 30-70%)，部分响应率为 30% (90% CI: 14-51%)。中位响应持续时间为 10 个月 (5.5-未达到)。中位无进展生存期为 8.7 个月 (90% CI 5-未达到)，中位总生存率未达到 (90% CI 25 个月-未达到)。在 24 个月的随访中检测到 huCART19-IL18 在患者中持续存在。未发现细胞剂量与结果之间的相关性，但先前接受过 CD28 CAR 治疗的患者的响应率和平均扩增 (拷贝数/µg gDNA) 高于先前接受过 4-1BB CAR 治疗的患者。   

结论： HuCART19-IL18 治疗具有可接受的安全性，并且尽管之前接受过 CAR T 细胞治疗，但对于接受过大量治疗的复发/难治性非霍奇金淋巴瘤患者仍能产生持久缓解。先前 CAR 产品的亚型可能会影响 huCART19-IL18 的扩增和有效性。

Background: HuCART19-IL18 is a 4th generation 4-1BB anti-CD19 construct with the ability to secrete the pro-inflammatory cytokine IL-18.

Methods: This was a first-in-human trial  (NCT04684563) using huCART19-IL18 for the treatment of CD19+ B-cell malignancies. Three-day rapid manufacturing was used to limit T-cell exhaustion. Patients must have relapsed/refractory non-Hodgkin lymphoma that had progressed after CD19 CAR T-cell therapy. Dose levels of huCART19-IL18+ cells ranged between 3×10⁶ and 3×10⁸, administered as a single intravenous infusion, following lymphodepleting chemotherapy. First assessment of response was performed at 3 months.

Results: As of January 20, 2024, 21 patients with CD19+ non-Hodgkin lymphoma were infused with huCART19-IL18. Patient characteristics included a median age of 64 years (47-74), 76% male, 9 (43%) diffuse large B-cell lymphoma, 6 (29%) follicular lymphoma, 3 (14%) mantle cell lymphoma, 2 (10%) t-follicular lymphoma, and 1 (5%) high-grade B-cell lymphoma. The median number of previously treated patients was 7 (4-14), of whom 20 (95%) were relapsed/refractory to prior anti-CD19 CAR T-cell therapy. Manufacturing of DL5 (3×10⁸) was not feasible due to inability to achieve the target dose in 4/6 (67%) pts assigned to DL5. Eighteen (86%) patients received bridging therapy (prior to HuCART19-IL18). Three patients received dose level 1 (3×10⁶), four patients received dose level 2 (7×10⁶), one patient received an undefined dose (2.8×10⁷), six patients received dose level 3 (3×10⁷), five patients received dose level 4 (7×10⁷), and two patients received dose level 5 (3×10⁸). No study-related deaths occurred in the 21 patients evaluable for safety. Cytokine release syndrome occurred in 15 (71%) patients: grade 1 in 8 (38%) patients, grade 2 in 4 (19%) patients, and grade 3 in 3 (14%) patients. ICANS occurred in 3 (14%) patients: grade 1 in 2 (10%) patients and grade 2 in 1 (5%) patient. The most common grade 3 adverse events that were at least possibly related to huCART19-IL18 included fatigue (38%), hypotension (29%), and low fibrinogen (23%). Twenty patients were evaluable for efficacy, with a median follow-up of 15 months (3-31). The 3-month overall response rate was 80% (90% CI: 60-93%), the complete response rate was 50% (90% CI: 30-70%), and the partial response rate was 30% (90% CI: 14-51%). The median duration of response was 10 months (5.5-not reached). The median progression-free survival was 8.7 months (90% CI 5-not reached), and the median overall survival rate was not reached (90% CI 25 months-not reached). HuCART19-IL18 was detected in patients at 24 months of follow-up. No correlation between cell dose and outcome was found, but the response rate and mean expansion (copy number/µg gDNA) were higher in patients who had previously received CD28 CAR therapy than in those who had previously received 4-1BB CAR therapy.

Conclusions: HuCART19-IL18 treatment has an acceptable safety profile and produces durable responses in heavily pretreated patients with relapsed/refractory non-Hodgkin lymphoma despite prior CAR T-cell therapy. The subtype of prior CAR products may affect the expansion and efficacy of huCART19-IL18.

参考文献

Svoboda J et al. J Clin Oncol 2024; 42: (suppl 16; abstr 7004)

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Afamitresgene autoleucel 治疗晚期滑膜肉瘤和粘液样圆细胞脂肪肉瘤 (6/29/2024)

Afamitresgene autoleucel for advanced synovial sarcoma and myxoid round cell liposarcoma

方法: SPEARHEAD-1  (NCT04044768) 是一项国际性, 开放标签, 非随机,II 期 试验，在加拿大, 美国和欧洲的 23 个地点进行。该试验包括三个队列，其中主要研究队列（队列 1）在此处报告。队列 1 包括 HLA-A*02 和表达 MAGE-A4患者，年龄为 16-75 岁，患有转移性或不可切除的滑膜肉瘤或粘液样圆细胞脂肪肉瘤，并且曾接受过至少一线含蒽环类或异环磷酰胺的化疗。患者在淋巴细胞清除后接受单次静脉注射 Afamitresgene autoleucel(afami-cel)（剂量范围为 1.0 × 10⁹–10.0 × 10⁹ T 细胞）。主要终点是总体响应率。  

结果: 2019 年 12 月 17 日至 2021 年 7 月 27 日期间，队列 1中招募了 52 名经细胞遗传学证实的滑膜肉瘤 (n =44) 和粘液样圆细胞脂肪肉瘤 (n =8) 患者，并接受了 afami-cel 治疗。患者曾接受了大量先前治疗（中位数为3 [IQR 2-4] 线全身治疗）。中位随访时间为 32.6 个月（IQR 29.4–36.1）。总体响应率为 37%（52 例中的 19 例；95% CI 24–51），滑膜肉瘤患者响应率为 39%（44 例中的 17 例；24–55），粘液样圆细胞脂肪肉瘤患者响应率为 25%（8 例中的 2 例；3–65）。52 例患者中有 37 例（71%）出现细胞因子释放综合征（1 例 3 级事件）。血细胞减少是最常见的 3 级或更严重的不良事件（52 例患者中有 50 例 [96%] 出现淋巴细胞减少，44 例 [85%] 出现中性粒细胞减少，42 例 [81%] 出现白细胞减少）。未发生与治疗相关的死亡。   

解释: Afami-cel 治疗对接受过大量治疗的 HLA-A*02 和表达 MAGE-A4滑膜肉瘤患者产生了持久的响应。这项研究表明，T 细胞受体疗法可有效针对实体肿瘤，并为将这种方法扩展到其他实体恶性肿瘤提供了理论依据。

Methods: SPEARHEAD-1 (NCT04044768) was an international, open-label, nonrandomized, phase II trial conducted at 23 sites in Canada, the United States, and Europe. The trial included three cohorts, of which the primary study cohort (cohort 1) was reported here. Cohort 1 included patients with HLA-A*02 and MAGE-A4 expressing disease, aged 16–75 years, with metastatic or unresectable synovial sarcoma or myxoid round cell liposarcoma, who had received at least one line of anthracycline- or ifosfamide-containing chemotherapy. Patients received a single intravenous infusion of afamitresgene autoleucel (afami-cel) (dose range 1.0 × 10⁹–10.0 × 10⁹ T cells) after lymphodepletion. The primary endpoint was overall response rate.

Results: Between Dec 17, 2019, and July 27, 2021, 52 patients with cytogenetically confirmed synovial sarcoma (n = 44) and myxoid round cell liposarcoma (n = 8) were enrolled in cohort 1 and treated with afami-cel. Patients had received extensive prior therapy (median 3 [IQR 2-4] lines of systemic therapy). Median follow-up was 32 6 months (IQR 29 4–36 1). The overall response rate was 37% (19 of 52; 95% CI 24–51), with a response rate of 39% (17 of 44; 24–55) for synovial sarcoma and 25% (2 of 8; 3–65) for myxoid round cell liposarcoma. Cytokine release syndrome occurred in 37 of 52 patients (71%) (1 grade 3 event). Cytopenias were the most common grade 3 or higher adverse events (lymphopenia in 50 of 52 patients [96%], neutropenia in 44 [85%], and leukopenia in 42 [81%]). No treatment-related deaths occurred.

Interpretation: Afami-cel treatment produced durable responses in heavily pretreated patients with HLA-A*02 and MAGE-A4-expressing synovial sarcomas. This study demonstrates that T-cell receptor therapy can be effective against solid tumors and provides a rationale for expanding this approach to other solid malignancies.

参考文献

D’Angelo SD et al. Lancet 2024; 403:1360

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抗 CD19 嵌合抗原受体 T 细胞疗法治疗 Richter 转化 (6/23/2024)

Anti-CD19 CAR-T therapy for Richter transformation

方法：研究者对接受 CAR-T 治疗的 Richter 转化患者进行了一项国际多中心回顾性研究。使用描述性统计数据总结患者, 疾病和治疗特征，并使用建模分析确定与无进展生存期和总生存期的关联。

结果：研究确定了 69 名患者。CAR-T 输注时的中位年龄为 64 岁（范围为 27-80 岁）。患者接受过 4 种（范围：1-15 种）慢性淋巴细胞白血病和/或 Richter 转化治疗，其中 58 名（84%）患者接受过 Bruton 酪氨酸激酶抑制剂和/或 BCL2 抑制剂治疗。44 名患者（64%）接受过 CAR-T 产品 axicabtagene ciloleucel，17 名患者（25%）接受过 tisagenlecleucel，7 名患者（10%）接受过 lisocabtagene maraleucel，1 名患者（1%）接受过 brexucabtagene autoleucel。11 名患者（16%）和 25 名患者（37%）分别出现 3 级以上细胞因子释放综合征和免疫效应细胞相关神经毒性综合征。总响应率为 63%，其中 46% 达到完全响应。中位随访时间为 24 个月，中位无进展生存期为 4.7 个月（95% CI，2.0 至 6.9）；2 年无进展生存期为 29%（95% CI，18 至 41）。中位总生存期为 8.5 个月（95% CI，5.1 至 25.4）；2 年总生存期为 38%（95% CI，26 至 50）。达到完全响应患者的中位响应持续时间为 27.6 个月（95% CI，14.5 至未达到）。

结论：CAR-T 对Richter 转化患者具有临床疗效。

Methods: The researchers performed an international multicenter retrospective study of patients with Richter’s transformation who received CAR-T therapy. Descriptive statistics were used to summarize patient, disease, and treatment characteristics, and modeling analyses were used to determine associations with progression-free and overall survival.

Results: The study identified 69 patients. The median age at CAR-T infusion was 64 years (range, 27-80 years). Patients had received 4 (range: 1-15) prior therapies for chronic lymphocytic leukemia and/or Richter’s transformation, of which 58 patients (84%) had received prior treatment with a Bruton’s tyrosine kinase inhibitor and/or a BCL2 inhibitor. The CAR-T products administered was axicabtagene ciloleucel  in 44 patients (64%), tisagenlecleucel  in 17 patients (25%), lisocabtagene maraleucel in 7 patients (10%), and brexucabtagene autoleucel in 1 patient (1%). Grade 3 or higher cytokine release syndrome and immune effector cell-related neurotoxicity syndrome occurred in 11 patients (16%) and 25 patients (37%), respectively. The overall response rate was 63%, of which 46% achieved a complete response. The median follow-up time was 24 months, and the median progression-free survival was 4.7 months (95% CI, 2.0 to 6.9); the 2-year progression-free survival was 29% (95% CI, 18 to 41). The median overall survival was 8.5 months (95% CI, 5.1 to 25.4); the 2-year overall survival was 38% (95% CI, 26 to 50). The median duration of response for patients who achieved a complete response was 27.6 months (95% CI, 14.5 to not reached).  

Conclusion: CAR-T therapy has clinical efficacy in patients with Richter’s transformation.

参考文献

Kittai AS et al. J Clin Onc 2024; 10:2071

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III 期 CheckMate 649 试验: 晚期胃癌, 胃食管连接部癌和食管腺癌的一线 Nivolumab 联合化疗 (6/22/2024)

Phase III CheckMate 649 Trial: First-line nivolumab plus chemotherapy for advanced gastric, GEJ, and esophageal adenocarcinoma

研究者报告了 III 期 CheckMate 649 试验的 3 年疗效和安全性结果。先前未接受过治疗的晚期或转移性胃食管腺癌患者被随机分配到 nivolumab 联合化疗或单独化疗组。主要终点是肿瘤表达 PD-L1 综合阳性评分 (CPS) ≥ 5 的患者的总生存期和无进展生存期，由盲法独立中央审查确定。

经 36.2 个月的最短随访，对于 PD-L1 CPS ≥5 的患者，nivolumab 联合化疗与化疗的总生存期风险比 (HR) 为 0.70（95% CI，0.61 至 0.81）；36 个月时分别为 21% 和 10% 的患者存活。无进展生存期 HR 为 0.70（95% CI，0.60 至 0.81）；36 个月无进展生存率分别为 13% 和 8%。根据盲法独立中央审查，nivolumab 联合化疗的客观响应率为 60% (95% CI, 55 至 65)，而化疗为 45% (95% CI, 40 至 50)；中位响应持续时间分别为 9.6 个月 (95% CI, 8.2 至 12.4) 和 7.0 个月 (95% CI, 5.6 至 7.9)。在总体人群中，与化疗相比，nivolumab 联合化疗还继续显示出总生存期. 无进展生存期和客观响应率的改善。

与单纯化疗相比，将 nivolumab 添加到化疗中可保持具有临床意义的长期生存益处，且安全性可接受，支持继续使用 nivolumab 联合化疗作为晚期胃食管腺癌的标准一线治疗。

Investigators reported 3-year efficacy and safety results from the phase III CheckMate 649 trial. Patients with previously untreated advanced or metastatic gastroesophageal adenocarcinoma were randomly assigned to nivolumab plus chemotherapy or chemotherapy alone. The primary endpoints were overall survival and progression-free survival as determined by blinded independent central review in patients whose tumors expressed PD-L1 combined positive score (CPS) ≥ 5. With a minimum follow-up of 36.2 months, the hazard ratio (HR) for overall survival with nivolumab plus chemotherapy versus chemotherapy was 0.70 (95% CI, 0.61 to 0.81) for patients with PD-L1 CPS ≥ 5; 21% and 10% of patients were alive at 36 months, respectively. The HR for progression-free survival was 0.70 (95% CI, 0.60 to 0.81); 36 months progression-free survival were 13% and 8% respectively. Based on blinded independent central review, the objective response rate was 60% (95% CI, 55 to 65) with nivolumab plus chemotherapy and 45% (95% CI, 40 to 50) with chemotherapy; the median duration of response was 9.6 months (95% CI, 8.2 to 12.4) and 7.0 months (95% CI, 5.6 to 7.9), respectively. In the overall population, nivolumab plus chemotherapy also continued to show improvements in overall survival, progression-free survival, and objective response rate compared with chemotherapy alone.

The addition of nivolumab to chemotherapy maintained a clinically meaningful long-term survival benefit compared with chemotherapy alone with an acceptable safety profile, supporting the continued use of nivolumab plus chemotherapy as a standard first-line treatment for advanced gastroesophageal adenocarcinoma.

参考文献

Janjigian YY et al. J Clin Onc 2024; 42:2012

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首创泛素特异性肽酶 1 (USP1) 抑制剂的首次人体 I 期试验用于晚期实体瘤 (6/16/2024)

First-in-human phase I trial of the oral first-in-class ubiquitin specific peptidase 1 (USP1) inhibitor in advanced solid tumors

背景： USP1 是一种去泛素酶，可调节 DNA 损伤反应途径。KSQi 是一种选择性的 USP1 小分子抑制剂，在具有同源重组修复 (HRR) 突变的肿瘤中具有抗增殖活性。KSQi 和 PARP 抑制剂 的组合在卵巢和三阴性乳腺癌患者来源的异种移植(PDX )模型中表现出强大的协同作用，这为临床试验提供了基础。

方法： 这是一项由两部分组成的研究(NCT05240898)：第 1 部分为剂量递增，探索 KSQi 作为单药（第 1 组）以及与 olaparib 200 毫克, 每天两次（第 2 组）或卡铂AUC = 4（第 3 组）联合使用时的安全性,药代动力学,  药效学和初步抗肿瘤活性，以确定最大耐受剂量和/或推荐的扩展剂量。第 2 部分将评估扩展队列中组合的疗效和安全性。    

结果： 截至 2024 年 1 月 4 日，64 名患者（19 名男性/45 名女性；中位年龄 63 岁）接受了 KSQi 100 – 1250 毫克；第 1 组：100 毫克（3 名患者）, 150（3 名）, 200（4 名）, 300（6 名）, 450（5 名）, 650（9 名）, 900（7 名）和 1250（5 名）；第 2 组：200（5 名）, 450（5 名）和 900（5 名）；第 3 组：200（3 名）和 450（4 名）。第 1, 2 和 3 组的既往治疗中位数分别为 5, 4 和 3。第 1 组中 29% 的患者曾接受过PARP 抑制剂治疗，第 2 组中 53% 的患者曾接受过PARP 抑制剂治疗，第 3 组中 71% 的患者曾接受过PARP 抑制剂 治疗。第 2 和第 3 组的所有患者均患有伴有有害 HRR 突变的肿瘤。

最常见的治疗中出现的不良事件是贫血（36%）, 单药导致的肌酐升高（33%）以及与 olaparib（87%）和卡铂（71%）联用时出现的贫血。最常见的3 级不良事件是单药引起的低钠血症 (12%) 和与 olaparib (73%) 和卡铂 (29%) 联合使用的贫血。剂量限制毒性（n = 3）分别是 1250 毫克（第 1 组）时的3 级 斑丘疹和 200 毫克时的3 级白细胞减少，450 毫克（第 2 组）时的3 级贫血。30% (19/64) 的患者中断 KSQi 给药，1 名 (1.6%) 患者停止治疗。

KSQi 治疗的患者的配对肿瘤活检中观察到泛素化 PCNA 诱导，支持肿瘤内 USP1 抑制。在接受 单药 KSQi 治疗的输卵管癌患者中观察到持续 7 周的部分响应，9 名患者为疾病稳定；与 olaparib联合治疗的最佳反应是 6 名患者为疾病稳定，使用卡铂治疗时为 2 名患者为疾病稳定。16 周时的疾病控制率为 28%（第 1 组）, 40%（第 2 组）和 29%（第 3 组）。  

结论： KSQi 是首创的 USP1 抑制剂，与单药和联合治疗相比具有可接受的安全性。任何组均未达到最大耐受剂量。药效学结果支持 USP1 抑制的作用机制。

参考文献

Yap TA et al. 2024 ASCO Ann Meeting abstr 3005

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局部晚期错配修复缺陷结肠癌的新辅助免疫疗法 (6/15/2024)

Neoadjuvant immunotherapy for locally advanced dMMR colon cancer

背景: 约 10% 至 15% 的非转移性结肠癌患者可发现错配修复缺陷 (dMMR) 肿瘤。化疗对这些患者的疗效有限; 新辅助免疫疗法的使用显示有希望。  

方法: 研究者进行了一项 II 期研究（NCT03026140），对非转移性, 局部晚期, 先前未接受过治疗的 dMMR 结肠癌患者给新辅助 nivolumab 加 ipilimumab 治疗。两个主要终点是安全性，定义为及时手术（即由于治疗相关毒性事件而计划手术延迟 ≤ 2 周）和 3 年无病生存期。次要终点包括病理响应和基因组分析结果。

结果: 115 名入组患者中，113 名（98%；97.5% 置信区间 [CI]，93 至 100）及时接受了手术；2 名患者的手术延迟超过 2 周。5 名患者（4%）发生了 3 级或 4 级免疫相关不良事件，没有患者因不良事件而停止治疗。在纳入疗效分析的 111 名患者中，109 名（98%；95% CI，94 至 100）出现病理响应，其中 105 名（95%）出现主要病理响应（定义为残留活肿瘤 ≤10%），75 名（68%）出现病理完全响应（残留活肿瘤为 0%）。中位随访时间为 26 个月（范围为 9 至 65 个月），无患者出现疾病复发。  

结论: 对于局部晚期 dMMR 结肠癌患者，新辅助 nivolumab 加 ipilimumab 具有可接受的安全性，并且导致大部分患者出现病理响应。

一些人认为只有随机试验才能证明新辅助或辅助免疫治疗后进行手术是否比单纯手术更有益处。

Background: Mismatch repair-deficient (dMMR) tumors can be found in approximately 10% to 15% of patients with nonmetastatic colon cancer. Chemotherapy has limited efficacy in these patients; the use of neoadjuvant immunotherapy shows promising results.

Methods: Researchers conducted a phase II study (NCT03026140) of neoadjuvant nivolumab plus ipilimumab in patients with nonmetastatic, locally advanced, previously untreated dMMR colon cancer. The two primary end points were safety, defined as timely surgery (i.e., delay of planned surgery ≤ 2 weeks due to treatment-related toxicity) and 3-year disease-free survival. Secondary end points included pathological response and results of genomic analyses.

Results: Of the 115 enrolled patients, 113 (98%; 97.5% confidence interval [CI], 93 to 100) underwent timely surgery; surgery was delayed by more than 2 weeks in 2 patients. Grade 3 or 4 immune-related adverse events occurred in 5 patients (4%), and no patient discontinued treatment due to adverse events. Of the 111 patients included in the efficacy analyses, 109 (98%; 95% CI, 94 to 100) had a pathological response, including 105 (95%) with a major pathological response (defined as ≤10% residual viable tumor) and 75 (68%) with a pathological complete response (0% residual viable tumor). No patient had disease recurrence at a median follow-up of 26 months (range, 9 to 65 months).

Conclusions: Neoadjuvant nivolumab plus ipilimumab had an acceptable safety profile and results in a high rate of pathological response.

Some think only randomized trial can prove whether neoadjuvant or adjuvant immune therapy  followed by surgery offers more benefit than surgery alone.

参考文献

Chalabi M et al. N Engl J Med 2024; 390:1949

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软组织肉瘤的新辅助放疗和手术联合或不联合派姆单抗 (6/9/2024)

Neoadjuvant radiation and surgery with or without pembrolizumab for soft tissue sarcoma

背景： SARC028 临床试验评估了派姆单抗对转移性软组织肉瘤的疗效，结果显示未分化多形性肉瘤和多形性/去分化脂肪肉瘤的响应率分别为 20% 和 8.7%。研究者假设，新辅助派姆单抗联合​​同期放疗治疗，随后进行手术和辅助派姆单抗治疗 III 期未分化多形性肉瘤（包括粘液纤维肉瘤或 脂肪肉瘤），将刺激抗肿瘤免疫反应，以消除微转移性疾病并提高无病生存期。

方法：SU2C-SARC032  (NCT03092323) 是一项多机构、国际、随机 II 期试验，旨在评估将派姆单抗添加到标准治疗(放疗和手术)中对患有 III 期未分化多形性肉瘤或脂肪肉瘤患者的安全性和有效性。 招募年龄 > 12 岁、患有 III 期未分化多形性肉瘤或肢体和肢带脂肪肉瘤的患者。患者随机分配 (1:1，按等级分层) 接受新辅助放疗 (50 Gy/25 fractions) 然后手术 (标准治疗组) 或新辅助派姆单抗和放疗然后手术和辅助派姆单抗 (试验组)。派姆单抗每 3 周静脉注射 200 毫克，共 3 次 放疗 前、放疗期间和放疗后)，最多 14 个辅助周期。主要终点是 2 年无病生存期。次要终点包括局部无复发生存期,远处无病生存期和总生存期。目标招募 126 名可评估患者（最多 144 名），通过对数秩检验提供 80% 的功效（单侧 α = 0.05）来区分 50% 2 年无病生存率的零假设和 75% 2 年无病生存率的备择假设，初步分析为 45 次无病生存期事件。Cox 模型按等级分层；主要分析是单侧分层对数秩检验。    

结果： 2017 年 7 月至 2023 年 11 月期间，招募了 143 名患者，主要为未分化多形性肉瘤（85%）和 3 级（64%）组织学。存活患者的中位随访时间为 24.1 个月。 试验组的无病生存期显著高于标准治疗组 (p = 0.023；HR 0.57，90% CI：0.35，0.91)。标准治疗组的估计 2 年无病生存期为 53% (90% CI：43，66%)，而试验组为 70% (90% CI：61，81%)。目前，局部无复发生存期 (HR 0.55，95% CI：0.21，1.42)、远处无病生存期 (HR 0.57，95% CI：0.32，1.01) 和总生存期 (HR 0.39，95% CI：0.14，1.12) 没有统计学上的显著差异。 3 级肉瘤患者使用派姆单抗后无病生存期有所改善（HR 0.47，95% CI：0.25，0.89），但 2 级肿瘤的无病生存期无差异（HR 1.21，95% CI：0.35，4.18）。试验组（52%）发生 3 级以上不良事件的患者比例明显高于标准治疗组（26%）（p = 0.002）。    

结论： 在放疗和手术中加入新辅助和辅助派姆单抗可显著改善肢体和肢带 III 期未分化多形性肉瘤或脂肪肉瘤 患者的无病生存期。

Background: SARC028 clinical trial evaluated the efficacy of pembrolizumab in metastatic soft tissue sarcomas and showed response rates of 20% for undifferentiated pleomorphic sarcomas and 8.7% for pleomorphic/dedifferentiated liposarcoma. The researchers hypothesized that neoadjuvant pembrolizumab combined with concurrent radiotherapy followed by surgery and adjuvant pembrolizumab for stage III undifferentiated pleomorphic sarcomas (including myxofibrosarcomas or liposarcoma) would stimulate an antitumor immune response to eliminate micrometastatic disease and improve disease-free survival.

Methods: SU2C-SARC032 (NCT03092323) was a multi-institutional, international, randomized, phase II trial designed to evaluate the safety and efficacy of adding pembrolizumab to standard therapy (radiation and surgery) in patients with stage III undifferentiated pleomorphic sarcoma or liposarcoma. Patients aged >12 years with stage III undifferentiated pleomorphic sarcoma or liposarcoma of the extremities and limb girdle were eligible. Patients were randomized (1:1, stratified by grade) to receive neoadjuvant RT (50 Gy/25 fractions) followed by surgery (standard-therapy group) or neoadjuvant pembrolizumab and RT followed by surgery and adjuvant pembrolizumab (experimental group). Pembrolizumab was given intravenously at 200 mg every 3 weeks for 3 doses (before, during, and after RT) for up to 14 adjuvant cycles. The primary endpoint was 2-year disease-free survival. Secondary endpoints included local recurrence-free survival, distant disease-free survival, and overall survival. The target enrollment was 126 evaluable patients (maximum 144), providing 80% power (one-sided α = 0.05) to distinguish between the null hypothesis of 50% 2-year disease-free survival and the alternative hypothesis of 75% 2-year disease-free survival by log-rank test, with a primary analysis of 45 disease-free survival events. Cox models were stratified by grade; primary analysis was one-sided stratified log-rank test.

Results: Between July 2017 and November 2023, 143 patients were enrolled, mainly with undifferentiated pleomorphic sarcoma (85%) and grade 3 (64%) histology. The median follow-up of surviving patients was 24.1 months. Disease-free survival was significantly higher in the trial group than in the standard-therapy group (p = 0.023; HR 0.57, 90% CI: 0.35, 0.91). The estimated 2-year disease-free survival was 53% (90% CI: 43, 66%) in the standard-therapy group and 70% (90% CI: 61, 81%) in the trial group. There were no statistically significant differences in local recurrence-free survival (HR 0.55, 95% CI: 0.21, 1.42), distant disease-free survival (HR 0.57, 95% CI: 0.32, 1.01), and overall survival (HR 0.39, 95% CI: 0.14, 1.12). Patients with grade 3 sarcomas had improved disease-free survival with pembrolizumab (HR 0.47, 95% CI: 0.25, 0.89), but there was no difference in disease-free survival for grade 2 tumors (HR 1.21, 95% CI: 0.35, 4.18). The proportion of patients with grade 3 or higher adverse events was significantly higher in the experimental group (52%) than in the standard treatment group (26%) (p = 0.002).

Conclusions: The addition of neoadjuvant and adjuvant pembrolizumab to radiotherapy and surgery significantly improves disease-free survival in patients with stage III undifferentiated pleomorphic sarcoma or liposarcoma of the limb and girdle.

参考文献

Mowery YM et al. 2024 ASCo ann Meeting abstr 11504

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下一代 PARP1 选择性抑制剂 Saruparib首次用于携带 BRCA1/2, PALB2 或 RAD51C/D 突变的患者 (6/8/2024)

Next generation PARP1-selective inhibitor Saruparib first clinical trial in patients with BRCA1/2, PALB2 or RAD51C/D mutations

背景：Saruparib 是一种强效, 高选择性 PARP1 抑制剂和捕获剂，与第一代双重 PARP1/2 抑制剂相比，具有更优异的耐受性, 靶向作用和疗效。

方法：PETRA 是一项多中心 I/II 期临床试验，纳入了 306 名接受过大量治疗的患者，患者患有晚期乳腺癌, 卵巢癌, 胰腺癌或前列腺癌，且携带 BRCA1, BRCA2, PALB2, 或RAD51C/D 突变。 研究人员首先在 A 部分评估了 saruparib 单药治疗，剂量范围从 10 mg 每日一次到 140 mg 每日一次。该剂量递增部分主要包括晚期或转移性 HER2 阴性乳腺癌（40.8%）, 卵巢癌（19.3%）和胰腺癌（9.8%）患者。A 部分中既往治疗线数中位数为三，45% 的患者之前接受过 PARP 抑制剂和/或含铂化疗。 试验 B 部分包括 HER2 阴性乳腺癌患者，这些患者之前未接受过 PARP 抑制剂治疗。此阶段的大多数患者都携带 BRCA 突变，转移性患者之前的化疗次数不受限制。

结果: 根据 IA 期建议的后续剂量（对于接受过中位数为三线治疗的患者）确定为每日 60 mg。在接受每日 60 mg的 31 名乳腺癌患者中，客观响应率为 48.4%，中位响应持续时间为 7.3 个月，中位无进展生存期为 9.1 个月。 在接受 60 mg 剂量治疗的所有癌症类型中（n = 141），

92.2% 的患者出现不良事件；12.1% 的患者报告了严重不良事件。76.6% 的患者报告了治疗相关不良事件；2.1% 的患者发生了严重的治疗相关不良事件。3.5% 的患者报告了因治疗相关不良事件而停用 saruparib。 在 HER2 阴性乳腺癌和PALB2, 或RAD51C/D突变患者中观察到响应。 在每日 60 mg 剂量下，HER2 阴性患者出现了深度和持久的反应。 与之前获批的 PARP 抑制剂相比，saruparib 的药代动力学和药效学更佳。 在推荐的 II 期剂量每日 60 mg 的 saruparib 下进行的探索性分析发现，循环肿瘤 DNA 动力学可能被证明是改善无进展生存期的早期生物标志物。

结论：Saruparib 是一种高度选择性的 PARP1 抑制剂和捕获剂，具有广泛的治疗指数。它可实现最大靶标参与，并显示出良好的临床活性，且耐受性良好。每日60 mg的剂量目前正在 III 期 ¬EvoPAR-Prostate01 试验中研究。

Background: Saruparib is a potent, highly selective PARP1 inhibitor and trapper that has superior tolerability, target engagement and efficacy compared with first-generation dual PARP1/2 inhibitors.

Methods: PETRA was a multicenter phase I/II clinical trial that enrolled 306 heavily pretreated patients with advanced breast, ovarian, pancreatic or prostate cancer harboring BRCA1, BRCA2, PALB2, or RAD51C/D mutations. Investigators first evaluated saruparib monotherapy in part A, with doses ranging from 10 mg once daily to 140 mg once daily. This dose-escalation portion primarily included patients with advanced or metastatic HER2-negative breast cancer (40.8%), ovarian cancer (19.3%), and pancreatic cancer (9.8%). The median number of prior lines of therapy in part A was three, and 45% of patients had previously received a PARP inhibitor and/or platinum-based chemotherapy. Part B of the trial included patients with HER2-negative breast cancer who had not been previously treated with a PARP inhibitor. Most patients in this phase had a BRCA mutation, and patients with metastatic disease had an unlimited number of prior chemotherapy lines.

Results: Subsequent dosing based on stage IA recommendations (for patients who had received a median of three prior lines of therapy) was determined to be 60 mg daily. Among the 31 breast cancer patients who received 60 mg daily, the objective response rate was 48.4%, the median duration of response was 7.3 months, and the median progression-free survival was 9.1 months.

Across all cancer types treated with the 60 mg dose (n = 141), 92.2% of patients experienced adverse events; 12.1% reported serious adverse events. 76.6% of patients reported treatment-related adverse events; 2.1% had serious treatment-related adverse events. 3.5% of patients reported discontinuation of saruparib due to treatment-related adverse events. Responses were observed in patients with HER2-negative breast cancer and PALB2, or RAD51C/D mutations. Deep and durable responses were seen in HER2-negative patients at a dose of 60 mg daily. Saruparib has superior pharmacokinetics and pharmacodynamics compared with previously approved PARP inhibitors. An exploratory analysis at the recommended phase II dose of 60 mg daily saruparib discovered that circulating tumor DNA dynamics may prove to be an early biomarker for improved progression-free survival.

Conclusions: Saruparib is a highly selective PARP1 inhibitor and trapper with a broad therapeutic index. It achieves maximal target engagement and shows promising clinical activity with a good tolerability profile. Phase II dose of 60 mg/d is currently being studied in the phase III ­EvoPAR-Prostate01 trial.

参考文献

Yap TA et al. AACR Ann Meeting 2024 April 8

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Raludotatug deruxtecan 单药用于既往接受过治疗的卵巢癌患者 (6/2/2024)

Monotherapy of Raludotatug deruxtecan in previously-treated ovarian cancer

CDH6 是一种跨膜蛋白，在 65% 至 85% 的卵巢上皮癌中过度表达，R-DXd 由人源化抗 CDH6 IgG1 单克隆抗体与拓扑异构酶 I 抑制剂有效载荷连接而成。

这是R-DXd 首次人体一项期临床试验，该研究招募了大多数铂耐药性晚期或转移性卵巢癌患者，这些患者不适合接受标准疗法，并且未根据肿瘤 CDH6 表达进行选择。患者接受了递增剂量（1.6 – 9.6 mg/kg），之后第二组剂量扩展组接受了 4.8 至 8.0 mg/kg 的 R-DXd。该报导介绍了 45 名接受 4.8 至 6.4 mg/kg 治疗的患者（37 名可评估）的结果。 确认的客观响应率为 48.6%，其中包括 1 例完全响应和 17 例部分响应；18 名患者病情稳定，疾病控制率为 97.4%。中位响应持续时间为 11.2 个月；中位响应时间为 5.7 周，中位无进展生存期为 8.1 个月。

R-DXd 的安全性是可控的，与其他 deruxtecan 抗体-药物偶联物的安全性相当。任何级别的最常见治疗相关不良事件是恶心（57.8%）, 呕吐（40.0%）, 疲劳（37.8%）和腹泻（31.1%）。有44.4% 的患者报告了 ≥ 3 级毒性，包括 15.6% 的贫血。两名患者出现了2 级药物相关性间质性肺病/肺炎；然而，在 8 mg/kg剂量水平（不是本分析的一部分）下，发生了 5 级间质性肺病事件。有11.1% 的患者停用 R-DXd，31.1% 的患者中断剂量，15.8% 的患者减少剂量。 

初步生物标志物评估表明，在含有广泛 CDH6 表达的肿瘤中观察到抗肿瘤活性，迄今为止观察到的 CDH6 表达与反应之间没有相关性。这些数据支持对卵巢癌患者进行 R-DXd 的进一步临床评估。

CDH6 is a transmembrane protein that is overexpressed in 65% to 85% of epithelial ovarian cancer. R-DXd consists of a humanized anti-CDH6 IgG1 monoclonal antibody linked to a topoisomerase I inhibitor payload. This was a first-in-human phase 1 clinical trial of R-DXd. It enrolled patients with mostly platinum-resistant advanced or metastatic ovarian cancer patients who were ineligible for standard therapy and were not selected based on tumor CDH6 expression. Patients received escalating doses (1.6 – 9.6 mg/kg), followed by a second dose expansion cohort that received 4.8 to 8.0 mg/kg of R-DXd.

The report presented results from 45 patients (37 evaluable) treated with 4.8 to 6.4 mg/kg. The confirmed objective response rate was 48.6%, including 1 complete response and 17 partial responses; 18 patients had stable disease, for a disease control rate of 97.4%. The median duration of response was 11.2 months; the median time to response was 5.7 weeks, and the median progression-free survival was 8.1 months.

The safety profile of R-DXd was manageable and comparable to that of other deruxtecan antibody-drug conjugates. The most common treatment-related adverse events of any grade were nausea (57.8%), vomiting (40.0%), fatigue (37.8%), and diarrhea (31.1%). Grade ≥ 3 toxicities were reported in 44.4% of patients, including anemia in 15.6%. Two patients experienced grade 2 drug-related interstitial lung disease/pneumonitis; however, grade 5 interstitial lung disease occurred at the 8 mg/kg dose level (which was not part of this analysis). R-DXd was discontinued in 11.1% of patients, dose interrupted in 31.1%, and reduced in 15.8%.

Preliminary biomarker assessments suggested that antitumor activity is observed in tumors with wide range of CDH6 expression, with no correlation between CDH6 expression and response observed to date. These data support further clinical evaluation of R-DXd in patients with ovarian cancer.

参考文献

Moore K et al. Soc Gynecol Onc 2024 Ann Meeting on Women’s Cancer. Presented March 16, 2024

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晚期肝细胞癌的全身治疗：ASCO 指南 (6/1/2024)

Systemic therapy for advanced hepatocellular carcinoma: ASCO Guideline

一线治疗

建议 1.1   Atezolizumab + 贝伐单抗或 durvalumab + tremelimumab 可作为 Child-Pugh A 级和体能状态 (ECOG PS) 0-1 晚期肝细胞癌的一线治疗 (证据质量：中等至高，推荐强度：强) 。

建议 1.2    当存在Atezolizumab + 贝伐单抗或durvalumab + tremelimumab的禁忌症时，sorafenib, lenvatinib, 或 durvalumab可作为 Child-Pugh A 级和 ECOG PS 0-1 晚期患者的一线治疗（证据质量：中等；推荐强度：强）。

二线治疗

建议 2.1   在使用Atezolizumab 进行一线治疗后，建议使用酪氨酸激酶抑制剂（TKI；即sorafenib, lenvatinib或cabozantinib）或ramucirumab（AFP ≥ 400 ng/mL）进行二线治疗（证据质量：低；推荐强度：弱）。

建议 2.2.    在使用 durvalumab + tremelimumab进行一线治疗后，建议使用 TKI 进行二线治疗（证据质量：低；建议强度：弱）。

建议 2.3   在接受sorafenib或lenvatinib一线治疗后，可建议合适的候选人接受另一种 TKI （cabozantinib 或regorafenib）, ramucirumab（AFP ≥ 400 ng/mL）, nivolumab + ipilimumab或durvalumab的二线治疗。对于在一线治疗中可能无法获得这些疗法且对这些组合没有禁忌症的患者，可考虑使用Atezolizumab + 贝伐单抗或或durvalumab + tremelimumab（证据质量：低至中等；建议强度：弱）。

First-Line Therapy

Recommendation 1.1.   Atezolizumab + bevacizumab or durvalumab + tremelimumab may be offered as first-line treatment for patients with Child-Pugh class A, and Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1 advanced hepatocellular carcinoma (Evidence quality: Moderate to High, Strength of recommendation: Strong).

Recommendation 1.2.   Where there are contraindications to Atezolizumab + bevacizumab or durvalumab + tremelimumab,  sorafenib, lenvatinib, or durvalumab may be offered as first-line treatment for patients with Child-Pugh class A, and ECOG PS 0-1 patients (Evidence quality: Moderate; Strength of recommendation: Strong).

Second-Line Therapy

Recommendation 2.1. Following first-line treatment with Atezolizumab + bevacizumab, second-line therapy with a tyrosine kinase inhibitor (TKI; ie, sorafenib, lenvatinib, or cabozantinib), or ramucirumab (AFP ≥400 ng/mL) are recommended (Evidence quality: Low; Strength of recommendation: Weak).

Recommendation 2.2.   Following first-line treatment with durvalumab + tremelimumab, second-line therapy with a TKI is recommended (Evidence quality: Low; Strength of recommendation: Weak).

Recommendation 2.3.   Following first-line treatment with sorafenib or lenvatinib, second-line therapy with another TKI (cabozantinib or regorafenib), ramucirumab (AFP ≥400 ng/mL), nivolumab + ipilimumab, or durvalumab may be recommended for appropriate candidates. Atezolizumab + bevacizumab or durvalumab + tremelimumab may be considered for patients who may not have had access to these therapies in the first-line setting, and do not have contraindications to these combinations. (Evidence quality: Low to Moderate; Strength of recommendation: Weak).

参考文献

Gordan JD et al. J Clin Onc 2024;42:1830

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5-氮杂胞苷和Venetoclax组合治疗多发性骨髓瘤 (5/26/2024)

5-azacitidine and Venetoclax combination to multiple myeloma

一部分多发性骨髓瘤患者（~20%）依赖 BCL-2 生存，BCL-2 拮抗剂 Venetoclax 在 t (11;14) 和 BCL-2 过表达多发性骨髓瘤患者中显示出临床疗效。 为了扩大可以接受 Venetoclax 治疗的 t (11;14) 以外的患者群体, 研究者筛选表观遗传修饰剂，以增强两种非 BCL-2 依赖性骨髓瘤细胞系中的 Venetoclax 敏感性。 结果发现去甲基酶抑制剂 5-氮杂胞苷与Venetoclax组合有增强细胞杀伤作用。 使用动态分析和免疫沉淀，发现协同作用的潜在机制是由于通过综合应激反应增加了 NOXA (是 一个促凋亡的Bcl-2 家族蛋白)表达。 PMAIP1 或 PKR 的敲低(knockdown)可部分挽救 Venetoclax 和 5-氮杂胞苷联合治疗的细胞死亡。 在联合治疗中添加类固醇并不会增加细胞死亡，有趣的是，添加类固醇会增加免疫细胞的死亡，这表明少用类固醇疗法可能对多发性骨髓瘤更有益。 最后，研究者首次在原发性骨髓瘤患者样本中显示，5-氮杂胞苷可增强对 Venetoclax 离体的反应，跨越不同的抗凋亡依赖性（BCL-2 或 MCL-1）和不同的细胞遗传学背景。      

总体而言，数据表明 5-氮杂胞苷和Venetoclax是一种有效的治疗组合，可能是一种可耐受的不含类固醇的方案，特别是对于老年多发性骨髓瘤患者。

A subset of patients with multiple myeloma (~20%) are dependent on BCL-2 for survival, and the BCL-2 antagonist Venetoclax has shown clinical efficacy in patients with t (11;14) and BCL-2-overexpressing multiple myeloma. To expand the patient population beyond t (11;14) who can receive venetoclax, researchers screened epigenetic modifiers to enhance venetoclax sensitivity in two BCL-2-independent myeloma cell lines. The results showed that the combination of the demethylase inhibitor 5-azacytidine and Venetoclax enhanced the cell killing effect. Using dynamic BH3 profiling and immunoprecipitations, the underlying mechanism of synergy was found to be due to increased NOXA (a pro-apoptotic Bcl-2 family protein) expression through an integrated stress response. Knockdown of PMAIP1 or PKR partially rescued cell death induced by combined treatment with Venetoclax and 5-azacytidine. Adding steroids to the combination therapy did not increase cell death, and interestingly, adding steroids increased immune cell death, suggesting that less steroid therapy may be more beneficial in multiple myeloma. Finally, it has been shown for the first time in primary myeloma patient samples that 5-azacytidine enhances the ex vivo response to venetoclax across different antiapoptotic dependencies (BCL-2 or MCL-1) and different cytogenetic background.

Overall, the data suggest that 5-azacytidine and venetoclax are an effective treatment combination and may be a tolerable steroid-free regimen, particularly in older patients with multiple myeloma.

参考文献

Flanagan L et al. Haematologica 2024; DOI: 10.3324/haematol.2023.283771

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同种异体 CD19 特异性 CAR-NK 细胞应用于CD19+ 的 B 淋细胞肿瘤 (5/25/2024)

Allogeneic CD19-specific CAR-NK cells in CD19+ B cell tumors

这是一项I/II期临床试验, 在 37 名 CD19+ B 细胞恶性肿瘤(弥漫性大B细胞淋巴瘤、慢性淋巴细胞白血病和各种非霍奇金淋巴瘤)患者中，使用表达抗 CD19 嵌合抗原受体和白细胞介素 15 (CAR19/IL-15) 的脐带血自然杀伤 (NK) 细胞。主要目标是安全性和有效性，定义为第 30 天的总体响应率。次要目标包括第 100天响应, 无进展生存期, 总体生存期和 CAR19/IL-15 NK 细胞持久性。

试验中没有观察到明显的毒性，例如细胞因子释放综合征, 神经毒性（常见于 CAR T 细胞疗法）或移植物抗宿主病。第 30 天和第 100 天的总体响应率均为 48.6%。1年总生存率和无进展生存率分别为 68% 和 32%。达到总体响应患者的 CAR-NK 细胞水平更高，持续时间更长。预测优异结果的最显著因素为从含有有核红细胞 ≤ 8 × 10⁷ 的脐带血单位接收CAR-NK细胞，并且从采集到冷冻保存时间 ≤ 24小时。来自这些最佳脐带血单位的 NK 细胞功能强大，并且富含效应子相关基因。相比之下，来自次优脐带血单位的 NK 细胞对炎症, 缺氧和细胞应激程序有上调作用。另外，使用多个小鼠模型，研究者证实了来自最佳脐带血单位的 CAR/IL-15 NK 细胞在体内具有卓越的抗肿瘤活性。   

这些发现揭示了 CAR-NK 细胞生物学的新特征，和同种异体细胞疗法供体选择的重要性。

This is a phase I/II clinical trial using cord blood natural killer (NK) cells expressing anti-CD19 chimeric antigen receptor and interleukin 15 (CAR19/IL-15) in 37 patients with CD19+ B-cell malignancies (diffuse large B-cell lymphoma, chronic lymphocytic leukemia, and various non-Hodgkin lymphomas). The primary objectives were safety and efficacy, defined as overall response rate at day 30. Secondary objectives include day 100 response, progression-free survival, overall survival and CAR19/IL-15 NK cell persistence.

No significant toxicities, such as cytokine release syndrome, neurotoxicity (seen frequently in CAR T-cell therapy) or graft-versus-host disease, were observed in the trial. The overall response rate at both day 30 and day 100 was 48.6%. The 1-year overall survival and progression-free survival rates were 68% and 32%, respectively. Patients who achieved an overall response had higher and longer-lasting CAR-NK cell levels. Receiving CAR-NK cells from a cord blood unit (CBU) with nucleated red blood cells ≤ 8 × 10⁷ and a collection-to-cryopreservation time ≤ 24 h was the most significant predictor for superior outcome. NK cells  from these optimal cord blood units are highly functional and enriched in effector-related genes. In contrast, NK cells from suboptimal cord blood units had upregulation of inflammation, hypoxia, and cellular stress programs. Additionally, using multiple mouse models, the investigators demonstrated that CAR/IL-15 NK cells derived from optimal cord blood units had superior antitumor activity in vivo.

These findings reveal new features of CAR-NK cell biology and the importance of donor selection for allogeneic cell therapy.

参考文献

Martin D et al. Nature Medicine 2024; 30: 772

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新辅助化疗淋巴结降期后省略腋窝淋巴结清扫 (5/19/2024)

Omission of axillary lymph node dissection following nodal downstaging with neoadjuvant chemotherapy

本研究旨在评估通过前哨淋巴结活检或靶向腋窝清扫(TAD, 结合前哨淋巴结活检与切除淋巴结的定位和检索)进行腋窝分期后，ypN0 患者是否可以省略 腋窝淋巴结清扫。这项多中心回顾性队列研究在 11 个国家的 25 个中心进行，纳入了 2013 年 4 月至 2020 年 12 月期间连续 II 期至 III 期活检证实淋巴结阳性乳腺癌的 1,144 名患者。 腋窝, 局部区域和任何侵袭性（局部或远处）复发率通过风险分析确定。主要终点是任何腋窝3 年和 5 年的复发率。 次要终点包括局部区域复发, 任何侵袭性（局部区域和远处）复发以及切除的淋巴结数量。  

结果: 共有 1,144 名患者（中位 [IQR] 年龄为 50 [41-59] 岁；78 名 [6.8%] 亚裔, 105 名 [9.2%] 黑人, 102 名 [8.9%] 西班牙裔和 816 名 [71.0%] 白人。 包括 666 例前哨淋巴结活检 [58.2%] 和 478 例 TAD [41.8%]）。 共有 1,060 名患者 (93%) 患有 N1 疾病，619 名患者 (54%) 患有HER2阳性疾病，758 名患者 (66%) 具有乳腺病理完全响应。 TAD 患者更有可能接受淋巴结放射治疗（85% 相对于 78%；P = .01）。 97% 的 TAD 病例和 86% 的前哨淋巴结活检病例成功取回被夹住的淋巴结。 取出的前哨淋巴结的平均(SD)数量为 3 (2) 相比于 4 (2) (P < .001)，TAD 组和前哨淋巴结活检组切除的总淋巴结的平均 (SD) 数量分别为 3.95 (1.97) 相比于 4.44 (2.04)  (P < .001)。 整个队列中任何腋窝、局部区域和任何侵袭性复发的 5 年发生率分别为 1.0%（95% CI，0.49%-2.0%）, 2.7%（95% CI，1.6%-4.1%）和 10 %（95% CI，8.3%-13%）。 TAD 和前哨淋巴结活检之间的 3 年腋窝复发累积发生率没有差异（0.5% 相比于 0.8%；P = .55）。

结论和相关性: 该研究结果表明，在省略腋窝淋巴清扫后腋窝复发的情况很少见;并且与前哨淋巴结活检相比，TAD 后腋窝复发率并没有显着降低。 这些结果支持在该人群中省略腋窝淋巴清扫。

This study aimed to evaluate whether axillary lymph node dissection can be omitted in ypN0 patients after axillary staging by sentinel lymph node biopsy (SLNB) or targeted axillary dissection (TAD, which combines sentinel lymph node biopsy with localization and retrieval of resected lymph nodes). This multicenter retrospective cohort study was conducted at 25 centers in 11 countries and included 1,144 patients with consecutive stage II to III biopsy-confirmed node-positive breast cancer between April 2013 and December 2020. Axillary, locoregional and any invasive (local or distant) recurrence rates were determined by competing risk analysis. The primary endpoint was 3- and 5-year recurrence rates in any axilla. Secondary endpoints included locoregional recurrence, any invasive (locoregional and distant) recurrence and the number of lymph nodes resected.

Results: There were 1,144 patients (median [IQR] age 50 [41-59] years; 78 [6.8%] Asian, 105 [9.2%], Black, 102 [8.9%] Hispanic, and 816 [71.0%] white, 666 sentinel lymph node biopsies [58.2%] and 478 TAD [41.8%]). A total of 1,060 patients (93%) had N1 disease, 619 patients (54%) had HER2-positive disease, and 758 patients (66%) had a complete breast pathologic response. Patients with TAD were more likely to receive nodal radiation therapy (85% vs. 78%; P = .01). Clamped lymph nodes were successfully retrieved in 97% of TAD cases and 86% of SLNB cases. The mean (SD) number of sentinel lymph nodes removed was 3 (2) compared with 4 (2) (P < .001), and the mean (SD) number of total lymph nodes removed was 3.95 in the TAD group and 3.95 (1.97) in the SLNB group compared with 4.44 (2.04) (P < .001). The 5-year incidence rates of any axillary, locoregional, and any invasive recurrence in the entire cohort were 1.0% (95% CI, 0.49%-2.0%), 2.7% (95% CI, 1.6%-4.1%), and 10%, respectively. (95% CI, 8.3%-13%). There was no difference in the 3-year cumulative incidence of axillary recurrence between TAD and SLNB (0.5% vs. 0.8%; P = .55).

Conclusion and relevance: The results of this study indicate that axillary recurrence is rare after omitting axillary lymph node dissection and that axillary recurrence rates are not significantly lower after TAD compared with SLNB. These results support the omission of axillary lymph node dissection in this population.

参考文献

Montagna G et al. JAMA Onc 2024 doi:10.1001/jamaoncol.2024.0578

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过去 20 年来美国年轻人的结直肠癌发病率在上升 (5/18/2024)  

Colorectal cancer rates rising among U.S. youth over the past 20 years

研究方法和结果: 研究人员利用美国疾病控制与预防中心数据库的数据来揭示 1999 年至 2020 年 10 岁至 44 岁患者结直肠癌发病率的趋势。

10至14岁: 结直肠癌发病率增加了500%

15至19岁: 结直肠癌发病率增加了333%

20至24岁: 结直肠癌发病率增加了185%

10至14岁: 1999年为每 10 万人中 0.1 人被诊断出患有结直肠癌

            2020 年为每 10 万人中 0.6 人被诊断出患有结直肠癌

15至19岁: 1999年为每 10 万人中 0.3人被诊断出患有结直肠癌

            2020 年为每 10 万人中 1.3人被诊断出患有结直肠癌

20至24岁: 1999年为每 10 万人中 0.7人被诊断出患有结直肠癌

            2020 年为每 10 万人中 2.0人被诊断出患有结直肠癌

在较高年龄组中，发病率也有上升:

30至34岁: 发病率增加71%(每10万人中6.5人)

35至39岁: 发病率增加58%(每10万人中11.7人)

40至44岁: 发病率增加37%(每10万人中30人)

结直肠癌的危险因素包括炎症性肠病或结直肠癌的家族史。可改变的危险因素包括肥胖, 抽烟, 饮酒,  食用加工肉类, 低纤维高脂肪饮食, 以及含糖饮料。此外，久坐的生活方式, 抗生素的使用和饮食添加剂也可能与结直肠癌有联系。

尽管年轻患者中结直肠癌病例的数量还不足以建议进行广泛的结肠镜检查，但需要进行公众教育并倡导健康的生活方式。

Methods and Results: Researchers used data from the Centers for Disease Control and Prevention database to uncover trends in colorectal cancer incidence among patients ages 10 to 44 years from 1999 to 2020.

10 to 14 years: Colorectal cancer incidence increased by 500%

15 to 19 years: Colorectal cancer rates increased by 333%

20 to 24 years: Colorectal cancer rates increase by 185%

10 to 14 years: in 1999, 0.1 per 100,000 people were diagnosed with colorectal cancer

                         In 2020, 0.6 per 100,000 people were diagnosed with colorectal cancer

18 to 19 years: in 1999, 0.3 per 100,000 people were diagnosed with colorectal cancer

                         In 2020, 1.3 per 100,000 people were diagnosed with colorectal cancer

20 to 24 years: in 1999, 0.7 per 100,000 people were diagnosed with colorectal cancer

                         In 2020, 2.0 per 100,000 people were diagnosed with colorectal cancer

In older age groups, incidence rates also increased:

Ages 30 to 34: incidence rates increased by 71% (6.5 per 100,000)

Ages 35 to 39: incidence rates increased by 58% (11.7 per 100,000)

Ages 40 to 44: incidence rates increased by 37% (30 per 100,000)

Risk factors for colorectal cancer include inflammatory bowel disease and a family history of colorectal cancer. Modifiable risk factors include obesity, smoking, alcohol, consumption of processed meats, a diet low in fiber and high in fat, and sugary drinks. Additionally, a sedentary lifestyle, antibiotic use and dietary additives may also be linked to colorectal cancer.

Although the number of colorectal cancer cases in young patients is not high enough to recommend widespread colonoscopy, public education and promotion of healthy lifestyles are needed.

参考文献

Mohamed I et al. Gastroenterology 2024;DOJ https://doi.org/10.1016/S0016-5085(24)02668-4

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PD-(L)1 阻断治疗非小细胞肺癌中产生耐药的基因组和免疫表型 (5/12/2024)

Genomic and immunologic phenotypes of acquired resistance to PD-(L)1 blockade in NSCLC

方法: 研究者对免疫检查点抑制剂治疗前后匹配的并对其产生了耐药的非小细胞肺癌患者进行了全面的肿瘤基因组分析, 采用机器学习的肿瘤浸润淋巴细胞评估, 多重免疫荧光和/或 HLA-I 免疫组织化学方法。另外两组在活检之间接受过化疗或靶向治疗的患者被纳入对照。

结果: 对 82 名非小细胞肺癌患者进行了免疫检查点抑制剂前后匹配的活检，并将结果与活检之间接受非免疫检查点抑制剂干预治疗的对照患者队列进行了比较（化疗，N = 32；靶向治疗, N = 89；两者，N = 17）。 在 27.8% 的免疫治疗病例中发现了耐药突变，其中包括 STK11, B2M, APC, MTOR, KEAP1 和 JAK1/2 的获得性功能丧失突变； 在对照组中没有观察到这些获得性改变。免疫检查点抑制剂前后匹配样本的免疫表型分析表明，肿瘤内淋巴细胞, CD3e+/CD8a+ T 细胞和 PD-L1-PD1 结合都显著减少，并且肿瘤细胞与 CD8+PD-1+ T 细胞之间的距离增加。产生耐药时免疫治疗组与化疗组 (P = .005) 和靶向治疗组 (P = .01) 相比, HLA 1类表达显著下降。

结论:这些发现可能有助于开发克服耐药性的新疗法。

Methods: A comprehensive tumor genome analysis was conducted on matched non-small cell lung cancer patients who developed resistance to immune checkpoint inhibitors before and after treatment tumor biopsies, using machine learning to evaluate tumor-infiltrating lymphocytes, multiple immunofluorescence and/or  HLA-I immunohistochemistry. Two additional groups of patients who received chemotherapy or targeted therapy between biopsies were included as controls.

Results: Eighty-two patients with NSCLC underwent matched pre- and post-immune checkpoint inhibitor biopsies, and results were compared to a control cohort of patients who received a non-immune checkpoint inhibitor intervention between biopsies (chemotherapy, N = 32; targeted therapy, N = 89; both, N = 17). Resistance mutations, including acquired loss-of-function mutations in STK11, B2M, APC, MTOR, KEAP1, and JAK1/2, were found in 27.8% of immunotherapy cases; these acquired changes were not observed in controls. Immunophenotypic analysis of matched samples before and after immune checkpoint inhibitors showed significant decreases in intratumoral lymphocytes, CD3e+/CD8a+ T cells, and PD-L1-PD1 engagement, as well as increased distance between tumor cells and CD8+PD-1+ T cells. There was a significant decrease  in HLA class 1 in the immunotherapy cohort at the time of acquired drug resistance,  compared with the chemotherapy (P = .005) and the targeted therapy (P = .01) cohorts.

Conclusion: The findings may help to develop novel therapy aimed at overcoming resistance.

参考文献

Ricciuti B et al. J Clin Onc 2024; 42:1311

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KEYNOTE-522: 派姆单抗治疗早期三阴性乳腺癌后残留癌症负担与无事件生存相关 (5/11/2024)

KEYNOTE-522: Residual cancer burden with pembrolizumab in early-stage triple-negative breast cancer associated with event-free survival

背景: KEYNOTE-522 已证明新辅助派姆单抗联合化疗对高危早期三阴性乳腺癌患者的病理完全响应和无事件生存期具有统计学显著改善, 还改善了许多未达到病理完全响应患者的无事件生存期。。 先前的研究还表明，残留癌症负担指数具有预后价值。 在这项预先计划的探索性分析中，对残留癌症负担指数分布相关于无事件生存期进行了评估。  

患者和方法: 总共 1,174 名 T1c/N1-2 或 T2-4/N0-2 期三阴性乳腺癌患者被随机分配至帕博利珠单抗 200 mg 或安慰剂组，每 3 周一次，接受四个周期的紫杉醇 + 卡铂治疗，随后接受四个周期的阿霉素治疗 或表阿霉素+环磷酰胺。 手术后，患者接受帕博利珠单抗或安慰剂九个周期或直到复发或不可接受的毒性。 主要终点是病理完全响应和无事件生存期。残留癌症负担指数是预先指定的探索性终点。 使用 Cox 回归模型评估无事件生存期和残留癌症负担指数之间的关联。  

结果: 与安慰剂相比，Pembrolizumab 将患者在整个队列转移至较低的残留癌症负担指数类别。 派姆单抗组中具有残留癌症负担指数-0 (病理完全响应) 的患者较多，而派姆单抗组中具有残留癌症负担指数-1, 残留癌症负担指数-2 和残留癌症负担指数-3 的患者较少。相应的无事件生存风险比（95% 置信区间）为 0.70 (0.38-1.31)、0.92 (0.39-2.20)、0.52 (0.32-0.82) 和 1.24 (0.69-2.23)。 最常见的首次无事件生存事件是远处复发，在所有残留癌症负担类别中，派姆单抗组中较少发生。 在 残留癌症负担指数-0/1 患者中，超过一半 [21/38 (55.3%)] 的所有事件是中枢神经系统复发，其中派姆单抗组为 13/22 (59.1%)，在安慰剂组中为 8/16 (50.0%)。  

结论: 在化疗中添加派姆单抗可减少残留癌症负担指数-0、残留癌症负担指数-1 和残留癌症负担指数-2 类别中的无事件生存事件，其中残留癌症负担指数-2 获益最大。 这些发现表明，派姆单抗不仅提高了病理完全响应率，而且还改善了大多数没有病理完全响应的患者的无事件生存期。

Background: KEYNOTE-522 has demonstrated that neoadjuvant pembrolizumab plus chemotherapy has a statistically significant improvement in pathological complete response and event-free survival in patients with high-risk early-stage triple-negative breast cancer. It also improved event-free survival in many patients who did not achieve pathological complete response. Previous studies have also shown that the residual cancer burden (RCB) index has prognostic value. In this preplanned exploratory analysis, RCB distribution and EFS within RCB categories by treatment group was evaluated.

Methods: A total of 1,174 patients with stage T1c/N1-2 or T2-4/N0-2 triple-negative breast cancer were randomly assigned to receive pembrolizumab 200 mg or placebo every 3 weeks for four cycles of paclitaxel + carboplatin, followed by four cycles of doxorubicin or epirubicin + cyclophosphamide. After surgery, patients received pembrolizumab or placebo for nine cycles or until recurrence or unacceptable toxicity. The primary endpoints were pathological complete response and event-free survival. RCB was a prespecified exploratory endpoint. Cox regression models were used to evaluate the association between event-free survival and RCB.

Results: Pembrolizumab shifted patients into lower RCB categories across the entire cohort compared with placebo. There were more patients in the pembrolizumab group with a RCB -0 (pathological complete response) and fewer patients with RCB -1, RCB -2, and RCB – 3. The corresponding hazard ratios (95% confidence intervals) for event-free survival were 0.70 (0.38-1.31), 0.92 (0.39-2.20), 0.52 (0.32-0.82), and 1.24 (0.69-2.23). The most common first event-free survival event was distant recurrence, which occurred less frequently in the pembrolizumab group across all RCB categories. Among patients with RCB-0/1, more than half [21/38 (55.3%)] of all events were CNS relapses, including 13/22 (59.1%) in the pembrolizumab group and 8/16 (50.0%) in the placebo group.

Conclusions: Adding pembrolizumab to chemotherapy resulted in fewer event-free events in the RCB-0, RCB-1, and RCB-2 categories, with the greatest benefit in RCB-2 categories. These findings indicate that pembrolizumab not only improves pathological complete response rate but also improves event-free survival in most patients who do not have a pathological complete response.

参考文献

Pusztai L et al. Ann Onc 2024; DOI:https://doi.org/10.1016/j.annonc.2024.02.002

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SYMPATICO 试验：Ibrutinib 联合 Venetoclax 可改善复发性套细胞淋巴瘤的无进展生存期 (5/5/2024)

Ibrutinib plus venetoclax improves progression-free survival in relapsed mantle cell lymphoma (SYMPATICO trial)

这是一项双盲,多国,安慰剂对照,III期临床研究, 旨在研究伊布替尼(ibrutinib)和维奈托克(venetoclax)联合用药对既往接受过一到五次治疗的复发性或难治性套细胞淋巴瘤患者的疗效和耐受性。

患者被随机分配接受口服依鲁替尼联合维奈托克或依鲁替尼联合安慰剂治疗，然后进行 24 个月的连续治疗阶段，直至出现疾病进展或出现不可接受的毒性。根据试验的中期分析，依鲁替尼/伊布替尼联合组的中位无进展生存期为 31.9 个月，而安慰剂组的中位无进展生存期为 22 个月（风险比 [HR] = 0.65；P = .0052）。 完全响应率也有统计学上的显著改善，联合组中有 54% 的人实现了完全响应，而安慰剂组只有 32%。 长期评估和随访还显示，与 安慰剂组（27.6 个月）相比，联合用药的中位缓解持续时间（42.1 个月）显著更长。 联合组的中位总生存期为 49.9 个月，而安慰剂组为 38.6 个月。 这些结果在中期分析中并不具有统计显著性。  

联合疗法的安全性与每种单一药物的已知不良事件一致，没有新的安全信号。 最常见的不良事件包括腹泻、中性粒细胞减少、恶心和疲劳。

这些发现可能为复发性套细胞淋巴瘤患者提供更好的治疗选择。

This was a double-blind, multinational, placebo-controlled, phase III clinical study designed to study the efficacy and tolerability of the combination of ibrutinib and venetoclax in patients with relapsed mantle cell lymphoma who had received one to five previous treatments.

Patients were randomly assigned to receive oral ibrutinib plus venetoclax or ibrutinib plus placebo, followed by a 24-month continuous treatment until disease progression or unacceptable toxicity. According to the trial’s interim analysis, median progression-free survival was 31.9 months in the ibrutinib/ibrutinib combination arm compared with 22 months in the placebo arm (hazard ratio [HR] = 0.65; P = .0052). There was also a statistically significant improvement in complete response rates, with 54% of those in the combination group achieving a complete response compared with 32% of those in the placebo group. Long-term assessment and follow-up also showed that the median duration of response was significantly longer with the combination (42.1 months) compared with placebo (27.6 months). Median overall survival was 49.9 months in the combination group and 38.6 months in the placebo group. These results were not statistically significant at the interim analysis.

The safety profile of the combination therapy was consistent with known adverse events for each single agent, with no new safety signals. The most common adverse events included diarrhea, neutropenia, nausea, and fatigue.

These findings may provide better treatment options for patients with relapsed mantle cell lymphoma.

参考文献

Wang M et al.  2023 ASH Ann Meeting  abstr LBA-2

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Atezolizumab 加贝伐单抗和化疗治疗 EGFR 或 ALK 突变非小细胞肺癌的III 期随机研究（5/3/2024）

Phase III study of atezolizumab plus bevacizumab and chemotherapy in EGFR- or ALK-mutated NSCLC

目的: 对具有驱动突变的非小细胞肺癌，在酪氨酸激酶抑制剂 (TKI) 治疗后抗 PD-(L)1 抗体的作用仍不清楚。 这项随机,开放标签,多中心,III 期研究（ATTLAS、KCSG-LU19-04）  评估了 atezolizumab 联合贝伐单抗,紫杉醇和卡铂在 TKI 治疗后进展的 EGFR 或 ALK 突变非小细胞肺癌中的疗效。

材料和方法: 研究者比较了紫杉醇和卡铂后用atezolizumab加贝伐单抗维持治疗(试验组)与培美曲塞加卡铂或顺铂后用培美曲塞维持治疗(对照组)的临床疗效。 主要终点是无进展生存期。

结果: 来自韩国 16 个地点的总共 228 名患有激活 EGFR 突变 (n = 215) 或 ALK 易位 (n = 13) 的患者被招募，并以 2:1 的比例随机分配到试验组 (n = 154) 或对照组（n = 74）。 中位随访时间为 26.1 个月（95% CI，24.7 至 28.2）。 试验组相比于对照组明显更好, 客观响应率（69.5% 相比于 41.9%，P < .001）和中位无进展生存期（8.48 相比于 5.62 个月，风险比 [HR]，0.62 [95% CI，0.45 至 0.86]；P = 0.004）。 无进展生存期获益随着 PD-L1 表达的增加而增加，PD-L1 ≥ 1%、≥ 10% 和 ≥ 50% 的 HR 分别为 0.47、0.41 和 0.24。 试验组和对照组的总生存期相似（20.63 vs 20.27 个月，HR，1.01 [95% CI，0.69 至 1.46]；P = .975）。 试验组的安全性与之前报道的相当，没有额外的安全信号，但与对照组相比，观察到与治疗相关的不良事件发生率更高。    

结论: 研究者认为这是第一个随机 III 期研究，旨在证明抗 PD-L1 抗体联合贝伐珠单抗和化疗对在靶向治疗后进展的 EGFR 或 ALK 突变非小细胞肺癌患者具有临床益处。

Purpose: The role of anti-PD-(L)1 antibodies after tyrosine kinase inhibitor (TKI) therapy in NSCLC with driver mutations remains unclear. This randomized, open-label, multicenter, phase III study (ATTLAS, KCSG-LU19-04) evaluated the efficacy of atezolizumab in combination with bevacizumab, paclitaxel, and carboplatin in EGFR- or ALK-mutated NSCLC patients that progressed after TKI therapy.

Materials and methods: Researchers compared paclitaxel and carboplatin followed by maintenance therapy with atezolizumab plus bevacizumab (trial group) with pemetrexed plus carboplatin or cisplatin followed by pemetrexed maintenance therapy (control group). The primary endpoint was progression-free survival.

Results: A total of 228 patients with activating EGFR mutations (n = 215) or ALK translocations (n = 13) from 16 sites in the republic of Korea were recruited and randomly assigned in a 2:1 ratio to the trial group (n = 154) or control group (n = 74). Median follow-up was 26.1 months (95% CI, 24.7 to 28.2). The experimental group had significantly better objective response rate (69.5% vs. 41.9%, P < .001) and median progression-free survival (8.48 vs. 5.62 months, hazard ratio [HR]) 0.62 [95% CI, 0.45 to 0.86]; P = 0.004) than the control group. The progression-free survival benefit increased with increasing PD-L1 expression, with HRs of 0.47, 0.41, and 0.24 for PD-L1 ≥1%, ≥10%, and ≥50%, respectively. Overall survival was similar in the experimental and control groups (20.63 vs 20.27 months, HR, 1.01 [95% CI, 0.69 to 1.46]; P = .975). Safety in the trial arm was comparable to that previously reported, with no additional safety signals, although a higher rate of treatment-related adverse events was observed compared with the control arm.

Conclusion: The investigators believe this is the first randomized phase III study to demonstrate the clinical benefit of an anti-PD-L1 antibody in combination with bevacizumab and chemotherapy in patients with EGFR or ALK-mutant NSCLC who have progressed after targeted therapy.   

参考文献

Park S et al. J Clin Onc 2024;42:1241

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人工智能模型和预测治疗反应 (4/28/2024)

AI model and treatment responses prediction

研究者开发了一种新型AI模型，用单细胞 RNA 测序数据用于预测癌症患者对肿瘤疗法的响应, 这是一种精准肿瘤学计算管道, 称为PERCEPTION (personalized single-cell Expression-based planning for treatments in oncology) 。

方法和结果: 研究者利用大量 RNA 测序数据和称为迁移学习的机器学习技术来训练人工智能模型来预测对某些癌症药物的反应, 再利用单细胞 RNA 测序数据对模型进行了微调，然后将这种新方法对大规模药物筛选中已发表的细胞系数据进行分析而为 44 种 FDA 批准的抗癌药物构建了 AI 模型。人工智能模型能准确预测单个细胞对癌症单一疗法和联合疗法的响应。研究者还根据已发表的数据测试了这种新方法，其中包括 41 名接受四种药物联合治疗的多发性骨髓瘤患者和 33 名接受两种药物联合治疗的乳腺癌患者。 结果发现，如果只有一个克隆对某种癌症药物有抗药性，那么即使所有其他克隆都有响应，患者也不会对治疗产生响应。 此外，这个 AI 模型还根据已发表的 24 名接受靶向治疗的非小细胞肺癌患者的数据成功预测了治疗耐药性的发展。   

结论: 如果单细胞 RNA 测序数据变得更广泛可用，这种新方法的准确性可能会提高。 研究者开发了一个研究网站（https://github.com/ruppinlab/PERCEPTION)，指导如何将新颖的人工智能模型与新数据结合使用。

Researchers have developed a new AI model that uses single-cell RNA sequencing data to predict response to tumor therapies. This is a precision oncology computing pipeline called PERCEPTION (personalized single-cell Expression-based planning for treatments in oncology).

Methods and Results: The researchers used widely available bulk RNA sequencing data and a machine learning technique known as transfer learning to train an AI model to predict response to certain cancer drugs. They subsequently fine-tuned the model using single-cell RNA sequencing data. This new method was used to analyze published cell line data from large-scale drug screens to build AI models for 44 FDA-approved anti-cancer drugs. The AI models accurately predicted how individual cells would respond to cancer monotherapies and combination therapies. The researchers also tested the new approach on published data that involving 41 patients with multiple myeloma who received a combination of four drugs and 33 patients with breast cancer who received a combination of two drugs. It was found that if just one clone was resistant to a cancer drug, the patient would not respond to the treatment, even if all other clones responded. Additionally, the AI model successfully predicted the development of treatment resistance based on published data from 24 patients with non-small cell lung cancer who received targeted therapy.

Conclusion: The accuracy of this new method could improve if single-cell RNA sequencing data becomes more widely available. The researchers developed a research website (https://github.com/ruppinlab/PERCEPTION) to provide guidance on how to use novel AI models with new data.

参考文献

Sinha S et al. Nature Medicine 2024; April 18

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新型 MDM-2 抑制剂 (Alrizomadlin)  治疗p53 野生型唾液腺癌(4/27/2024)

A novel MDM-2 inhibitor (Alrizomadlin) in p53 wild type salivary gland cancers

最常见的恶性唾液腺癌组织学是腺样囊性癌，未经治疗患者的中位无进展生存期为 2.8 个月 。 MDM2 基因扩增在这些肿瘤中很常见，临床前证据支持 MDM2 抑制剂作为单一疗法和与化疗联合的活性。 APG-115/alrizomadlin 是一种有效的口服药物 小分子MDM2抑制剂。

方法：这是一项I/II期临床多中心研究，以评估 APG-115单一疗法(单药臂)和与卡铂联合(联合臂)在p53 野生型唾液腺癌中的安全性和有效性。 参加者为高度恶性唾液腺癌，没有 p53 证据 突变，并且在之前 12 个月内疾病进展 ≥20%。 主要终点是剂量限制性毒性和总体响应率, 次要终点包括无进展生存期、响应持续时间和总体生存。 使用连续监测数据并分配剂量 事件发生时间持续重新评估方法。

结果：总体而言，82% (32/34) 的患者先前进展的疾病已稳定（临床获益率为 94%）。 单药臂和联合臂的总体响应 率分别为 10% 和 25% ，单药臂中位无进展生存期为 10.5 个月。 在单一治疗队列中, 腺样囊性癌患者 （部分响应率：13%，疾病稳定 83%，中位无进展生存期 10.5 个月）与非腺样囊性癌相比（部分响应率：0%，疾病稳定 86%，中位无进展生存期6 个月）似乎具有更大的获益。有 2 个患者发生剂量限制毒性。  

最常见的任何级别的治疗相关不良事件包括恶心（77%）, 疲劳（73%）和血小板减少（50%）。 70% 具有 ≥ 3级不良事件。 在联合臂中，任何级别最常见的不良事件包括：贫血（100%）, 血小板减少症（100%）和中性粒细胞减少症 （75%）。 联合臂中所有患者均有≥ 3级不良事件。

结论：APG-115 单一疗法显示对p53 野生型唾液腺癌有抗肿瘤作用并有可接受的安全性。对腺样囊性癌患者的活性最为明显。 这是第一个研究 评估唾液腺癌患者中 MDM2 抑制剂的活性。

The most common histology of malignant salivary gland cancer is adenoid cystic carcinoma, and the median progression-free survival in untreated patients is 2.8 months. MDM2 gene amplification is common in these tumors, and preclinical evidence supports the activity of MDM2 inhibitors as monotherapy or in combination with chemotherapy. APG-115/alrizomadlin is a potent oral small molecule MDM2 inhibitor.

Methods: This is a phase I/II clinical multicenter study to evaluate the safety and efficacy of APG-115 monotherapy (single-agent arm) and in combination with carboplatin (combination arm) in p53 wild-type salivary gland cancer. Participants had high-grade salivary gland cancer, no evidence of p53 mutation, and ≥ 20% disease progression in the previous 12 months. The primary endpoints were dose-limiting toxicities and overall response rate, and secondary endpoints included progression-free survival, duration of response, and overall survival. Data were continuously monitored and doses assigned using the time-to-event continual reassessment method.

Results: Overall, 82% (32/34) of patients had stabilization of previously progressive disease (clinical benefit rate 94%). The overall response rates in the single-agent arm and the combination arm were 10% and 25% respectively, and the median progression-free survival in the single-agent arm was 10.5 months. In the single-drug cohort, patients with adenoid cystic carcinoma (partial response rate: 13%, stable disease 83%, median progression-free survival 10.5 months) appeared to have a greater benefit compared with non-adenoid cystic carcinoma (partial response rate: 0 %, stable disease 86%, median progression-free survival 6 months). Dose-limiting toxicities were reported in 2 patients.

The most common treatment-related adverse events of any grade included nausea (77%), fatigue (73%) and thrombocytopenia (50%). A total of 70% had grade ≥ 3 adverse events. In the combination arm, the most common adverse events of any grade included: anemia (100%), thrombocytopenia (100%) and neutropenia (75%). All patients in the combination arm had grade ≥ 3 adverse events.

Conclusions: APG-115 monotherapy demonstrated antitumor activity against p53 wild-type salivary gland cancer with an acceptable safety profile. Activity was most pronounced in patients with adenoid cystic carcinoma. This is the first study to evaluate the activity of an MDM2 inhibitor in patients with salivary gland cancer.

参考文献

Pearson A. et al  2024 Multidisciplinary Head and Neck Cancers Symp Abstr 8

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一线 tiragolumab  + atezolizumab 和化疗治疗食管鳞状细胞癌的III 期试验(4/21/2024)

A phase III study of first-line tiragolumab + atezolizumab and chemotherapy in esophageal squamous cell carcinoma

背景： TIGIT (T cell immunoreceptor with Immunoglobulin and ITIM domains)是一种新型检查点抑制剂，其抑制可能通过补充 PD-L1/PD-1 通路来进一步放大免疫反应。 III 期试验(from Taiwan)SKYSCRAPER-08  (NCT04540211) 旨在评估 tiragolumab（抗 TIGIT）+ atezolizumab（抗 PD-L1）联合化疗与安慰剂 + 化疗作为一线治疗在不可切除的局部晚期/复发性/转移性食管鳞状细胞癌的亚洲人群中的疗效和安全性。    

方法： 符合条件的患者按 1:1 随机分配接受 tiragolumab 600 mg + atezolizumab 1200 mg + 化疗（紫杉醇 175毫克/平方米 + 顺铂 60–80毫克/平方米）(试验组)或安慰剂 + 化疗(对照组)，在每个 21 天周期（第 1-6 周期）的第 1 天进行； 随后进行 tiragolumab + atezolizumab 或安慰剂维持治疗，直至失去临床益处/出现不可接受的毒性。 主要终点：独立审查机构评估的无进展生存期和总生存期。 次要终点：研究者评估的无进展生存期、客观响应率, 响应持续时间和安全性。  

结果：一共461 名患者被随机分配到试验组（n = 229) 和对照组(n = 232）。 截至 2022 年 6 月 15 日（最短生存期随访 6.5 个月），试验组的独立审查机构评估的中位无进展生存期为 6.2 个月，而对照组为 5.4 个月（HR 0.56；95% CI : 0.45, 0.70; P <0.0001)。 截至 2023 年 2 月 13 日（最短生存期随访 14.5 个月）, 试验组的的中位总生存期为 15.7 个月，对照组为 11.1 个月（HR：0.70；95% CI：0.55，0.88； P = 0.0024）。 

一共98.2% 的患者（两组）发生了治疗相关不良事件； 59.6%（试验组）和 56.4%（对照组）的患者出现  3/4 级 治疗相关不良事件； 2.6%（试验组）和 0.9%（对照组）的患者出现 5 级治疗相关不良事件。安全概况与已知风险一致。    

结论：与安慰剂 + 化疗相比，tiragolumab + atezolizumab + 化疗 在无进展生存期和总生存期方面具有统计学意义和临床意义的改善。 在各个亚组中观察到总体一致的益处，包括 PD-L1 状态。

Background: TIGIT (T cell immunoreceptor with Immunoglobulin and ITIM domains) is a new checkpoint inhibitor, and its inhibition may further amplify the immune response by supplementing the PD-L1/PD-1 pathway. Phase III trial (from Taiwan) SKYSCRAPER-08 (NCT04540211) was designed to evaluate the efficacy and safety of tiragolumab (anti-TIGIT) + atezolizumab (anti-PD-L1) combined with chemotherapy versus placebo + chemotherapy as first-line treatment in unresectable locally advanced/recurrent/metastatic esophageal squamous cell carcinoma in an Asian population.

Methods: Eligible patients were randomly assigned 1:1 to receive tiragolumab 600 mg + atezolizumab 1200 mg + chemotherapy (paclitaxel 175 mg/m2 + cisplatin 60–80 mg/m2) (experimental group) or placebo + chemotherapy ( control group) on Day 1 of each 21-day cycle (Cycles 1-6); followed by maintenance treatment with tiragolumab + atezolizumab or placebo until loss of clinical benefit/unacceptable toxicity. Primary endpoints: progression-free survival and overall survival by independent review. Secondary endpoints: investigator-assessed progression-free survival, objective response rate, duration of response, and safety.

Results: A total of 461 patients were randomly assigned to the experimental group (n = 229) and the control group (n = 232). As of June 15, 2022 (minimum survival follow-up 6.5 months), the independent review agency-assessed median progression-free survival was 6.2 months in the experimental arm compared with 5.4 months in the control arm (HR 0.56; 95% CI : 0.45, 0.70; P <0.0001). As of February 13, 2023 (minimum survival follow-up 14.5 months), the median overall survival was 15.7 months in the experimental group and 11.1 months in the control group (HR: 0.70; 95% CI: 0.55, 0.88; P = 0.0024).

A total of 98.2% of patients (both groups) experienced treatment-related adverse events; 59.6% (experimental group) and 56.4% (control group) experienced grade 3/4 treatment-related adverse events; 2.6% (experimental group) and 0.9% (Control) patients experienced grade 5 treatment-related adverse events. The safety profile is consistent with the known risks of the individual treatment.

Conclusions: Tiragolumab + atezolizumab + chemotherapy resulted in statistically significant and clinically meaningful improvements in progression-free survival and overall survival compared with placebo + chemotherapy. In general, consistent benefit was observed across subgroups, including PD-L1 status.

参考文献

Hsu C-H et al. J Clin Oncol 2024; 42（suppl-3) abstr 245

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Abemaciclib 辅助内分泌疗法治疗激素受体阳性/HER2 阴性, 高风险早期乳腺癌 (4/20/2024)

Adjuvant abemaciclib plus endocrine therapy for ER+/HER2- high-risk breast cancer: Results from monarchE trial

MonarchE 研究的主要终点已经报告: 两年的辅助 abemaciclib 联合内分泌治疗使激素受体阳性/HER2 阴性高风险早期乳腺癌患者的无侵袭性疾病生存期和远处无复发生存期显著改善，并且在 2 年治疗期后仍持续存在。

本文报告了预先指定的总生存期中期分析的 5 年疗效结果。 在意向治疗人群中，中位随访时间为 54 个月，abemaciclib 的益处持续存在，无侵袭性疾病生存期的风险比为 0.680（95% CI，0.599 至 0.772），远处无复发生存期的风险比为 0.675（95% CI，0.588 至 0.774）。5 年无侵袭性疾病生存和远处无复发生存绝对改善率加深，分别为 7.6% 和 6.7%，而 4 年时分别为 6% 和 5.3% , 3 年时为和 4.8% 和 4.1%。 与单独使用内分泌疗法组相比，abemaciclib 加内分泌疗法组的死亡人数较少（208 比 234），但总生存期未达到统计学显著性。 没有观察到新的安全信号。  

总之，abemaciclib 加内分泌疗法继续降低治疗完成后发生侵袭性和远处疾病复发的风险。 5 年时绝对改善的增加与残留效应一致，并进一步支持 abemaciclib 在高风险早期乳腺癌患者中的使用。

The primary endpoint of the MonarchE study has been previously reported: Two years of adjuvant abemaciclib plus endocrine therapy resulted in a significant improvement in invasive disease-free survival and distant recurrence-free survival in patients with hormone receptor-positive/HER2-negative high-risk early-stage breast cancer, and the benefit persists after two years of treatment.

This article reported 5-year efficacy results from a prespecified interim analysis of overall survival. In the intention-to-treat population, with a median follow-up of 54 months, the benefit of abemaciclib persisted, with a hazard ratio for invasive disease-free survival of 0.680 (95% CI, 0.599 to 0.772) and a hazard ratio for distant recurrence-free survival of 0.675 (95% CI, 0.588 to 0.774). Absolute improvements in invasive disease-free survival and distant recurrence-free survival deepened at 5 years to 7.6% and 6.7%, respectively, compared with 6% and 5.3% at 4 years and 4.8% and 4.1% at 3 years. There were fewer deaths in the abemaciclib plus endocrine therapy group compared with the endocrine therapy alone group (208 vs. 234), but overall survival did not reach statistical significance. No new safety signals were observed.

In summary, abemaciclib plus endocrine therapy continues to reduce the risk of invasive and distant disease recurrence beyobd completion of treatment. The increase in absolute improvement at 5 years is consistent with a carry-over effect and further supports the use of abemaciclib in patients with high-risk early-stage breast cancer.

参考文献

Rastogi P et al. J Clin Onc 2024; 42:987

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个性化新抗原 DNA 疫苗和派姆单抗作为晚期肝细胞癌的二线治疗 (4/14/2024)

Personalized neoantigen DNA vaccine and pembrolizumab as second-line treatment for advanced hepatocellular carcinoma

该试验旨在评估针对个体肿瘤中的新抗原定制的个性化治疗性癌症疫苗 (PTCV) 是否可以通过诱导肿瘤特异性免疫来增强对 PD-1 抑制剂的反应。 该试验评估了编码多达 40 种新抗原的 DNA 质粒 (GNOS-PV02) 与质粒编码的 IL-12 (pIL12) 与派姆单抗联合给药。

方法：这是一项Ib/2a期临床试验，招募了 36 名在疾病进展或对一线酪氨酸激酶抑制剂不耐受的肝细胞癌患者。 通过体内电穿孔皮内施用 PTCV [GNOS-PV02 (1 mg) 和 pIL12 (0.34mg)] 每3星期一次 x 4 剂，此后每9星期一次。派姆单抗 按 200mg 每3星期一次。 主要终点是安全性和免疫原性。次要终点为客观响应率。

结果：在接受至少一剂治疗的36名入组患者中，没有发生剂量限制性毒性或与治疗相关的≥3级事件。 最常见的治疗相关不良事件是在41.6% 的患者中观察到注射部位反应。

客观响应率为 30.6%（11/36；9 例确诊，2 例未确诊），其中 8.3% (3/36) 的患者达到完全响应。 这达到了统计显著性，单侧 p 值 = 0.031（单侧 90% CI 20.4%-100%）, 中位总生存期为 19.9 个月。 ctDNA 变化与放射学反应相关并且先于放射学反应。 在 7 名患者中检测到完整的分子反应（100% ctDNA 清除率），其中包括 3 名放射学完全响应，以及另外 4 名继续表现出持久肿瘤控制的患者（3名部分响应, 1 名疾病稳定）。

免疫学分析证实干扰素γ-ELISpot 在 19/22 (86.4%) 的可评估患者中诱导了新抗原特异性 T 细胞反应，并且具有较大 ELISpot 反应的患者显示出总生存期更长的趋势。 多参数细胞分析和单细胞分析揭示了免疫患者血液中存在活性, 增殖性和溶细胞性疫苗特异性 CD4+ 和 CD8+ 效应 T 细胞。 在 14/14 (100%) 的接受治疗前和治疗中血液和肿瘤活检的患者中，通过T细胞受体β 批量测序鉴定出外周血中扩增的 T 细胞克隆也流入了肿瘤。   

结论：PTCV 加派姆单抗对晚期肝细胞癌患者耐受性良好且具有临床活性，并支持基于诱导外周血和肿瘤中抗肿瘤 T 细胞的 PTCV 作用机制。研究者计划进行一项评估总生存期的验证性 III 期临床研究。

The trial aims to evaluate whether a personalized therapeutic cancer vaccine (PTCV) tailored to neoantigens in individual tumors can enhance responses to PD-1 inhibitors by inducing tumor-specific immunity. The trial evaluated a DNA plasmid encoding up to 40 neoantigens (GNOS-PV02) administered in combination with plasmid-encoded IL-12 (pIL12) with pembrolizumab.

Methods: This was a phase Ib/2a clinical trial enrolling 36 hepatocellular carcinoma patients who had disease progression or were intolerant to first-line tyrosine kinase inhibitor. The PTCV [GNOS-PV02 (1 mg) and pIL12 (0.34mg)] were administered intradermally by in vivo electroporation every 3 weeks x 4 doses and every 9 weeks thereafter. Pembrolizumab 200 mg was given every 3 weeks. The primary endpoints were safety and immunogenicity. The secondary endpoint was objective response rate.

Results: Among the 36 enrolled patients who received at least one dose of treatment, there were no dose-limiting toxicities or treatment-related grade ≥3 events. The most common treatment-related adverse event was injection site reaction observed in 41.6% of patients.

The objective response rate was 30.6% (11/36; 9 confirmed, 2 unconfirmed), with 8.3% (3/36) of patients achieving a complete response. This reached statistical significance, one-sided p-value = 0.031 (one-sided 90% CI 20.4%-100%), with a median overall survival of 19.9 months. ctDNA changes correlated with and preceded radiologic responses. Complete molecular responses (100% ctDNA clearance) were detected in 7 patients, including 3 radiological complete responses, and 4 additional patients who continued to demonstrate durable tumor control (3 partial responses, 1 stable disease ).

Immunological analyses confirmed that interferon gamma-ELISpot induced neoantigen-specific T cell responses in 19/22 (86.4%) of evaluable patients, and patients with larger ELISpot responses showed a trend toward longer overall survival. Multiparametric cellular profiling and single-cell analysis revealed the presence of active, proliferative and cytolytic vaccine-specific CD4+ and CD8+ effector T cells in the blood of immunized patients. In 14/14 (100%) patients who underwent pre- and on-treatment blood and tumor biopsies, expanded T cell clones in the peripheral blood identified by T cell receptor beta bulk sequencing also trafficked into the tumor.

Conclusions: PTCV plus pembrolizumab is well tolerated and clinically active in patients with advanced hepatocellular carcinoma and supports a mechanism of action of PTCV based on the induction of antitumor T cells in peripheral blood and tumors.  A confirmatory phase III clinical study is planned to assess overall survival.

参考文献

Yachoan M et al. AACR 2024 Ann Meeting abstr 1191/25

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非侵入性外泌体的液体活检用于早期检测胰腺导管腺癌 (4/13/2024)

An exosome-based liquid biopsy for non-invasive, early detection of pancreatic ductal adenocarcinoma

方法：这项多中心、前瞻性队列研究招募了来自日本, 美国, 韩国和中国的胰腺导管腺癌患者和健康捐赠者。 研究者使用来自四个前瞻性队列的血浆生物样本进行了基于实时定量聚合酶链反应（RT-qPCR）的测定; 还评估了 miRNA 特征与血浆 CA19-9 在检测早期胰腺导管腺癌中的性能。  

结果：研究者建立了两个不同的组，cf-miRNA (circulating cell-free microRNA) 和 ex (exosome) -miRNA，它们可以在训练队列（日本）中有力地区分胰腺导管腺癌患者与健康者。 这些面板的曲线下面积 (AUC) 值分别为 0.95 和 0.97。 将这两个面板组合后，所得签名表现出区分胰腺导管腺癌患者与健康者的显著能力，并且在训练队列中具有很高的准确性（AUC = 0.98）。 更重要的是，该特征在三个独立队列中得到了成功验证和评估（AUC = 0.93，美国；AUC = 0.91 韩国；AUC = 0.88，中国）。 值得注意的是, 当研究者将这些特征与美国队列中的 CA19-9 相结合时，这种液体活检检测的整体诊断性能对于胰腺导管腺癌患者的早期检测显著提高（AUC = 0.97，灵敏度 = 0.95，特异性， 0.96）。     

结论：一种基于外泌体的非侵入性液体活检检测方法，可用于早期检测胰腺导管腺癌患者，并有可能在不久的将来进一步验证其临床应用。

Methods: This multicenter, prospective cohort study recruited patients with pancreatic ductal adenocarcinoma and healthy donors from Japan, the United States, South Korea, and China. Researchers performed a real-time quantitative polymerase chain reaction (RT-qPCR)-based assay using plasma biospecimens from four prospective cohorts; they also evaluated the performance of miRNA signatures with plasma CA19-9 in detecting early-stage pancreatic ductal adenocarcinoma.

Results: Two distinct groups were established, cf-miRNA (circulating cell-free microRNA) and ex (exosome) -miRNA, that robustly differentiated pancreatic ductal adenocarcinoma patients from healthy subjects in a training cohort (Japan). The area under the curve (AUC) values for these panels were 0.95 and 0.97, respectively. When these two panels were combined, the resulting signature showed significant ability to distinguish patients with pancreatic ductal adenocarcinoma from healthy individuals with high accuracy in the training cohort (AUC = 0.98). More importantly, this feature was successfully validated and evaluated in three independent cohorts (AUC = 0.93, United States; AUC = 0.91 South Korea; AUC = 0.88, China). Notably, when the researchers combined these features with CA19-9 in a US cohort, the overall diagnostic performance of this liquid biopsy test significantly improved for early detection of patients with pancreatic ductal adenocarcinoma (AUC = 0.97, sensitivity = 0.95, specificity, 0.96).

Conclusion: An exosome-based non-invasive liquid biopsy detection method can be used for early detection of patients with pancreatic ductal adenocarcinoma, and may further validate its clinical application.

参考文献

Xu C et al. AACR 2024 Ann Meeting abstr 3899

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阿替珠单抗(Atezolizumab) 联合改良多西他赛、顺铂和氟尿嘧啶作为晚期肛门癌的一线治疗 (4/7/2024)

Atezolizumab plus modified docetaxel, cisplatin, and fluorouracil (mDCF)as first-line treatment for advanced anal cancer

方法: 这是一项随机,开放标签,非比较性 II 期临床试验（SCARCE C17-02 PRODIGE 60, NCT03519295），来自法国 21 个中心的参与者患有未接受化疗, 转移性或不可切除的局部晚期或复发性肛门鳞状细胞癌患者被随机分配 (2:1) 接受: A 组）阿替珠单抗治疗（每 2 周静脉注射 800 毫克，最长 1 年）加 mDCF （八个周期，第一天 40毫克/平方米多西紫杉醇和 40 毫克/平方米顺铂，持续 2 天每天 1200 毫克/平方米氟尿嘧啶，每 2 周静脉注射一次；B 组）单独使用 mDCF。 主要终点是研究者评估的 A 组意向治疗人群的 12 个月无进展生存期。

发现: 2018年7月3日至2020年8月19日期间入组了97名可评估参与者（A组64名，B组33名）。中位随访时间为26.5个月（95% CI 24.8–28.4） 。 参与者的中位年龄为 64.1 岁（IQR 56.2–71.6），其中 71 名（73%）为女性。 A 组的 12 个月无进展生存率为 45% (90% CI 35-55)，B 组为 43% (29-58)。在 PD-L1 综合阳性评分为 5 或更高的参与者中， A 组的12个月无进展生存率为 70% (95% CI 47-100)，B 组为 40% (19-85)（交互作用 p =0.051）两组均表现出较高的依从性。

A 组有 39 名 (61%) 参与者和 B 组有 14 名 (42%) 参与者观察到 3 级或以上不良事件。最常见的 3-4 级不良事件是中性粒细胞减少症（A 组有 9 名 [14%] ） B 组为 5 例 [15%]）, 贫血（9 例 [14%] 相比于 1 例 [3%]）、疲劳（3 例 [5%] 相比于 4 例 [12%]）以及腹泻（7 例 [11%] 相比于 1 例[3%]）。 A 组有 16 名 (25%) 参与者发生严重不良事件，B 组有 4 名 (12%) 发生严重不良事件，其中 A 组有 7 名 (11%) 相比于 B 组 4 名 (12%) 发生与 mDCF 相关的不良事件。 A 组中有 9 名 (14%) 参与者发生了与 Atezolizumab 相关的严重不良事件，包括 3 名 (5%) 参与者发生 2 级输注相关反应，2 名 (3%) 参与者发生 3 级感染，以及 2 级结肠炎, 3 级急性 肾损伤,3 级结节病和 4 级血小板计数各有一名参与者减少（2%）。 没有出现与治疗相关的死亡。

解释: 尽管不良事件发生率较高，但将 atezolizumab 与 mDCF 联合使用是可行的，两组的剂量强度相似，但未达到主要疗效终点。 PD-L1 综合阳性评分为 5 或更高的预测价值需要在未来的研究中得到证实。

Methods: This was a randomized, open-label, non-comparative phase II clinical trial (SCARCE C17-02 PRODIGE 60, NCT03519295) with participants from 21 centers in France. They were chemotherapy-naïve and had metastatic or unresectable localized advanced or recurrent anal squamous cell carcinoma. They were randomly assigned (2:1) to receive: Arm A) atezolizumab (800 mg intravenously every 2 weeks for up to 1 year) plus mDCF (eight cycles, 40 mg/m2 docetaxel and 40 mg/m2 cisplatin on day 1, 1200 mg/m2 fluorouracil daily for 2 days, intravenously every 2 weeks; Group B) mDCF alone. The primary endpoint was investigator-assessed 12-month progression-free survival in the Arm A intention-to-treat population.

Findings: 97 evaluable participants were enrolled between July 3, 2018, and August 19, 2020 (64 in Group A, 33 in Group B). Median follow-up was 26.5 months (95% CI 24.8–28.4). The median age of participants was 64.1 years (IQR 56.2–71.6), and 71 (73%) were female. The 12-month progression-free survival rate was 45% (90% CI 35-55) in Arm A and 43% (29-58) in Arm B. Among participants with a composite positive PD-L1 score of 5 or higher, the 12-month progression-free survival rate was 70% (95% CI 47-100) in Arm A and 40% (19-85) in Arm B (interaction p =0.051). Both groups showed higher compliance.

Grade 3 or higher adverse events were observed in 39 (61%) participants in Arm A and 14 (42%) in Arm B. The most common grade 3-4 adverse events were neutropenia (9 [14%] in Arm A vs. 5 [15%] in Arm B), anemia (9 [14%] vs. 1 [3%]), fatigue (3 [5%] vs. 4 [12%]), and diarrhea (7 [11%] vs. 1 [3%]). Serious adverse events occurred in 16 (25%) participants in group A and 4 (12%) in group B, including 7 (11%) in group A compared with 4 (12%) in group B ) adverse events related to mDCF. Serious adverse events related to atezolizumab occurred in 9 (14%) participants in Arm A, including grade 2 infusion-related reactions in 3 (5%) participants and grade 3 in 2 (3%) participants,  grade 2 colitis, grade 3 acute kidney injury, grade 3 sarcoidosis, and grade 4 platelet count were reduced in one participant (2%). There were no treatment-related deaths.

Interpretation: Despite the higher rate of adverse events, combining atezolizumab with mDCF was feasible with similar dose intensities in both groups but did not meet the primary efficacy endpoint. The predictive value of a composite positive PD-L1 score of 5 or higher needs to be confirmed in future studies.

参考文献

Kim S. et al. Lancet Onc 2024; Published:April, 2024DOI:https://doi.org/10.1016/S1470-2045(24)00081-0

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氟维司群或/和Palbociclib或/和avelumab治疗 CDK4/6–/芳香酶-抑制剂治疗中出现进展的转移性乳腺癌 (4/6/2024)

Fulvestrant and/or palbociclib and/or avelumab treat metastatic breast cancer that has progressed on CDK4/6-/aromatase-inhibitor combination

方法: 这是一项机多中心随机II期临床试验（PACE）， 纳入了激素受体阳性/HER2- 转移性乳腺癌患者，这些患者在之前的 CDK4/6抑制剂和芳香酶抑制剂治疗中病情出现进展。 患者以 1:2:1 的比例随机分配接受氟维司群(F), 氟维司群加Palbociclib (F + P) 或氟维司群加Palbociclib 和 avelumab (特异性结合PD-L1的人IgG1单克隆抗体) (F + P + A)。 主要终点是研究者评估的 F组相比对于 F + P组 患者的无进展生存期。

结果: 2017 年 9 月至 2022 年 2 月期间随机分配了 220 名患者。中位年龄为 57 岁（范围为 25-83 岁）。 大多数患者为绝经后患者（80.9%），40% 最初诊断为新发的转移性乳腺癌。 Palbociclib 是最常见的先前 CDK4/6抑制剂 (90.9%)。F组 的中位无进展生存期为 4.8 个月，F + P 组的中位 无进展生存期为 4.6 个月（风险比 [HR]，1.11 [90% CI，0.79 至 1.55]；P = .62）。 F + P + A 组的中位无进展生存期为 8.1 个月（HR vs F，0.75 [90% CI，0.50 至 1.12]；P = .23）。 在基线 ESR1 和 PIK3CA 改变的患者中，F + P  组和 F + P + A 组与 F 组的无进展生存期差异更大。   

结论: 对于激素受体阳性/HER2- 转移性乳腺癌患 患者（其疾病在先前的 CDK4/6抑制剂加芳香酶抑制剂治疗中出现进展），与单独使用氟维司群相比，在氟维司群中添加哌柏西利并不能改善无进展生存期。 添加 avelumab 后观察到的无进展生存期增加值得在该患者群体中进行进一步研 究。

Methods: This was a multicenter, randomized phase II clinical trial (PACE) that enrolled patients with hormone receptor-positive/HER2- metastatic breast cancer who had progressed after they previously received CDK4/6 inhibitors and aromatase inhibitors. Patients were randomly assigned in a 1:2:1 ratio to receive fulvestrant (F), fulvestrant plus palbociclib (F + P), or fulvestrant plus palbociclib and avelumab (human IgG1 that specifically binds PD-L1 monoclonal antibodies) (F + P + A). The primary endpoint was investigator-assessed progression-free survival in the F arm compared with the F + P arm.

Results: 220 patients were randomized between September 2017 and February 2022. Median age was 57 years (range, 25-83 years). The majority of patients were postmenopausal (80.9%), and 40% were initially diagnosed with de novo metastatic breast cancer. Palbociclib was the most common prior CDK4/6 inhibitor (90.9%). The median progression-free survival was 4.8 months in the F group and 4.6 months in the F + P group (hazard ratio [HR], 1.11 [90% CI, 0.79 to 1.55]; P = . 62). The median progression-free survival for group F + P + A was 8.1 months (HR vs F, 0.75 [90% CI, 0.50 to 1.12]; P = .23). Among patients with baseline ESR1 and PIK3CA alterations, the difference in progression-free survival was greater between the F + P group and the F + P + A group versus the F group.

Conclusions: In patients with hormone receptor-positive/HER2- metastatic breast cancer whose disease had progressed on prior CDK4/6 inhibitor plus aromatase inhibitor therapy adding palbociclib to fulvestrant compared to fulvestrant alone did not improve progression-free survival. The increase in progression-free survival observed with the addition of avelumab warrants further study in this patient population.

参考文献

Mayer EL et al. J Clin Onc 2024; doi.org/10.1200/JCO.23.01940

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基因与环境相互作用分析用于了解红肉摄入量与结直肠癌风险之间的关系 (3/31/2024)

Gene–environment interaction analyses to understand the relationship between red meat consumption and colorectal cancer risk

背景： 大量食用红肉（牛肉、猪肉和羊肉）和加工肉类（培根、香肠、午餐/熟食肉和热狗）是结直肠癌的危险因素。 研究者进行了全基因组基因-环境相互作用分析，以确定可能改变这些关联的遗传变异。

方法： 来自 27 项研究的 29,842 例结直肠癌病例和 39,635 名欧洲血统对照样本被纳入其中。 红肉和加工肉类摄入量的分位数是根据统一的问卷数据构建的。 对于每个类别，研究者计算了每天的份量，根据体重指数进行调整，并根据参与者的红肉或加工肉类摄入量将其分为四组。红肉和加工肉类摄入量最高的参与者患结直肠癌的风险分别增加 30% 和 40%。 然而，风险增加并没有考虑到遗传变异性，遗传变异性可能会使某些人比其他人面临更高的风险。因此，研究人员使用 DNA 样本收集了每位研究参与者基因组中超过 700 万个基因变异的数据。 然后，对红肉摄入量与癌症风险之间的联系进行了全基因组基因-环境相互作用分析。 利用单核苷酸多态性检查了某种基因变异是否会改变食用更多红肉的人患结直肠癌的风险。

研究人员发现，在基因组上的几乎每一个单核苷酸多态性中，无论参与者具有哪种基因变异，他们基于红肉摄入的癌症风险都保持不变。 然而，两个特定的单核苷酸多态性是例外。

第一个是靠近HAS2基因的8号染色体上发现了rs4871179单核苷酸多态性。 该基因是编码细胞内蛋白质修饰途径的一部分，在之前的研究中已发现与结直肠癌有关，但与红肉消费无关。 分析显示，具有 HAS2 基因常见变体的参与者（占总人口的 66%）如果食用最高水平的肉类，患结直肠癌的可能性会增加 38%。 相比之下，那些携带 HAS2 基因罕见变异的人在食用更多红肉时，患结直肠癌的风险并没有增加。  

第二个是 18 号染色体上的 rs35352860 单核苷酸多态性，该染色体是负责调节铁调素基因 SMAD7的一部分, 铁调素是一种与铁代谢相关的蛋白质。 由于红肉和加工肉类含有高含量的血红素铁， 一种推测是 SMAD7 的不同变体可能因为改变身体处理铁的方式而导致增加的结直肠癌风险。参加者中携带 SMAD7 基因最常见变体两个拷贝（约占人口的 74%），并食用大量红肉，患结直肠癌的风险会增加 18%。 相比之下, 那些只有一个最常见变异拷贝或两个不太常见变异拷贝的人患结直肠癌的风险要高得多：分别为 35% 和 46%。

这些发现表明，不同的基因变异可能会导致食用红肉的个体患结直肠癌的风险不同，有一部分人群如果吃红肉或加工肉类，则面临更高的结直肠癌风险。这种关联将帮助了解该风险背后的潜在机制。但该研究尚未证明这些基因变异之间存在因果关系。

结论: 研究人员提出了两种新型生物标志物，支持肉类消费与结直肠癌风险增加的作用。

Background: High consumption of red meat (beef, pork, and lamb) and processed meat (bacon, sausage, lunch/deli meats, and hot dogs) are risk factors for colorectal cancer. The researchers performed a genome-wide gene-environment interaction analysis to identify genetic variants that may modify these associations.

Methods: A sample of 29,842 colorectal cancer cases and 39,635 controls of European ancestry from 27 colorectal cancer studies were included. The researchers harmonized the data from the various studies to create standard measures for the consumption of red meat and processed meat. For each category, the researchers calculated daily portion sizes, adjusted for body mass index, and divided participants into four groups based on their red meat or processed meat intake. Participants with the highest intakes of red meat and processed meat had a 30% and 40% increased risk of colorectal cancer, respectively. However, the increased risk does not consider genetic variability, which may put some people at higher risk than others. So the researchers used DNA samples to collect data on more than 7 million genetic variants in each study participant’s genome. A genome-wide gene-environment interaction analysis of the association between red meat intake and cancer risk was performed, using single nucleotide polymorphisms to examine whether a certain genetic variant alters the risk of colorectal cancer in people who eat more red meat. The researchers found that at nearly every single nucleotide polymorphism on the genome, regardless of which genetic variant the participants had, their cancer risk based on red meat intake remained the same. However, two specific single nucleotide polymorphisms were exceptions.

The first is the rs4871179 single nucleotide polymorphism found on chromosome 8 near the HAS2 gene. The gene is part of a pathway that codes for intracellular protein modifications and has been linked to colorectal cancer in previous studies, but not to red meat consumption. The analysis showed that participants with a common variant of the HAS2 gene (66% of the population) who ate the highest levels of meat were 38% more likely to develop colorectal cancer. In contrast, those with a rare variant of the HAS2 gene did not have an increased risk of colorectal cancer when they ate more red meat.

The second is the rs35352860 single nucleotide polymorphism on chromosome 18, which is part of the gene SMAD7 responsible for regulating hepcidin, a protein related to iron metabolism. Since red meat and processed meat contain high levels of heme iron, one hypothesis is that different variants of SMAD7 may contribute to increased colorectal cancer risk by changing how the body processes iron. Participants who carried two copies of the most common variant of the SMAD7 gene (about 74% of the population) and ate large amounts of red meat had an 18% increased risk of colorectal cancer. In contrast, those with only one copy of the most common variant or two copies of the less common variant had a much higher risk of developing colorectal cancer: 35% and 46%, respectively.

These findings suggest that different genetic variants may contribute to different risks of colorectal cancer among individuals who eat red meat, with some groups facing a higher risk of colorectal cancer if they eat red or processed meat. This association will help understand the underlying mechanisms behind this risk. But the study has not proven a cause-and-effect relationship between these genetic variants.

Conclusions: Researchers propose two novel biomarkers supporting the role for meat consumption with increased colorectal cancer risk.

参考文献

Stern MC et al. Cancer Epidemiol Biomarkers Prev 2024; 33:400

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Dostarlimab 的组合治疗晚期子宫内膜癌 (3/30/2024)

Dostarlimab combination treating advanced endometrial cancer

临床III 期试验RUBY (ENGOT-EN6/GOG3031/NSGO)的目标是评估原发性晚期或复发性子宫内膜癌患者可能受益于 dostarlimab  (人源化抗 PD-1 单克隆抗体)联合化疗（加用或不加用 niraparib 维持治疗）。

RUBY试验的第 1 部分正在研究 dostarlimab 加标准护理化疗（卡铂/紫杉醇）和随后使用 dostarlimab (治疗组)与化疗加安慰剂和随后使用安慰剂(对照组)的比较。观察到 dostarlimab 组总体生存率有统计学意义和临床意义的改善，达到了该研究的主要终点。 在总体人群中，治疗组与对照组相比显示： 死亡风险统计显著降低 31%（风险比 [HR] = 0.69，95% 置信区间 [CI] = 0.539–0.890）,  中位总生存期延长了 16.4 个月（44.6 个月相比于28.2 个月）。 在对 pMMR/MSS (proficient mismatch repair/Microsatellite stable) 人群的预先设定的探索性分析中，Dostarlimab联合化疗与对照组相比显示： 死亡风险降低 21% （HR = 0.79，95% CI = 0.602–1.044） 中位总生存期延长了 7 个月（34.0 个月相比于 27.0 个月）。 

在 RUBY 第 1 部分中，与对照组相比，治疗组中 3 级或以上以及严重治疗引起的不良事件大约高 12%。在试验中，治疗组中 19.1% 的患者和对照组中 8.1% 的患者因治疗中出现的不良事件而停用Dostarlimab或安慰剂。

RUBY 试验的第 2 部分正在评估 dostarlimab 加标准护理化疗、随后 dostarlimab 加 niraparib (PARP 抑制剂)作为维持治疗(治疗组）与化疗加安慰剂, 随后安慰剂(对照组)的比较。

结果显示，与对照组相比，在维持治疗中在 dostarlimab 中添加 niraparib 显著改善了一线原发性晚期或复发性子宫内膜癌的无进展生存期，达到了试验的主要终点。 在总体人群中，治疗组相比于治疗组疾病进展或死亡风险统计显著降低 40%（HR = 0.60，95% CI = 0.43–0.82） 中位无进展生存期延长了 6.2 个月，（14.5 个月相比于 8.3 个月）。 在 pMMR/MSS 人群中，疾病进展或死亡风险统计显着降低 37%（HR = 0.63，95% CI = 0.44–0.91） 中位无进展生存期延长了 6.0 个月（14.3 个月 vs 8.3 个月）。

在 RUBY 第 2 部分中，与对照组相比，治疗组中 3 级或以上不良事件和严重治疗引起的不良事件分别高出约 36% 和 24%。治疗组中 24.1% 的患者和对照组中 5.2% 的患者因治疗中出现的不良事件而停用Dostarlimab或安慰剂。 治疗组中 15.7% 的患者和对照组中 4.2% 的患者因治疗中出现的不良事件而停用或安慰剂。

结论：针对原发性晚期或复发性子宫内膜癌成人患者的 RUBY/ENGOT-EN6/GOG3031/NSGO III 期试验第 1 部分的总生存期结果和第 2 部分的无进展生存期结果具有统计学意义和临床意义。

The goal of the phase III clinical trial RUBY (ENGOT-EN6/GOG3031/NSGO) was to evaluate whether patients with primary advanced or recurrent endometrial cancer may benefit from dostarlimab (a humanized anti-PD-1 monoclonal antibody) combined with chemotherapy (plus maintenance therapy with or without niraparib).

Part 1 of the RUBY trial is studying dostarlimab plus standard of care chemotherapy (carboplatin/paclitaxel) followed by dostarlimab (treatment arm) versus chemotherapy plus placebo followed by placebo (control arm). A statistically significant and clinically meaningful improvement in overall survival was observed in the dostarlimab arm, meeting the study’s primary endpoint. In the overall population, the treatment group compared with the control group showed: a statistically significant 31% reduction in the risk of death (hazard ratio [HR] = 0.69, 95% confidence interval [CI] = 0.539–0.890), and an increase in median overall survival 16.4 months (44.6 months compared to 28.2 months). In a prespecified exploratory analysis of the pMMR/MSS (proficient mismatch repair/Microsatellite stable) population, dostarlimab plus chemotherapy showed a 21% reduction in the risk of death compared with control (HR = 0.79, 95% CI = 0.602– 1.044). Median overall survival was extended by 7 months (34.0 months vs. 27.0 months).

In RUBY Part 1, grade 3 or above and serious treatment-emergent adverse events were approximately 12% higher in the treatment group compared with the control group. In the trial, 19.1% of patients in the treatment group and 8.1% of patients in the control group discontinued dostarlimab or placebo due to treatment-emergent adverse events.

Part 2 of the RUBY trial is evaluating dostarlimab plus standard-of-care chemotherapy, followed by dostarlimab plus niraparib (a PARP inhibitor) as maintenance therapy (treatment arm) versus chemotherapy plus placebo, followed by placebo (control arm). Results showed that adding niraparib to dostarlimab during maintenance therapy significantly improved progression-free survival compared with control in first-line primary advanced or recurrent endometrial cancer, meeting the trial’s primary endpoint. In the overall population, the risk of disease progression or death was statistically significantly reduced by 40% in the treatment group (HR = 0.60, 95% CI = 0.43–0.82) and the median progression-free survival was extended by 6.2 months (14.5 months compared to 8.3 months). In the pMMR/MSS population, the risk of disease progression or death was statistically significantly reduced by 37% (HR = 0.63, 95% CI = 0.44–0.91) and median progression-free survival was extended by 6.0 months (14.3 months vs 8.3 months).

In RUBY Part 2, grade 3 or above adverse events and serious treatment-emergent adverse events were approximately 36% and 24% higher, respectively, in the treatment group compared with the control group. 24.1% of patients in the treatment group and 5.2% of patients in the control group discontinued dostarlimab or placebo due to treatment-emergent adverse events. 15.7% of patients in the treatment group and 4.2% of patients in the control group discontinued treatment or placebo due to treatment-emergent adverse events.

Conclusion: conclusion: Statistically significant and clinically meaningful overall survival results from Part 1 and progression-free survival results from Part 2 of the RUBY/ENGOT-EN6/GOG3031/NSGO Conclusion: In adult patients with primary advanced or recurrent endometrial cancer,  statistically significant and clinically meaningful overall survival results were found in part 1 and progression-free survival results in part 2 of the RUBY/ENGOT-EN6/GOG3031/NSGO phase III trial.

参考文献

Mirza MR et al. SGO 2024 Annual Meeting on Women’s Cancer. Plenary session

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派姆单抗在乳腺癌新辅助治疗中的应用 (3/24/2024)

Pembrolizumab in neoadjuvant therapy in breast cancer (KEYNOTE756)

这是一项国际III期临床试验（KEYNOTE-756），1,278 名浸润性导管癌患者在新辅助化疗的基础上随机分配接受派姆单抗或安慰剂治疗，然后接受辅助派姆单抗或安慰剂联合内分泌治疗。  

与接受安慰剂的患者相比，接受派姆单抗的患者的病理完全响应率有统计学上的显著增加。派姆单抗组的病理完全响应率为 24.3%，而安慰剂组为 15.6%。在 50 岁以下的患者中，派姆单抗组为 23.8% (n = 76/319)，而安慰剂组为 16.9% (n = 55/326)； 在 50 岁或以上的患者中，派姆单抗组为 24.7% (n = 78/316)，而安慰剂组为 14.2% (n = 45/317)。

在新辅助化疗中添加派姆单抗并不会延迟手术时间。 两组患者平均手术时间均为1个月左右。两组的保乳手术和乳房切除术率相似。 在接受保乳手术的患者中，41.3% (n = 262) 接受了派姆单抗治疗，43.7% (n = 281) 接受了安慰剂治疗； 而接受派姆单抗治疗的患者中有 55.3% (n = 351) 和接受安慰剂治疗的患者中有 54.4% (n = 350) 接受了乳房切除术。

无论该药物阻断 PD-L1 的效果如何，接受派姆单抗治疗的患者中有 35.0% (n = 222) 与安慰剂治疗的患者中分别有 23.6% (n = 152) 没有或只有很少的残留癌症负担。此外，在癌细胞少于 10% 的 ER 阳性乳腺癌患者中，派姆单抗组为 64.7% (n = 22/34)，而安慰剂组为 37.2% (n = 16/43)。 相反，在癌细胞 10% 或以上的 ER 阳性乳腺癌患者中，分别有 33.3% (n = 200/601) 和 22.7% (n = 136/600) 的患者没有或只有很少的癌细胞。 与 KEYNOTE-756 试验之前的报告相比，治疗的不良事件没有变化，并且与对每种治疗方案的已知了解一致。

结论: 研究者认为, 在新辅助化疗中添加派姆单抗可显著增加手术时的病理完全缓解，无论 PD-L1 水平和 ER 阳性如何; 但较高的 PD-L1 水平和 ER 低的肿瘤具有更大的益处。需要更长时间的随访来观察是否有无病生存益处。

This is an international phase III clinical trial (KEYNOTE-756) in which 1,278 patients with invasive ductal carcinoma were randomly assigned to receive pembrolizumab or placebo in addition to neoadjuvant chemotherapy, followed by adjuvant pembrolizumab or placebo combined with endocrine therapy.

Patients receiving pembrolizumab had a statistically significant increase in pathological complete response rates compared with those receiving placebo. The pathological complete response rate was 24.3% in the pembrolizumab group and 15.6% in the placebo group. Among patients under 50 years old, 23.8% (n = 76/319) in the pembrolizumab group compared with 16.9% (n = 55/326) in the placebo group; among patients 50 years or older, The pCR rate was 24.7% (n = 78/316) vs. 14.2% (n = 45/317).

Adding pembrolizumab to neoadjuvant chemotherapy did not delay time to surgery. The average operation time for both groups of patients was about 1 month. Rates of breast-conserving surgery and mastectomy were similar in both groups.

Regardless of the drug’s effectiveness at blocking PD-L1, 35.0% (n = 222) of patients treated with pembrolizumab versus 23.6% (n = 152) of patients treated with placebo had none or very little of residual cancer burden. In addition, among patients with ER-positive breast cancer who had less than 10% cancer cells, 64.7% (n = 22/34) in the pembrolizumab group compared with 37.2% (n = 16/43) in the placebo group. In contrast, among patients with ER-positive breast cancer in 10% or more of their cancer cells, 33.3% (n = 200/601) and 22.7% (n = 136/600) had no or few cancer cells, respectively. Adverse events from treatment were unchanged from previous reports in the KEYNOTE-756 trial and were consistent with what is known about each treatment regimen.

Conclusions: the addition of pembrolizumab to neoadjuvant chemotherapy significantly increases pathologic complete response at the time of surgery, regardless of PD-L1 levels and ER positivity. It was observed that tumors with higher PD-L1 levels and low ER had greater benefit, It needs longer follow-up to see if there is benefit of disease-free survival.

参考文献

Cardoso et al. 2024 Eur Breast Cancer Conf abstr 4

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无驱动突变/改变的 IV 期非小细胞肺癌治疗：ASCO 指南，2023.3 版 (3/23/2024)

Therapy for stage IV non–small cell lung cancer without driver alterations: ASCO living guideline, Version 2023.3

非鳞状细胞癌（最有效的一线治疗选择, 身体状态良好）

类别	推荐	类型	质量	实力
PD-L1 TPS>50%	Pembro*1 或 cemiplimab或atezolizumab	循证	高	强
	Pembro+Carbo3+ pemetrexed 或 cemiplimab + carbo + pemetrexed	循证	中	弱
	atezolizumab + carbo + nab-paclitaxel + bevacizumab	循证	中	弱
	nivolumab 和 ipilimumab	循证	中	弱
	nivolumab 和 ipilimumab 加两个周期铂类化疗	循证	中	弱
	durvalumab 和 tremelimumab加铂类化疗	循证	中	弱
PD-L1 TPS 1-49%	pembro + carbo + pemetrexed 或 cemiplimab + carbo + pemetrexed	循证	中	强
	atezolizumab + carbo + (nab)-paclitaxel ± bevacizumab	循证	中	弱
	nivolumab and ipilimumab	循证	中	弱
	nivolumab and ipilimumab 加两个周期铂类化疗	循证	中	弱
	durvalumab and tremelimumab 加铂类化疗	循证	中	弱
	如果患者不符合化疗资格或拒绝化疗，则采用抗 PD-1 单一疗法	循证	中	弱
PD-L1未知或阴性, TPS <1%	pembro + carbo + pemetrexed 或 cemiplimab + carbo + pemetrexed	循证	中	弱
	atezolizumab + carbo + (nab)-paclitaxel ± bevacizumab	循证	中	弱
	nivolumab 和 ipilimumab	循证	中	弱
	nivolumab 和 ipilimumab 加两个周期铂类化疗	循证	中	弱
	durvalumab 和 tremelimumab 加铂类化疗	循证	中	弱

鳞状细胞癌

类别	推荐	类型	质量	实力
PD-L1 TPS>50%	Pembro 或 cemiplimab 或 atezolizumab	循证	中	强
	pembro + carbo + paclitaxel (或 nab-paclitaxel) 或 cemiplimab + carboplatin + paclitaxel	循证	中	弱
	nivolumab 和 ipilimumab	循证	中	弱
	nivolumab 和 ipilimumab 加两个周期铂类化疗	循证	中	弱
	durvalumab 和 tremelimumab 加铂类化疗	循证	中	弱
PD-L1 TPS 1-49%	pembro + carbo + paclitaxel (或nab-paclitaxel) 或 cemiplimab + carboplatin + paclitaxel	循证	中	强
	nivolumab 和 ipilimumab	循证	中	弱
	nivolumab 和 ipilimumab 加两个周期铂类化疗	循证	中	弱
	durvalumab 和 tremelimumab 加铂类化疗	循证	中	弱
	如果患者不符合化疗资格或拒绝化疗，则采用抗 PD-1 单一疗法	循证	中	弱
PD-L1未知或阴性, TPS <1%	pembrolizumab + carbo + paclitaxel ((或 nab-paclitaxel) (或cemiplimab + carbo + paclitaxel	循证	中	弱
	nivolumab 和 ipilimumab	循证	中	弱
	nivolumab 和 ipilimumab 加两个周期铂类化疗	循证	中	弱
	durvalumab 和 tremelimumab 加铂类化疗	循证	中	弱

病理组织学未明确的患者

类别	推荐	类型	质量	实力
身体状态良好	不适合免疫检查点抑制剂治疗：铂类疗法	循证	高	强
铂类药禁忌症	非铂类治疗组合	循证	中	弱
贝伐单抗禁忌症	对于有临床显著咯血, 器官功能不足, ECOG PS >1、显著心血管疾病或药物无法控制的高血压的患者, 应避免使用贝伐珠单抗	循证	高	强
	贝伐单抗联合培美曲塞维持治疗没有生存优势且毒性显著增加	循证	中	弱

Nonsquamous cell carcinoma (most effective first-line treatment options with good performance status)

Category	Recommendation	Type	Quality	Strength
PD-L1 TPS>50%	Pembro*1 or cemiplimab or atezolizumab	E.B.2	High	Strong
	Pembro+Carbo3+ pemetrexed or cemiplimab + carbo + pemetrexed	E.B.	Moderate	weak
	atezolizumab + carbo + nab-paclitaxel with or without bevacizumab	E.B.	Moderate	weak
	nivolumab and ipilimumab	E.B.	Moderate	weak
	nivolumab and ipilimumab plus two cycles of platinum-based chemotherapy	E.B.	Moderate	weak
	durvalumab and tremelimumab plus platinum-based chemotherapy	E.B.	Moderate	weak
PD-L1 TPS 1-49%	pembro + carbo + pemetrexed or cemiplimab + carbo + pemetrexed	E.B.	Moderate	Strong
	atezolizumab + carbo + (nab)-paclitaxel ± bevacizumab	E.B.	Moderate	weak
	nivolumab and ipilimumab	E.B.	Moderate	weak
	nivolumab and ipilimumab plus two cycles of platinum-based chemotherapy	E.B.	Moderate	weak
	durvalumab and tremelimumab plus platinum-based chemotherapy	E.B.	Moderate	weak
	monotherapy with anti-PD-1 if pt4 ineligible for or decline chemo	E.B.	Moderate	weak
Unknown or negative PD-L1, TPS <1%	pembro + carbo + pemetrexed or cemiplimab + carbo + pemetrexed	E.B.	Moderate	Weak
	atezolizumab + carbo + (nab)-paclitaxel ± bevacizumab	E.B.	Moderate	weak
	nivolumab and ipilimumab	E.B.	Moderate	weak
	nivolumab and ipilimumab plus two cycles of platinum-based chemotherapy	E.B.	Moderate	weak
	durvalumab and tremelimumab plus platinum-based chemotherapy	E.B.	Moderate	weak

Squamous cell carcinoma

Category	Recommendation	Type	Quality	Strength
PD-L1 TPS>50%	Pembro or cemiplimab or atezolizumab	E.B.	High	Strong
	pembro + carbo + paclitaxel (or nab-paclitaxel) or cemiplimab + carboplatin + paclitaxel	E.B.	Moderate	weak
	nivolumab and ipilimumab	E.B.	Moderate	weak
	nivolumab and ipilimumab plus two cycles of platinum-based chemotherapy	E.B.	Moderate	weak
	durvalumab and tremelimumab plus platinum-based chemotherapy	E.B.	Moderate	weak
PD-L1 TPS 1-49%	pembro + carbo + paclitaxel (or nab-paclitaxel) or cemiplimab + carboplatin + paclitaxel	E.B.	Moderate	Strong
	nivolumab and ipilimumab	E.B.	Moderate	weak
	nivolumab and ipilimumab plus two cycles of platinum-based chemotherapy	E.B.	Moderate	weak
	durvalumab and tremelimumab plus platinum-based chemotherapy	E.B.	Moderate	weak
	monotherapy with anti-PD-1 if pt ineligible for or decline chemo	E.B.	Moderate	weak
Unknown or negative PD-L1, TPS <1%	pembrolizumab + carbo + paclitaxel (or nab-paclitaxel) or cemiplimab + carbo + paclitaxel	E.B.	Moderate	Weak
	nivolumab and ipilimumab	E.B.	Moderate	weak
	nivolumab and ipilimumab plus two cycles of platinum-based chemotherapy	E.B.	Moderate	weak
	durvalumab and tremelimumab plus platinum-based chemotherapy	E.B.	Moderate	weak

Patients with unspecified histology

Category	Recommendation	Type	Quality	Strength
preserved PS	not candidates for immune checkpoint inhibitor therapy: platinum doublet combination therapy	E.B.	High	Strong
contraindications to platinum	nonplatinum therapy combinations	E.B.	Moderate	weak
contraindications to bevacizumab	Bevacizumab should be avoided for patients with clinically significant hemoptysis, inadequate organ function, ECOG PS >1, significant cardiovascular disease, or medically uncontrolled hypertension	E.B.	High	Strong
	Maintenance bevacizumab given with pemetrexed has no survival advantage and significant increased toxicity	E.B.	Moderate	weak

*1 pembro: pembrolizumab

*2 E.B. evidence-based

*3 carbo: carboplatin

*pt. patient

参考文献 Reference

Jaiyesimi IA et al. J Clin Onc 2024; Feb. 28

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具有驱动突变/改变的 IV 期非小细胞肺癌的治疗：ASCO 指南，2023.3版本 (3/17/2024)

Therapy for stage IV non–small cell lung cancer with driver alterations: ASCO Guideline, Version 2023.3

基于驱动突变改变的最有效的一线治疗方案

驱动突变/改变…………………………………………………………..选择……………………..证据…………………质……实力

EGFR

外显子 19 缺失，外显子 21 L858R 替换 ……………….. 奥希替尼 ……………………. 循证 ……………………. 高 …….. 强

其他 改变（G719X、L861Q、S768I) ……………………… 阿法替尼 …………………… 非正式共识 …………. 低 …….. 弱

…………………………………………………………………………………… 奥希替尼 …………………… 非正式共识 ………….. 低 …….. 弱

………………………………………………………………………………… 无突变标准治疗^*1 ………… 非正式共识 ………….. 低 ……… 弱

外显子 20 插入 ……………………………………………………… 化疗和阿米万他单抗 ……….. 循证 …………………… 中 …….. 强

如果没有阿米万他单抗 ………………………………………….. 无突变标准治疗 ……………….. 循证 ………………….. 中 …….. 强

任何EGFR 改变，无论 PD-L1 …………………………. 单药免疫检查点抑制剂      

表达水平如何 …………………………………………………….. 不应作为一线治疗 ………………….. 循证 …………………. 中 ……… 强

ALK

………………………………………………………………… alectinib or brigatinib or lorlatinib ……………. 循证 ……………….. 高 ………. 强

如果三者都没有 ………………………………………… ceritinib or crizotinib ………………………………. 循证 ……………….. 高 ………. 强

ROS1

………………………………………………………………………. crizotinib or Entrectinib ……………………….. 循证 …………….. 中 ……….. 强

如果两者都没有…………………………………………….. ceritinib or lorlatinib …………………………….. 循证 …………….. 低 ……….. 弱

BRAF^V600E

……………………………………………………………………….. dabrafenib and trametinib ,……………………. 循证 ………………. 低 ………. 强

………………………………………………………………………. or encorafenib and binimetinib ………………. 循证 ………………. 低 ………. 强

如果这些药都没有 ………………………………………… 无突变标准治疗 ………………………………… 非正式共识 …………. 低 ………. 强

MET 外显子 14 跳跃突变

………………………………………………………………………. capmatinib or tepotinib …………………………….. 循证 …………………. 低 ………. 强

如果这些药都没有 ………………………………………….. 无突变标准治疗 ……………………………… 非正式共识 ……………….. 低 ………. 强

RET 重组

……………………………………………………………………………….. Selpercatinib ………………………………………….. 循证 ……………….. 高 …….. 强

如果该药没有………………………………………………………… pralsetinib ………………………………….... 循证 ………………. 中 ……… 强

如果这些药都没有 ………………………………………………… 无突变标准治疗 ……………………..……. 非正式共识 ……….. 低 …….. 弱

NTRK 重组

 …………………………………………………………………. entrectinib or Larotrectinib ……………………….…… 循证 ……………… 低 ……… 强

HER2

………………………………………………………….……… trastuzumab deruxtecan ………………………………….. 循证 ………………. 低 ……… 强

KRAS G12C

 …………………………………………………………….…… Sotorasib ……………………….………………………………….. 循证 ………………… 中 ……… 强

…………………………………………………………….…… Adagrasib ……………………………………………………………. 循证 ………………… 低 ……… 强

*1 无突变标准治疗: 遵循非驱动突变/改变指南的标准治疗

Most effective first-line treatment options based on the driver mutation alterations:

Driver alteration   …………………  Option…..…  Evidence …. Quality .. Strength

EGFR

Exon 19 deletion, exon 21 L858R substitution ………… osimertinib ……. ……… E.B.^*1……..……. High …….. Strong

Other alterations, (G719X, L861Q, S768I) ………………. afatinib …………… Infor con^*2………… Low ……… Weak

……………………………………………………………………………………. Osimertinib ………………… Infor con ……… Low ………. Weak

……………………………………………………………………………………. Standard therapy^*3………… Infor con ………. Low ………. Weak

Exon 20 insertions ……………………………………………………… chemo & amivantamab …… E.B. ……….. Moderate …….. Strong

If amivantamab is available ……………………………………… Standard therapy …..……………. E.B. ……… Moderate …….. Strong

Any activating EGFR alteration, …………………………………. No single-agent ICI^*4    

regardless of PD-L1 expression levels ………………………. as first-line therapy …………… E.B. …………….. High ……….. Strong

ALK

…………………………………………………….…………….alectinib or brigatinib or lorlatinib …………… E.B. ………… High ………….. Strong 

If none of the three are available ……………… ceritinib or crizotinib ………………………………. E.B. ………… High …………. Strong

ROS1

…………………………………………………….…………… crizotinib or Entrectinib …………………………… E.B. ………… Moderate …….. Strong     

If none of the two are available …………………. ceritinib or lorlatinib …………………………….. E.B. ……………. Low …………….. Weak

BRAF^V600E

…………………………………………………….……….. dabrafenib and trametinib,

…………………………………………………….………… or encorafenib and binimetinib …………………… E.B. ………………. Low. ……………. Strong

If none of the these are available ……………….. Standard therapy ………………………………. Infor con. …………. Low ……………. Strong

MET exon 14 skipping mutation

 …………………………………………………….……….. capmatinib or tepotinib ………….…………………. E.B. ………..……. Low ………. Strong                      

If none of the these are available .…………… Standard therapy .………………………………….. Infor con .………… Low .…………. Strong

RET rearrangement

………………………………………………….………….. Selpercatinib ………………….………….………….. E.B. ……….…………. High ……….……… Strong

If selpercatinib is not available …………….. pralsetinib ………..…………………………………… E.B. ……….……  moderate ……….… Strong

If none of the these are available …………… Standard therapy  ………………………….…… Infor con ………..  Low …….. ……….… Weak

NTRK rearrangement

………………………………………………….…………. entrectinib or Larotrectinib ………………….….. E.B. ………………. Low ……….….. Strong

HER2

………………………………………………….………… trastuzumab deruxtecan ………………….………… E.B. ……..………… Low …………. Strong

KRAS G12C

………………………………………………….……….. Sotorasib …………………………………………………… E.B. …………… Moderate …………… Strong

………………………………………………….………. Adagrasib …………………………………………….……… E.B. ……….…….… Low ……..………… Strong

*1 E.B.: evidence-based

*2 Infor con: informal consensus

*3 Standard therapy: standard treatment following the non-driver alteration guideline

*4 ICI: immune checkpoint inhibitor

参考文献 Reference

Jaiyesimi IA et al. J Clin Onc 2024; Feb. 28

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阿比特龙 + 奥拉帕尼治疗转移性去势抵抗性前列腺癌 (3/16/2024)

Abiraterone plus olaparib in patients with metastatic castration-resistant prostate cancer

BRCAAway (NCT03012321)是一项生物标志物预选, 多中心, 随机II 期试验，评估了雄激素受体抑制剂与 PARP抑制剂相比于两种抑制剂组合对具有 BRCA1/2 或 ATM 种系和/或体细胞突变的一线转移性去势抵抗性前列腺癌 (mCRPC) 的疗效。

方法： 参加者为从未接受过 PARP抑制剂, 雄激素受体抑制剂, 化疗，放疗和其他研究药物。 符合条件的患者接受了肿瘤下一代测序/种系检测； 具有失活 BRCA1/2 和/或 ATM 改变的患者按 1:1:1 随机分配至 1) 第 1组每天阿比特龙（1000 mg）+ 每天两次强的松（5 mg）; 2)第 2 组每天两次奥拉帕尼（300 mg）; 3) 第 3 组奥拉帕尼 + 阿比特龙/ 强的松。 主要终点是无进展生存期或死亡。 次要终点包括可测量的疾病响应率,PSA 响应率和毒性。 第1组和第2组的患者在疾病进展时可以交叉。    

结果： 165 名符合条件的患者已注册并接受了 NGS/种系检测； 61 名具有失活 BRCA1/2 和/或 ATM 改变的患者被随机分配至第 1-3组。 中位年龄：67岁（范围42-85岁）。BRCA1 n =3，BRCA2 n =46，ATM n =11，多重 n =1（33 个种系，28 个体细胞发病部位：骨骼n =44，内脏n =12，淋巴结n =31，其他n =3； 中位基线 PSA：14 ng/ml（范围 0.15-4,037 ng/ml）。 仍然活着的第 1, 2和 3组为患者中(n =56)，从随机化到最后一次相遇的中位（范围）时间分别为 16 (0.8-60), 15 (4.1-36) 和 23 (2.9-56) 个月 。

在进展时，8/19 名患者从阿比特龙转为奥拉帕尼，8/21 名患者从阿比特龙转为奥拉帕尼。中位无进展生存期 (95% CI): 交叉至奥拉帕尼 8.3个月 (5.5, 15), 交叉至阿比特龙 7.2 个月 (2.8, NR)  。 从随机化开始的中位无进展生存期(95% CI) 为：奥拉帕尼 16 个月 (7.8-25) 和阿比特龙 16 个月 (11-28)。 交叉治疗的疾病响应率：奥拉帕尼 38%，阿比特龙 25%。 交叉治疗的 PSA 疾病响应率：奥拉帕尼 50%，阿比特龙 63%。

有51 名患者出现与治疗相关的副作用； 最常见的 3 级为: 疲劳 n =3，贫血 n =2，ALT 升高 n =2。，第 1组 中有 3 例死亡，第 2组中有 2 例死亡。总生存期数据还不成熟。  

结论： 在具有 BRCA1/2 或 ATM 改变的 mCRPC 患者中，阿比特龙/泼尼松 + 奥拉帕尼的耐受性良好，并且与单独使用或序贯使用任一药物相比，可实现更长的无进展生存期。

BRCAAway (NCT03012321) is a biomarker-preselected, multicenter, randomized phase II trial evaluating the efficacy and safety of an androgen receptor inhibitor versus a PARP inhibitor versus the combination of the two inhibitors as a first-line therapy in mCRPC patients with germline and/or somatic mutations in BRCA1/2 and/or ATM. Efficacy of/or somatic mutations.

Methods: Participants never received PARP inhibitors, androgen receptor inhibitors, chemotherapy, radiation therapy, and other study drugs. Eligible patients underwent tumor next-generation sequencing/germline testing; patients with inactivating BRCA1/2 and/or ATM alterations were randomized 1:1:1 to 1) Arm 1 daily abiraterone (1000 mg) + prednisone (5 mg twice daily); 2) Arm 2 olaparib (300 mg twice daily); 3) Arm 3 olaparib + abiraterone/prednisone. The primary endpoint was progression-free survival or death. Secondary endpoints include measurable disease response rate, PSA response rate and toxicity. Patients in Groups 1 and 2 could cross over as their disease progressed.

Results: 165 eligible patients were enrolled and underwent NGS/germline testing; 61 patients with inactivating BRCA1/2 and/or ATM alterations were randomized to arms 1-3. Median age: 67 years (range 42-85 years). BRCA1 n =3, BRCA2 n =46, ATM n =11, multiplex n =1 (33 germ lines, 28 somatic cells). Site of disease: bone n =44, visceral n =12, lymph node n =31, other n =3 ; Median baseline PSA: 14 ng/ml (range 0.15-4,037 ng/ml).

Among patients still alive in groups 1, 2, and 3 (n = 56), median time from randomization to last encounter was ( range) 16 (0.8-60), 15 (4.1-36) and 23 (2.9-56) months respectively. At progression, 8/19 patients were switched from abiraterone to olaparib and 8/21 patients were switched from abiraterone to olaparib. Median progression-free survival (95% CI): crossover to olaparib 8.3 months (5.5, 15), crossover to abiraterone 7.2 months (2.8, NR). Median progression-free survival (95% CI) from randomization was: 16 months (7.8-25) with olaparib and 16 months (11-28) with abiraterone. Response rate to crossover treatment: 38% for olaparib, 25% for abiraterone. PSA response rates to crossover treatment: 50% for olaparib, 63% for abiraterone.

Treatment-related side effects occurred in 51 patients; the most common grade 3 were: fatigue n =3, anemia n =2, and elevated ALT n =2. There were 3 deaths in group 1 and 2 deaths in group 2. Overall survival data were immature.

Conclusions: In mCRPC patients with BRCA1/2 or ATM alterations, abiraterone/prednisone + olaparib was well tolerated and resulted in a longer progression-free survival than either agent alone or sequentially.

参考文献 Reference

Hussain MHA et al.  2024 ASCO GU Cancers Symp Abstr 19

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外用双氯芬酸预防卡培他滨所引起的手足综合征 (3/10/2024)

Topical diclofenac for prevention of capecitabine-associated hand-foot Syndrome

手足综合征是卡培他滨的剂量限制性副作用。 塞来昔布(celecoxib)通过抑制环氧合酶 2来预防手足综合征。 然而，塞来昔布的全身副作用限制了常规处方。 外用双氯芬酸可局部抑制环氧合酶 2，且全身不良事件的风险最小。  

方法: 在这项单中心 III 期随机双盲试验中，招募共有264名计划接受卡培他滨治疗的乳腺癌或胃肠道癌症患者。 参与者以 1:1 的比例随机分配接受外用双氯芬酸或安慰剂凝胶治疗 12 周或直至发生手足综合征（以较早者为准）。 主要终点是 2 级或 3 级手足综合征不良事件的发生率，使用简单逻辑回归对两组进行比较。

结果: 参加者为随机分配接受外用双氯芬酸凝胶 (n = 131) 或安慰剂 (n = 133)。 双氯芬酸组有 3.8% 的参与者出现 2 级或 3 级手足综合征，而安慰剂组为 15.0%（绝对差异，11.2%；95% CI，4.3 至 18.1；P = 0.003）。 双氯芬酸组的 1-3 级 手足综合征低于安慰剂组（6.1% vs 18.1%；绝对风险差异，11.9%；95% CI，4.1 至 19.6）。 双氯芬酸组因手足综合征而减少卡培他滨剂量的频率 (3.8%) 低于安慰剂组 (13.5%；绝对风险差异，9.7%；95% CI，3.0 至 16.4)。

结论 外用双氯芬酸可预防接受卡培他滨治疗的患者发生手足综合征。 该试验支持使用局部双氯芬酸来预防卡培他滨相关的手足综合征。

Hand-foot syndrome is a dose-limiting side effect of capecitabine. Celecoxib prevents hand-foot syndrome by inhibiting cyclooxygenase 2. However, the systemic side effects of celecoxib limit routine prescription. Topical diclofenac locally inhibits cyclooxygenase 2 with minimal risk of systemic adverse events.

Methods: A total of 264 patients with breast or gastrointestinal cancer scheduled to receive capecitabine were enrolled in this single-center phase III randomized, double-blind trial. Participants were randomly assigned in a 1:1 ratio to receive topical diclofenac or placebo gel for 12 weeks or until the onset of hand-foot syndrome, whichever occurred earlier. The primary endpoint was the incidence of grade 2 or 3 hand-foot syndrome adverse events, compared between the two groups using simple logistic regression.

Results: The participants were random assigned to receive topical diclofenac (n = 131) or placebo gel (n = 133). Grade 2 or 3 hand-foot syndrome occurred in 3.8% of participants in the diclofenac group compared with 15.0% in the placebo group (absolute difference, 11.2%; 95% CI, 4.3 to 18.1; P = 0.003). Grade 1-3 hand-foot syndrome was lower in the diclofenac group than in the placebo group (6.1% vs 18.1%; absolute risk difference, 11.9%; 95% CI, 4.1 to 19.6). Capecitabine dose reductions due to hand-foot syndrome were less frequent in the diclofenac group (3.8%) than in the placebo group (13.5%; absolute risk difference, 9.7%; 95% CI, 3.0 to 16.4).

Conclusion Topical diclofenac prevented hand-foot syndrome in patients receiving capecitabine. This trial supports the use of topical diclofenac to prevent capecitabine-associated hand-foot syndrome.

参考文献 Reference

Santhosh A et al. J Clin Onc 2024; Feb 27.

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FDA 批准首个细胞疗法治疗不可切除或转移性黑色素瘤(3/9/2024)

First cellular therapy for unresectable or metastatic melanoma approved by FDA

Amtagvi  (lifileucel)是一种源自肿瘤的自体 T 细胞免疫疗法，由患者自身的 T 细胞组成。患者的部分肿瘤组织被切除, T 细胞从肿瘤组织中分离出来，在体外进一步制造，然后作为单剂量输注回同一患者体内。

Amtagvi的安全性和有效性在一项全球, 多中心, 多队列临床研究中进行了评估，研究对象包括患有不可切除或转移性黑色素瘤的成年患者，这些患者之前接受过至少一种全身治疗，包括 PD-1 阻断抗体，并且如果 BRAF V600 突变, 接受过BRAF 抑制剂或 BRAF 抑制剂与 MEK 抑制剂。 有效性是根据治疗的客观响应率和响应持续时间。   

在按推荐剂量接受Amtagvi治疗的73例患者中，客观响应率为31.5%，其中3例（4.1%）患者完全响应，20例（27.4%）患者部分缓解。 在对治疗有响应的患者中，分别有 56.5%, 47.8% 和 43.5% 在 6, 9 和 12 个月时继续维持响应，没有肿瘤进展或死亡。

治疗相关并发症: 可能会表现出长期严重的低血细胞计数, 严重感染, 心脏病, 或出现呼吸或肾功能恶化或出现致命的。黑框警告包含有关这些风险的信息。 接受本产品的患者在输注前后应密切监测不良反应的体征和症状。 如出现这些症状，应暂停或停止治疗。 与 Amtagvi 相关的最常见不良反应包括寒战、发烧、疲劳、心动过速, 腹泻, 发热性中性粒细胞减少症,水肿, 皮疹, 低血压, 脱发, 感染, 缺氧和呼吸困难 。

Amtagvi (lifileucel) is a tumor-derived autologous T-cell immunotherapy composed of the patient’s own T cells. A portion of the patient’s tumor tissue is removed, and the T cells are isolated from the tumor tissue, further manufactured in vitro, and then infused back to the same patient as a single dose.

The safety and efficacy of Amtagvi were evaluated in a global, multicenter, multi-cohort clinical study in adult patients with unresectable or metastatic melanoma who had received at least one prior systemic therapy , including PD-1 blocking antibodies, and if BRAF V600 mutated, received a BRAF inhibitor or a BRAF inhibitor combined with a MEK inhibitor. Effectiveness was based on objective response rate and duration of response to treatment.

Among the 73 patients who received Amtagvi treatment at the recommended dose, the objective response rate was 31.5%, of which 3 (4.1%) patients had a complete response and 20 (27.4%) patients had a partial response. Among patients who responded to treatment, 56.5%, 47.8%, and 43.5% continued to respond without tumor progression or death at 6, 9, and 12 months, respectively.

Treatment-Related Complications: Patients may manifest long-term severe low blood cell counts, serious infection, heart disease, or worsening or fatal respiratory or kidney function. Black box warnings contain information about these risks. Patients receiving this product should be closely monitored for signs and symptoms of adverse reactions before and after infusion. If these symptoms occur, treatment should be suspended or discontinued. The most common adverse reactions associated with Amtagvi include chills, fever, fatigue, tachycardia, diarrhea, febrile neutropenia, edema, rash, hypotension, alopecia, infection, hypoxia, and dyspnea.

参考文献 Reference

https://www.fda.gov/news-events/press-announcements/fda-approves-first-cellular-therapy-treat-patients-unresectable-or-metastatic-melanoma

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[¹⁷⁷Lu]Lu-DOTA-TATE （177Lu-DOTATATE）放射配体治疗第一线治疗晚期胃肠胰神经内分泌肿瘤 (3/3/2024)

177Lu-DOTATATE for newly-diagnosed advanced gastroenteropancreatic neuroendocrine tumor

方法： 这是一项III期临床试验（NETTER-2, NCT03972488），参加者在入组前的最后 6 个月内新诊断出生长抑素受体阳性,  2 级和 3 级高级晚期胃肠胰神经内分泌肿瘤（Ki-67 ≥10% 且≤55%）。 患者被随机 (2:1) 接受 4 个周期的 177Lu-DOTATATE (4 × 7.4 GBq) 加 30 mg 奥曲肽长效释放，在 177Lu-DOTATATE 治疗期间每 8 周一次，然后每 4 周接受一次 (177Lu- DOTATATE 组），或每 4 周 60 mg 奥曲肽长效释放（对照组），按级别（G2 与 G3）和肿瘤来源（胰腺与其他）分层。 主要终点是无进展生存期。 客观响应率是一个关键的次要终点，在无进展生存期后进行了分层测试。

结果： 总体而言，226 名患者被随机分配至 177Lu-DOTATATE（n = 151）组或对照组（n = 75）。 大多数肿瘤起源于胰腺（54.4%）或小肠（29.2%）； 35.0% 的患者报告有3 级肿瘤。 177Lu-DOTATATE 的中位累积剂量为 29.2 GBq，87.8% 的患者接受了全部 4 剂剂量。 中位无进展生存期（95% 置信区间 [CI]）显著延长约 14.3 个月，从对照组的 8.5 个月（7.7，13.8）延长至 177Lu-DOTATATE 组的 22.8 个月（19.4，不可估计）； 分层风险比 0.276（95% CI：0.182，0.418；p < 0.0001）。 177Lu-DOTATATE 组 (43.0%) 的客观响应率显著高于对照组 (9.3%)； 分层比值比 7.81（95% CI：3.32，18.4；p < 0.0001）。 所有预先指定的人口统计和预后亚组的无进展生存期和客观响应率结果均一致。 在与放射配体治疗相关的特别关注的不良事件中，3/4 级白细胞减少症, 贫血和血小板减少症各发生率≤3 例, 有 1 例骨髓增生异常综合征。  

结论： 在新诊断的晚期2 级和 3 级胃肠胰神经内分泌肿瘤患者中，与高剂量奥曲肽长效释放相比，177Lu-DOTATATE 显著延长无进展生存期，并表现出具有临床意义的客观响应率。 安全性符合 177Lu-DOTATATE 的既定特征。 研究者认为这是第一项证明放射配体治疗作为第一线治疗在任何恶性肿瘤中的功效的随机研究。

Methods: This was a phase III clinical trial (NETTER-2, NCT03972488). Participants had newly diagnosed somatostatin receptor-positive, grade 2 and 3 high-grade advanced gastroenteropancreatic neuroendocrine tumors (Ki-67 ≥10% and ≤55%)  within the last 6 months prior to enrollment. Patients were randomized (2:1) to receive 4 cycles of 177Lu-DOTATATE (4 × 7.4 GBq) plus 30 mg octreotide long-acting release (LAR) every 8 weeks during 177Lu-DOTATATE treatment and then every 4 weeks (177Lu- DOTATATE group), or 60 mg octreotide LAR every 4 weeks (control group), stratified by grade (G2 vs. G3) and tumor origin (pancreatic vs. other). The primary endpoint was progression-free survival. Objective response rate was a key secondary endpoint stratified after progression-free survival.

Results: Overall, 226 patients were randomly assigned to 177Lu-DOTATATE (n = 151) or control (n = 75). Most tumors originated from the pancreas (54.4%) or small intestine (29.2%); grade 3 tumors were reported in 35.0% of patients. The median cumulative dose of 177Lu-DOTATATE was 29.2 GBq, with 87.8% of patients receiving all 4 doses. Median progression-free survival (95% confidence interval [CI]) was significantly prolonged by approximately 14.3 months, from 8.5 months (7.7, 13.8) in the control group to 22.8 months (19.4, not estimable) in the 177Lu-DOTATATE group; stratified hazard ratio 0.276 (95% CI: 0.182, 0.418; p < 0.0001). The objective response rate was significantly higher in the 177Lu-DOTATATE group (43.0%) than in the control group (9.3%); stratified odds ratio 7.81 (95% CI: 3.32, 18.4; p < 0.0001). Progression-free survival and objective response rate results were consistent across all prespecified demographic and prognostic subgroups. Among adverse events of particular concern related to radioligand therapy, grade 3/4 leukopenia, anemia, and thrombocytopenia occurred in ≤ 3 cases each, and myelodysplastic syndrome occurred in 1 case.

Conclusions: 177Lu-DOTATATE significantly prolonged progression-free survival and demonstrated clinically meaningful objective responses compared with high-dose octreotide LAR in patients with newly diagnosed advanced grade 2 and 3 gastroenteropancreatic neuroendocrine tumors. Safety meets the established characteristics of 177Lu-DOTATATE. The researchers believe this is the first randomized study to demonstrate the efficacy of radioligand therapy as first-line therapy in any malignancy.

参考文献 Reference

Singh S et al. 2024 ASCO GI Cancer Sym abstr LBA 588

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阿法替尼相对于化疗对罕见 EGFR 突变非小细胞肺癌 (NSCLC) (3/2/2024)

Afatinib versus chemotherapy for NSCLC with uncommon EGFR mutation

方法: 这是一项开放标签III期临床试验（ACHILLES/TORG1834），在这项研究中，患有致敏的罕见 EGFR 突变 (如 G719X 或 L861Q)，以及复合突变的NSCLC 初治患者以 2:1 的比例随机接受口服阿法替尼（每天 30 或 40 mg）或联合铂类药物（顺铂 75 mg/m2 或卡铂 AUC 5 或 6) 和培美曲塞 (500 mg/m2)，随后每三周进行培美曲塞维持治疗。 主要终点是无进展生存期 。 样本量 (n = 106) 基于 75% 功效，检测无进展生存期风险比为 0.6，α= 0.05，这是在入组完成时预先计划的。

结果: 2019年2月至2023年2月期间共有109名患者入组。中位随访时间为12.5个月。 阿法替尼治疗的中位无进展生存期显著长于化疗（10.6 个月与 5.7 个月；死亡或疾病进展的风险比，0.422；95% 置信区间，0.256–0.694；p = 0.0007）。 数据和安全监测委员会建议提前终止研究。 两组的客观响应率相似：阿法替尼治疗组的客观响应率为 61.4%，化疗组的客观响应率为 47.1% (p = 0.2069)。 两组≥ 3级治疗导致不良事件的发生率分别为43.8%和37.1%。 阿法替尼组最常见的不良事件是腹泻, 皮疹和甲沟炎。 在阿法替尼组中观察到 1 例因肺炎导致的治疗相关死亡。   

结论: 作为罕见或复合 EGFR 突变阳性晚期 NSCLC 的初始治疗，阿法替尼优于铂类双药化疗。研究人者认为，在世界某些地区，认可阿法替尼治疗罕见 EGFR 突变比其他地区更可行(由于一些国家不能使用奥希替尼治疗罕见的 EGFR 突变)。

Methods: This was an open-label phase III clinical trial (ACHILLES/TORG1834). Participants were treatment-naïve NSCLC patients with sensitizing rare EGFR mutations (such as G719X or L861Q) and multiplexed mutations. They were randomized at a 2:1 ratio to receive oral afatinib (30 or 40 mg daily) or platinum combination (cisplatin 75 mg/m2 or carboplatin AUC 5 or 6) and pemetrexed (500 mg/m2), followed by pemetrexed maintenance therapy every three weeks. The primary endpoint is progression-free survival. The sample size (n = 106) was based on 75% power to detect a hazard ratio of 0.6 in progression-free survival with α = 0.05, which was preplanned at the time of completion of enrollment.

Results: A total of 109 patients were enrolled between February 2019 and February 2023. The median follow-up time was 12.5 months. Median progression-free survival was significantly longer with afatinib than with chemotherapy (10.6 months vs. 5.7 months; hazard ratio for death or disease progression, 0.422; 95% confidence interval, 0.256–0.694; p = 0.0007). The data and safety monitoring board recommended early termination of the study. Objective response rates were similar in the two groups: 61.4% in the afatinib group and 47.1% in the chemotherapy group (p = 0.2069). The rates of grade ≥ 3 adverse events resulting from treatment in the two groups were 43.8% and 37.1%, respectively. The most common adverse events in the afatinib group were diarrhea, rash, and paronychia. One treatment-related death due to pneumonia was observed in the afatinib group.

Conclusions: Afatinib is superior to platinum doublet chemotherapy as initial treatment for rare or combined EGFR mutation-positive advanced NSCLC. The researchers believe that approval of afatinib for the treatment of rare EGFR mutations is more feasible in some parts of the world than in others (because osimertinib cannot be used in some countries for the treatment of uncommon EGFR mutations).

参考文献 Reference

Miura S et al. Ann Onc 2023; 34 (suppl_2) : S1310)

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恩替司他, 纳武单抗和伊匹单抗治疗晚期 HER2 阴性乳腺癌 (2/25/2024)

Entinostat, nivolumab and ipilimumab for women with advanced HER2-negative breast cancer

这是一项多中心Ib期临床试验旨在通过使肿瘤微环境敏感来改善对检查点抑制剂的反应，参加的 24 名女性其中 50% (N = 12) 患有激素受体阳性乳腺癌，50% (N = 12) 患有晚期三阴性乳腺癌，接受恩替司他 [组蛋白脱乙酰酶 (HDAC) 抑制剂] + nivolumab + ipilimumab 治疗, 从ETCTN-9844 (NCT02453620) 剂量递增（N = 6) 到扩展队列 (N = 18)。 主要终点是安全性。 次要终点是总体响应率, 临床获益率, 无进展生存期和肿瘤 CD8:FoxP3 比率的变化。

试验没有发现剂量限制性毒性, 没有人需要停止治疗。 在可评估的参与者 (N = 20) 中，总体响应率为 25% (N = 5)，其中三阴性乳腺癌为 40% (N = 4)，激素受体阳性乳腺癌为 10% (N = 1) 。 临床获益率为40%（N = 8），6个月无进展生存率为50%。

探索性分析表明，骨髓细胞的变化可能有助于肿瘤响应； 然而，CD8:FoxP3 比率的变化、PD-L1 状态与肿瘤突变负荷和肿瘤响应之间没有相关性。 这些发现支持在 II 期试验中进一步研究这种治疗方法。

This is a multicenter phase Ib clinical trial designed to improve response to checkpoint inhibitors by sensitizing the tumor microenvironment. The trial enrolled 24 women, 50% (N = 12) of whom had hormone receptor-positive breast cancer. 50% (N = 12) with advanced triple-negative breast cancer. They received entinostat [a histone deacetylase (HDAC) inhibitor] + nivolumab + ipilimumab from the dose escalation (N=6)  and expansion cohort (N=18) of ETCTN-9844 (NCT02453620). The primary endpoint was safety. Secondary endpoints were overall response rate, clinical benefit rate, progression-free survival and changes in tumor CD8:FoxP3 ratio.

There was no dose-limiting toxicities and no one required to discontinue treatment. Among evaluable participants (N = 20), the overall response rate was 25% (N = 5), including 40% in triple-negative breast cancer (N = 4) and 10% in hormone receptor-positive breast cancer (N = 1). The clinical benefit rate was 40% (N = 8), and the 6-month progression-free survival rate was 50%.

Exploratory analyses suggested that changes in myeloid cells may contribute to tumor response; however, there was no correlation between changes in CD8:FoxP3 ratio, PD-L1 status, and tumor mutation load and tumor response. These findings support further investigation of this treatment in phase II trials.

参考文献 Reference

Roussos Torres ET et al. Nature Cancer 2024; 14 Feb 2024

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第一个临床试验评估双特异性抗体治疗接受过抗 PD-(L)1疗法的非小细胞肺癌 (NSCLC) (2/24/2024)

First clinical trial evaluating dual-specific antibody in NSCLC patients who failed anti-PD (L1) therapy

1313MO AZD7789（Sabestomig) 是一种单价, 双特异性, 人源化 IgG1，可阻断 PD-1 和 T 细胞免疫球蛋白和粘蛋白结构域 3 (TIM-3), 调节抗肿瘤 T 细胞活性和骨髓激活的受体。 PD-1 和 TIM-3 的双重阻断可以克服或延迟抗 PD-(L)1 耐药性。

方法: 这是一项首次多中心, 开放标签I/IIa期临床试验的剂量递增结果，该试验针对接受过 ≥1 种既往全身治疗（包括 ≥1 种抗 PD-(L)1  药物）的 IIIB-IV 期 NSCLC 患者进行 AZD7789 单药治疗。剂量组范围为每3星期 2–2000 mg IV。 主要目标是安全性，包括剂量限制毒性。 次要/探索性目标包括功效, 药代动力学,  PD-1 受体占据和免疫原性。 安全性数据截止日期为 2023 年 2 月 13 日，有效性数据截止日期为 2023 年 1 月 11 日。  

结果 总共有39名患者接受了 AZD7789 2–2000 mg； 中位年龄66岁，56%为男性，36% PD-L1 状态 <1%，33% PD-L1 1–49%，28% PD-L1 ≥50%，80%对既往抗 PD-(L)1 药物产生耐药性疗法（≥6 个月的疗程）。 82% 的患者发生治疗中出现的治疗引起的不良反应，23%的患者发生级别 ≥ 3。 最常见的是血肌酐升高（18%）； 没有因为治疗引起的不良反应而导致停药。 41% 的患者发生治疗相关的不良反应； 最常见的是乏力（8%）。 没有剂量限制毒性 或级别 ≥ 3 不良反应。

19 名患者接受了治疗中扫描：7 名患者病情稳定，其中 2 名患者有未确认的部分缓解，11 名患者病情进展，1 名患者无法评估。 8 名患者观察到目标病灶缩小。药代动力学一般与剂量成正比，t_½ ～7天； 抗药物抗体对药代动力学的影响有限。 剂量≥ 225 mg 导致外周 T 细胞持久 PD-1 受体占据 > 90%。 截至 2023 年 2 月 13 日，24位患者还继续接受AZD7789。  

结论: AZD7789 具有可控的安全性，并在可耐受剂量下显示出初步疗效。 正在对未接受过免疫治疗的 NSCLC 患者和对免疫治疗产生获得性耐药的患者进行评估。

1313MO AZD7789 (Sabestomig) is a monovalent, bispecific, humanized IgG1 that blocks PD-1 and T cell immunoglobulin and mucin domain 3 (TIM-3), modulating anti-tumor T cell activity and myeloid-activated receptors. Dual blockade of PD-1 and TIM-3 can overcome or delay anti-PD-(L)1 resistance.

Methods: Reported was dose-escalation results from a first-ever multicenter, open-label phase I/IIa clinical trial in stage IIIB-IV NSCLC patients who had received ≥1 prior systemic therapy, including ≥1 anti-PD-(L)1 agent. Patients were treated with AZD7789 monotherapy. Dosage group range was 2–2000 mg IV every 3 weeks. The primary goal was safety, including dose-limiting toxicities. Secondary/exploratory objectives included efficacy, pharmacokinetics, PD-1 receptor occupancy and immunogenicity. Safety data were due by February 13, 2023, and efficacy data were due by January 11, 2023.

Results: A total of 39 patients received AZD7789 2–2000 mg; median age 66 years, 56% male, 36% PD-L1 status <1%, 33% PD-L1 1–49%, and 28% PD-L1 ≥50%. Eighty percentage developed resistance to previous anti-PD-(L)1 drug therapy (≥ 6 months exposure). Treatment-emergent adverse effects occurred in 82% of patients, grade ≥ 3 in 23%. The most common was an increase in serum creatinine (18%); no treatment-emergent adverse effects led to discontinuation. Treatment-related adverse effects occurred in 41% of patients; the most common was fatigue (8%). There were no dose-limiting toxicities or grade ≥ 3 adverse effects.

On-treatment scans were available for 19 patients: 7 patients had stable disease, 2 of whom had an unconfirmed partial response, 11 patients had progressive disease, and 1 patient was not evaluable. Target lesion shrinkage was observed in 8 patients. Pharmacokinetics were generally dose proportional, t_½ ∼ 7 days; anti-drug antibodies had limited impact on pharmacokinetics. Doses ≥ 225 mg resulted in persistent PD-1 receptor occupancy > 90% on peripheral T cells. As of February 13, 2023, 24 patients remained on AZD7789.

Conclusion: AZD7789 has a manageable safety profile and shows preliminary efficacy at tolerable doses. It is being evaluated in immunotherapy-naïve NSCLC patients and in patients with acquired resistance to immunotherapy.

参考文献 Reference

Besse, B et al. Ann Oncology 2023; 34 (suppl_2): S755

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新辅助免疫检查点阻断治疗腹膜后去分化脂肪肉瘤和四肢/躯干未分化多形性肉瘤 (2/18/2024)

Neoadjuvant immune-checkpoint blockade in retroperitoneal dedifferentiated liposarcoma and extremity/truncal undifferentiated pleomorphic sarcoma

这是一项随机, 非比较II期临床试验（NCT03307616）, 参加者患有可切除的腹膜后去分化脂肪肉瘤 (n = 17) 和四肢/躯干未分化多形性肉瘤（n = 10）。去分化脂肪肉瘤患者接受新辅助纳武单抗或纳武单抗/伊匹单抗, 未分化多形性肉瘤的患者接受新辅助纳武单抗或纳武单抗/伊匹单抗+同时纳武利尤单抗/放射治疗。主要终点是病理响应（玻璃样变变百分比）; 次要终点是免疫浸润, 放射学反应, 12 个月和 24 个月无复发生存率以及总生存率的变化。

结果显示在去分化脂肪肉瘤患者中玻璃样变为 8.8%，在未分化多形性肉瘤中为 89%。治疗前较低密度的调节性 T 细胞与主要病理响应（玻璃样变 > 30%）相关。 新辅助治疗后 B 细胞的肿瘤浸润增加，并且与去分化脂肪肉瘤的总生存率相关。 B 细胞浸润与治疗前较高密度的调节性 T 细胞相关，而免疫检查点阻断治疗后调节性 T 细胞会丢失。

数据表明，新辅助免疫检查点阻断与去分化脂肪肉瘤和未分化多形性肉瘤中肿瘤微环境内复杂的免疫变化相关，并且新辅助免疫检查点阻断治疗联合同步放疗对未分化多形性肉瘤具有显著疗效。  

This was a randomized, noncomparative phase II clinical trial (NCT03307616) in participants with resectable retroperitoneal dedifferentiated liposarcoma (n = 17) and undifferentiated pleomorphic sarcoma of the extremities/trunk (n = 10). Patients with dedifferentiated liposarcoma received neoadjuvant nivolumab or nivolumab/ipilimumab, and patients with undifferentiated pleomorphic sarcoma received neoadjuvant nivolumab or nivolumab/ipilimumab plus concurrent nivolumab/radiation therapy. The primary endpoint was pathologic response (percent hyalinization); secondary endpoints were changes in immune infiltration, radiologic response, 12- and 24-month relapse-free survival, and overall survival.

Results showed hyalinization in 8.8% of patients with dedifferentiated liposarcoma and 89% of patients with undifferentiated pleomorphic sarcoma. Lower densities of regulatory T cells before treatment was associated with a major pathological response (hyalinization >30%). Tumor infiltration of B cells increased after neoadjuvant therapy and is associated with overall survival in dedifferentiated liposarcoma. B cell infiltration was associated with higher densities of regulatory T cells before treatment, whereas regulatory T cells were lost after immune checkpoint blockade therapy.

Data indicate that neoadjuvant immune checkpoint blockade is associated with complex immune changes within the tumor microenvironment in dedifferentiated liposarcoma and undifferentiated pleomorphic sarcoma, and that neoadjuvant immune checkpoint blockade combined with concurrent radiotherapy has significant efficacy in undifferentiated pleomorphic sarcoma.

参考文献 Reference

Roland Cl et al. Nature Cancer 2024; Feb 13

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生物标志物导向的靶向治疗加 durvalumab 医治免疫疗法难治性非小细胞肺癌(2/17/2024)

Biomarker-directed targeted therapy (ceralasertib) plus durvalumab in checkpoint-inhibitor resistant non-small-cell lung cancer

非小细胞肺癌 (NSCLC) 肿瘤患者对免疫检查点封锁的抵抗很常见。 了解耐药机制（包括 DNA 损伤反应和修复途径的缺陷、STK11/LKB1 的改变或功能突变、抗原呈递途径的改变以及肿瘤微环境中的免疫抑制细胞亚群）并开发有效的疗法来克服它们， 仍然是一个未满足的需求。

这是一项II期临床试验 (HUDSON), 评估了含抗 PD-(L)1 的免疫疗法和铂类双药疗法失败后晚期 NSCLC 的合理联合治疗方案。 总共 268 名患者接受了 durvalumab（抗 PD-L1 单克隆抗体）–ceralasertib（ATR 激酶抑制剂）, durvalumab–olaparib（PARP 抑制剂）, durvalumab–danvatirsen（STAT3 反义寡核苷酸）或 durvalumab–oleclumab（抗 CD73 单克隆抗体）。 Durvalumab-ceralasertib 观察到最大的临床获益； 客观响应率（主要结果）为 13.9% (11/79)，相对于其他治疗方案的 2.6% (5/189)，汇总后，中位无进展生存期（次要结果）为 5.8（80% 置信区间 4.6-7.4） 相对于2.7 (1.8–2.8) 个月，中位总生存期（次要结果）为 17.4 (14.1–20.3) 个月相对于 9.4 (7.5–10.6) 个月。 Durvalumab-ceralasertib 的益处在已知的免疫治疗难治性亚组中是一致的。

Durvalumab-ceralasertib 的安全性/耐受性状况是可控的。 生物标志物分析表明，抗 PD-L1/ATR 抑制可诱导免疫变化，从而重振抗肿瘤免疫力。

Resistance to immune checkpoint blockade is common in patients with non-small cell lung cancer (NSCLC) . Understanding resistance mechanisms (including defects in DNA damage response and repair pathways, alterations or functional mutations in STK11/LKB1, alterations in antigen presentation pathways, and immunosuppressive cell subpopulations in the tumor microenvironment) and developing effective therapies to overcome them, remains an unmet need.

This is a phase II clinical trial (HUDSON) evaluating a rational combination regimen for advanced NSCLC after failure to anti-PD-(L)1-containing immunotherapy and platinum doublet therapy. A total of 268 patients received durvalumab (anti-PD-L1 monoclonal antibody)–ceralasertib (ATR kinase inhibitor), durvalumab–olaparib (PARP inhibitor), durvalumab–danvatirsen (STAT3 antisense oligonucleotide), or durvalumab–oleclumab (anti-CD73 monoclonal antibody). The greatest clinical benefit was observed with durvalumab-ceralasertib; objective response rate (primary outcome) was 13.9% (11/79), compared with 2.6% (5/189) for other treatment regimens, and median progression-free survival when pooled (secondary outcome) was 5.8 (80% confidence interval 4.6-7.4) versus 2.7 (1.8–2.8) months, and median overall survival (secondary outcome) was 17.4 (14.1–20.3) months versus 9.4 ( 7.5–10.6) months. The benefit of durvalumab-ceralasertib was consistent across subgroups known to be refractory to immunotherapy. The safety/tolerability profile of durvalumab-ceralasertib is manageable.

Biomarker analysis suggests\ed that anti-PD-L1/ATR inhibition induces immune changes that reinvigorate anti-tumor immunity.

参考文献 Reference

Besse B et al. Nature Med 2024; Feb. 13 2024

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辅助派姆单抗相比于安慰剂治疗透明细胞肾细胞癌:  KEYNOTE-564 研究结果 (2/11/2024)

Adjuvant pembrolizumab versus placebo in clear cell renal cell carcinoma: results from the KEYNOTE-564 study

背景： 随机, 多中心, 双盲, III 期 KEYNOTE-564 研究 (NCT03142334) 表明，对于复发风险增加的透明细胞肾细胞癌参与者，肾切除术后，与安慰剂相比，辅助派姆单抗可改善无病生存。 该文报告了预先指定的中期分析的结果，中位随访时间约为 57 个月。

方法： 患者年龄 ≥18岁，组织学确诊为透明细胞肾细胞癌，伴或不伴肉瘤样特征，复发风险增加，随机分组前 ≤12周进行肾切除术和/或转移瘤切除术，且既往未接受肾细胞癌全身治疗。 患者以 1:1 的比例随机分配，每 3 周静脉注射 200 mg 派姆单抗或安慰剂，持续 ≥17 个周期（约 1 年）或直至疾病复发、无法耐受的毒性或撤回同意。 研究者评估的无病生存是主要终点。 总生存期是一个关键的次要终点。 安全性是次要终点。

结果： 994 名患者按照 1:1 的比例随机分配至派姆单抗 (n =496) 或安慰剂 (n =498)。 从随机化到数据截止日期 2023 年 9 月 15 日的中位时间为 57.2 个月（范围，47.9−74.5）。 与安慰剂相比，派姆单抗在总生存期方面有统计学上的显著改善（未达到中位数，HR 0.62，95% CI 0.44−0.87；P =.0024）。 在派姆单抗组中总共观察到 55 例总生存期事件，在安慰剂组中观察到 86 例总生存期事件。 派姆单抗组 48 个月时的估计总生存率为 91.2%，安慰剂组为 86.0%。 在关键亚组中观察到总生存期获益，包括 M0 疾病患者（HR 0.63，95% CI 0.44−0.90）或 M1 没有疾病证据（HR 0.51，95% CI 0.15−1.75），PD-L1 CPS <1（HR 0.65） ，95% CI 0.31−1.38）或 CPS ≥1（HR 0.62，95% CI 0.42−0.91），并且存在肉瘤样特征（HR 0.69，95% CI 0.28−1.70）或不存在肉瘤样特征（HR 0.57，95% CI 0.39−0.84）。 与安慰剂相比，派姆单抗观察到的无病生存获益与之前的中期分析一致（HR 0.72；95% CI 0.59−0.87）。 没有观察到新的安全信号。    

结论： 经过中位约 57 个月的随访后，对于术后复发风险增加的肾细胞癌患者，辅助派姆单抗与安慰剂相比，显示出具有统计学意义和临床意义的总生存率改善。 KEYNOTE-564 是第一个显示肾细胞癌辅助治疗可改善生存的 III 期研究。 这些结果继续支持辅助派姆单抗作为护理标准。

Background: The randomized, multicenter, double-blind, phase III KEYNOTE-564 study (NCT03142334) demonstrated the disease-free survival benefit of adjuvant pembrolizumab compared with placebo after nephrectomy in patients with clear cell renal cell carcinoma who were at increased risk for recurrence. The article reported results from a prespecified interim analysis with a median follow-up of approximately 57 months.

Methods: Patients aged ≥18 years, with histologically confirmed clear cell renal cell carcinoma, with or without sarcomatoid features, and increased risk of recurrence. They had nephrectomy and/or metastasectomy ≤12 weeks before randomization, and did not receive previous systemic treatment for renal cell carcinoma. Patients were randomly assigned in a 1:1 ratio to receive 200 mg of pembrolizumab or placebo intravenously every 3 weeks for ≥17 cycles (approximately 1 year) or until disease recurrence, intolerable toxicity, or withdrawal of consent. Investigator-assessed disease-free survival was the primary endpoint. Overall survival was a key secondary endpoint. Safety was a secondary endpoint.

Results: 994 patients were randomized 1:1 to pembrolizumab (n =496) or placebo (n =498). The median time from randomization to the data cutoff date of September 15, 2023 was 57.2 months (range, 47.9−74.5). Pembrolizumab resulted in a statistically significant improvement in overall survival compared with placebo (median not reached, HR 0.62, 95% CI 0.44−0.87; P =.0024). A total of 55 overall survival events were observed in the pembrolizumab group and 86 overall survival events were observed in the placebo group. The estimated overall survival rate at 48 months was 91.2% in the pembrolizumab group and 86.0% in the placebo group. An overall survival benefit was observed in key subgroups, including patients with M0 disease (HR 0.63, 95% CI 0.44−0.90) or M1 without evidence of disease (HR 0.51, 95% CI 0.15−1.75), PD-L1 CPS < 1 (HR 0.65, 95% CI 0.31−1.38) or CPS ≥1 (HR 0.62, 95% CI 0.42−0.91) with or without sarcomatoid features (HR 0.69, 95% CI 0.28−1.70) or without sarcomatoid characteristics (HR 0.57, 95% CI 0.39−0.84). The disease-free survival benefit observed with pembrolizumab compared with placebo was consistent with the previous interim analysis (HR 0.72; 95% CI 0.59−0.87). No new safety signals were observed.

Conclusions: After a median follow-up of approximately 57 months, adjuvant pembrolizumab demonstrated a statistically significant and clinically meaningful improvement in overall survival compared with placebo in patients with renal cell carcinoma who were at increased risk for postoperative recurrence. KEYNOTE-564 is the first phase III study to show improved survival with adjuvant therapy in renal cell carcinoma. These results continue to support adjuvant pembrolizumab as the standard of care.

参考文献 Reference

Choueiri TK et al. 2024 ASCO GU cancer symposium abstr 359

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长期随访显示新副助 T-DM1 优于曲妥珠单抗治疗术后残留浸润性HER2+乳腺癌 (2/10/2024)

Long-term follow-up demonstrated benefit of neoadjuvant T-DM1 over trastuzumab in HER2+ breast cancer patients with residual cancer after surgery

这是一项III期前瞻性, 随机临床试验（KATHERINE），入组了 1,486 名 HER2 阳性早期乳腺癌患者，接受了六个周期的化疗和至少 9 周的曲妥珠单抗新辅助治疗。手术后，他们的乳房和淋巴结中残留有浸润性肿瘤。 患者在手术后 12 周内以 1:1 的比例随机分配接受 14 个周期的 T-DM1 (n = 740) 或曲妥珠单抗 (n = 720)。 研究者自行决定是否允许进行放射治疗和内分泌治疗，如果患者在 T-DM1 上出现不良事件，则允许交叉使用曲妥珠单抗。

在 8.4 年的时间点，接受 T-DM1 的 521 名患者（70.1%）和接受曲妥珠单抗的 461 名患者（62.0%）仍然活着。 两个治疗组分组平衡, 大约三分之二的人患有原发性可切除疾病，三分之二的人患有激素受体阳性疾病，80％的人曾接受过曲妥珠单抗治疗，46％的人患有淋巴结阳性疾病，53％的人患有淋巴结阴性疾病（1％未知）。曲妥珠单抗组与 T-DM1 组相比，经历侵袭性无病生存事件的患者分别为 32.2% 和 19.7% (P < .0001)。 曲妥珠单抗和T-DM1的远处复发率分别为21.5%和14.7%，其中中枢神经系统转移率分别为5.1%和7.0%。 局部复发率分别为 6.2% 和 2.2%。 对侧乳腺癌的发现率分别为 2.6% 和 0.9%。 每组中 1.9% 的患者在没有既往事件的情况下死亡。

使用 T-DM1 7 年的绝对总体生存获益为 4.7%，反映出死亡风险降低了 34%。 T-DM1 组中乳腺癌特定死因的发生率为 9.5%，而曲妥珠单抗组中这一比例为 15%。 因不良事件导致的死亡分别为 0.1% 和 0%； 患有激素受体阳性和阴性疾病的患者，以及那些具有可测量的残留疾病阳性和阴性疾病的患者，都在无侵袭性疾病生存方面受益。

没有从 T-DM1 中获益的一个亚组包括发生脑转移的患者：接受 T-DM1 治疗的患者中有 7% 接受治疗，而接受曲妥珠单抗治疗的患者中这一比例为 5.4%。

This is a phase III prospective, randomized clinical trial (KATHERINE) that enrolled 1,486 patients with HER2-positive early breast cancer and received six cycles of chemotherapy and at least 9 weeks of neoadjuvant trastuzumab. After surgery, they had residual invasive tumors in their breasts and lymph nodes. Patients were randomly assigned in a 1:1 ratio to receive 14 cycles of T-DM1 (n = 740) or trastuzumab (n = 720) within 12 weeks of surgery. Radiotherapy and endocrine therapy were allowed at the discretion of the investigators, with crossover to trastuzumab allowed if patients experienced adverse events on T-DM1.

At the 8.4-year time point, 521 patients (70.1%) who received T-DM1 and 461 patients (62.0%) who received trastuzumab were still alive. The two treatment arms were well balanced, with approximately two-thirds having primary resectable disease, two-thirds having hormone receptor-positive disease, and 80% having previously received trastuzumab. Forty-six percentage had node-positive disease and 53% had node-negative disease (1% unknown). A total of 32.2% of patients experienced an invasive disease-free survival event in the trastuzumab group compared with 19.7% in the T-DM1 group (P < .0001). The distant recurrence rates of trastuzumab and T-DM1 were 21.5% and 14.7%, respectively, with central nervous system metastasis rates of 5.1% and 7.0%, respectively. Local recurrence rates were 6.2% and 2.2%, respectively. Contralateral breast cancer was detected in 2.6% and 0.9%, respectively. In each group 1.9% of patients died without prior events.

The absolute overall survival benefit at 7 years with T-DM1 was 4.7%, reflecting a 34% reduction in the risk of death. The incidence of breast cancer-specific death was 9.5% in the T-DM1 group compared with 15% in the trastuzumab group. Deaths due to adverse events were 0.1% and 0%, respectively; patients with hormone receptor-positive and -negative disease, as well as those with measurable residual disease-positive and -negative disease, all benefited in terms of invasive disease-free survival.

One subgroup that did not appear to benefit from T-DM1 included those who developed brain metastases: 7% of patients given T-DM1 compared with 5.4% of those given trastuzumab.

参考文献 Reference

Loibl S et al. 2023 San San Antonio Breast Cancer Symp Abstr GS03-12

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Actinium-225-PSMA 放射配体治疗转移性去势抵抗性前列腺癌（2/4/2024）

Actinium-225-PSMA radioligand treating metastatic castration-resistant prostate cancer

背景: Actinium-225 (225Ac) 前列腺特异性膜抗原 (PSMA) 放射性配体疗法 (RLT) 是一种治疗转移性去势抵抗性前列腺癌的新型疗法。报告目的是 225Ac-PSMA RLT 在世界各地多个中心患者的安全性和抗肿瘤活性。

方法: 这是一项回顾性研究包括在澳大利亚, 印度, 德国和南非的七个中心接受治疗的转移性去势抵抗性前列腺癌患者, 报告汇总了任何年龄和表现状态的连续患者的数据，这些患者接受一个或多个周期的 8 MBq 225Ac-PSMA RLT 静脉注射治疗。 先前的转移性去势抵抗性前列腺癌 治疗包括基于紫杉烷的化疗, 雄激素受体轴抑制剂, 镥 177 (177Lu) PSMA RLT 和镭 223 二氯化物。 主要结局是总生存期和无进展生存期。  

发现: 2016 年 1 月 1 日至 2023 年 5 月 31 日期间，488 名转移性去势抵抗性前列腺癌男性接受了 1,174 个周期的 225Ac-PSMA RLT（中位两个周期，IQR 2-4）。 患者的平均年龄为 68.1 岁 (SD 8.8)，中位基线前列腺特异性抗原为 169.5 ng/mL (IQR 34.6–519.8)。 既往治疗方案包括 324 名 (66%) 患者接受多西他赛治疗，103 名 (21%) 名患者接受卡巴他赛治疗，191 名 (39%) 名患者接受阿比特龙治疗，188 名 (39%) 名患者接受恩杂鲁胺治疗，154 名 (32%) 名患者接受 177Lu-PSMA RLT) 患者，以及 18 名 (4%) 患者使用二氯化镭 223。 中位随访时间为 9.0 个月 (IQR 5.0–17.5)。 中位总生存期为 15.5 个月（95% CI 13.4–18.3），中位无进展生存期为 7.9 个月（6.8–8.9）。

在 488 名患者中，有 347 名 (71%) 获得了有关治疗引起的口干症的信息，347 名患者中有 236 名 (68%) 在 225Ac-PSMA RLT 第一个周期后报告了口干症。 所有接受 7 个以上周期 225Ac-PSMA RLT 的患者均报告有口干症。 488 名患者中有 64 名（13%）出现 3 级或以上贫血，19 名患者（4%）出现白细胞减少，32 名患者（7%）出现血小板减少，22 名患者（5%）出现肾毒性。 没有记录严重不良事件或与治疗相关的死亡。

解释: 225Ac-PSMA RLT 在转移性去势抵抗性前列腺癌中显示出显著的抗肿瘤作用，对于使用先前批准的药物系列治疗的患者来说是一种可行的治疗选择。 口干是一种常见的副作用。 严重的骨髓和肾毒性是不太常见的不良事件。

Background: Actinium-225 (225Ac) prostate-specific membrane antigen (PSMA) radioligand therapy (RLT) is a novel therapy for the treatment of metastatic castration-resistant prostate cancer. The purpose of the report is about the safety and antitumor activity of 225Ac-PSMA RLT in patients at multiple centers around the world.

Methods: This was a retrospective study of patients with metastatic castration-resistant prostate cancer treated at seven centers in Australia, India, Germany and South Africa, reporting pooled data from consecutive patients of any age and performance status. Patients received one or more cycles of 8 MBq 225Ac-PSMA RLT intravenously. Previous treatments for metastatic castration-resistant prostate cancer included taxane-based chemotherapy, androgen-receptor-axis inhibitors, lutetium 177 (177Lu) PSMA RLT, and radium 223 dichloride. The primary outcomes were overall survival and progression-free survival.

Findings: Between January 1, 2016, and May 31, 2023, 488 men with metastatic castration-resistant prostate cancer received 1,174 cycles of 225Ac-PSMA RLT (median two cycles, IQR 2-4) . The mean age was 68.1 years (SD 8.8), and the median baseline prostate-specific antigen was 169.5 ng/mL (IQR 34.6–519.8). Prior treatment regimens included docetaxel in 324 (66%) patients, cabazitaxel in 103 (21%) patients, abiraterone in 191 (39%) patients, enzalutamide in 188 (39%) patients, 177Lu-PSMA RLT in 154 (32%) patients, and radium-223 dichloride in 18 (4%) patients. Median follow-up was 9.0 months (IQR 5.0–17.5). Median overall survival was 15.5 months (95% CI 13.4–18.3) and median progression-free survival was 7.9 months (6.8–8.9).

Information on treatment-induced xerostomia was available for 347 of 488 patients (71%), and 236 of 347 patients (68%) reported xerostomia after the first cycle of 225Ac-PSMA RLT. All patients who received more than 7 cycles of 225Ac-PSMA RLT reported xerostomia. Anemia of grade 3 or higher occurred in 64 of 488 patients (13%), leukopenia in 19 patients (4%), thrombocytopenia in 32 patients (7%), and nephrotoxicity in 22 patients (5%) . No serious adverse events or treatment-related deaths were recorded.

Interpretation: 225Ac-PSMA RLT displays significant antitumor effects in metastatic castration-resistant prostate cancer and is a viable treatment option for patients treated with previously approved lines of drugs. Dry mouth is a common side effect. Serious bone marrow and renal toxicity are less common adverse events.

参考文献 Reference

Sathekge M et al. Lancet Onc 2024; 25:175

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Amivantamab与lazertinib相比于奥希替尼作为 EGFR 突变晚期非小细胞肺癌 (NSCLC) 的一线治疗 (2/3/2024)

Amivantamab plus lazertinib versus osimertinib as first-line therapy for EGFR-mutated NSCLC

Amivantamab (ami) 是一种靶向 EGFR 和间充质上皮转化因子（MET）的全人源双特异性抗体，具有 3 种不同的潜在作用机制，包括配体阻断,受体降解和免疫细胞导向活性，例如抗体依赖性细胞毒性和吞噬作用。Lazertinib 是一种口服第三代不可逆EGFR TKI，具有中枢神经系统渗透性, 靶向 EGFR 单突变（Ex19del、L858R、T790M）和双突变（Ex19del/T790M 和 L858R/T790M）。

方法: 这是一项III期全球随机对照临床试验（MARIPOSA, NCT04487080），未经治疗的 EGFR 突变（Ex19del 或 L858R）局部晚期或转移性 NSCLC 患者按 2:2:1 随机分配至 ami+laz、奥希替尼或 laz。 主要终点是无进展生存期。 次要终点包括总生存期, 客观响应率, 响应持续时间, 首次后续治疗后的无进展生存期和安全性。 患者需要中枢神经系统监测。  

结果: 1,074 名患者被随机分配（ami+laz，429；奥希替尼，429；laz，216）。中位年龄为 63 岁，62% 为女性，59% 为亚洲人，41% 有脑转移病史。 中位随访时间为 22.0 个月，ami+laz 与奥希替尼相比，疾病进展或死亡风险降低 30%（HR，0.70；95% CI，0.58–0.85；P <0.001）， 中位无进展生存期分别为 23.7 个月（95% CI，19.1–27.7）相比于 16.6 个月（95% CI，14.8–18.5）。 ami+laz 的客观响应率为 86% (95% CI, 83–89)，奥希替尼为 85% (95% CI, 81–88)，客观响应者的中位响应持续时间为 25.8 个月 (95% CI, 20.1–未达到) 相比于 16.8 个月 (95% CI，14.8–18.5)。 与奥希替尼相比, 首次后续治疗后的无进展生存期数据倾向于  ami+laz（HR，0.75；95% CI，0.58–0.98）。 在中期分析总生存期时，ami+laz 比奥希替尼有有利的趋势（HR，0.80；95% CI，0.61 至 1.05；P =0.1）。 Ami+laz 的相关副作用较高，但奥希替尼的腹泻副作用较高。 Ami+laz 的静脉血栓栓塞增加，大多为 1-2 级，发生较早，并可通过抗凝药物有效控制。间质性肺病发生率较低且各组间相似。   

结论 Ami+laz 在统计学上优于奥希替尼，具有临床意义的无进展生存期改善，具有更高客观响应持续时间和有利的总生存期趋势。 Ami+laz 的安全性与之前的报告一致。 MARIPOSA 将 ami+laz 确立为 EGFR 突变晚期 NSCLC 的新一线护理标准。

Amivantamab (ami) is a fully human bispecific antibody targeting EGFR and mesenchymal epithelial transition factor (MET), with 3 different potential mechanisms of action, including ligand blocking, receptor degradation and immune cell-directed activities such as antibody-dependent cytotoxicity and phagocytosis. Lazertinib is an oral third-generation irreversible EGFR TKI that can penetrate central nervous system and targets EGFR single mutations (Ex19del, L858R, T790M) and double mutations (Ex19del/T790M and L858R/T790M).

Methods: This is a phase III global randomized controlled clinical trial (MARIPOSA, NCT04487080) in which patients with untreated EGFR-mutated (Ex19del or L858R) locally advanced or metastatic NSCLC were randomized 2:2:1 to ami+laz, osimertinib or laz. The primary endpoint was progression-free survival. Secondary endpoints included overall survival, objective response rate, duration of response, progression-free survival after first subsequent treatment and safety. Patients required central nervous system monitoring.

Results: 1,074 patients were randomized (ami+laz, 429; osimertinib, 429; laz, 216). The median age was 63 years, 62% were female, 59% were Asian, and 41% had a history of brain metastases. With a median follow-up of 22.0 months, ami+laz reduced the risk of disease progression or death by 30% compared with osimertinib (HR, 0.70; 95% CI, 0.58–0.85; P <0.001), with a median PFS of 23.7 months (95% CI, 19.1–27.7) versus 16.6 months (95% CI, 14.8–18.5). Objective response rates were 86% (95% CI, 83–89) with ami+laz and 85% (95% CI, 81–88) with osimertinib, and the median duration of response among objective responders was 25.8 months (95% CI, 20.1–not reached) versus 16.8 months (95% CI, 14.8–18.5). PFS data after first subsequent treatment favored ami+laz compared with osimertinib (HR, 0.75; 95% CI, 0.58–0.98). At the interim analysis of overall survival, there was a trend favoring ami+laz over osimertinib (HR, 0.80; 95% CI, 0.61 to 1.05; P =0.1). Ami+laz was associated with higher side effects, except osimertinib was associated with a higher rate of diarrhea. Venous thromboembolism was increased with Ami+laz, mostly grade 1-2, and occurred earlier, and was effectively controlled with anticoagulants. The incidence of interstitial lung disease was low and similar across arms.

Conclusions Ami+laz was statistically superior to osimertinib, with a clinically meaningful improvement in progression-free survival, higher objective duration of response, and a favorable overall survival trend. The safety profile of Ami+laz was consistent with previous reports. MARIPOSA establishes ami+laz as the new first-line standard of care for EGFR-mutated advanced NSCLC.

参考文献 Reference

Cho BC et al. Ann Onc 2023; 34:(suppl_2): S1302

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达雷妥尤单抗, 硼替佐米, 来那度胺和地塞米松治疗多发性骨髓瘤 (1/28/2024)

Daratumumab plus bortezomib, lenalidomide, and dexamethasone for multiple myeloma

方法: 在这项III期试验(PERSEUS, NCT03710603)中，709名符合移植条件的新诊断多发性骨髓瘤患者接受皮下注射daratumumab(达雷妥尤单抗, 靶向CD38 的单克隆抗体)联合硼替佐米, 来那度胺和地塞米松 (VRd) 诱导和巩固治疗以及来那度胺维持治疗（D-VRd组）或VRd诱导和巩固治疗加来那度胺 单独维持治疗（VRd 组）。 主要终点是无进展生存期。 关键的次要终点是完全响应或更好以及微小残留病阴性状态(MRD)。

结果: D-VRd 组和 VRd 组中位随访48 个月时无进展生存的患者估计百分比为 84.3%，VRd 组为 67.7%（疾病进展或死亡的风险比，0.42；95% 置信区间，0.30 至 0.59；P <0.001); P 值越过了预先指定的停止边界 (P =0.0126)。 D-VRd 组中完全缓解或更好的患者比例高于 VRd 组（87.9% 相对于 70.1%，P  <0.001），MRD 阴性状态的患者比例也高于 VRd 组（75.2% 相对于 47.5%，P <0.001）。 D-VRd 组有 34 名患者死亡，VRd 组有 44 名患者死亡。 两组中大多数患者均发生了 3 级或 4 级不良事件； 最常见的是中性粒细胞减少症（D-VRd 组为 62.1%，VRd 组为 51.0%）和血小板减少症（分别为 29.1% 和 17.3%）。 D-VRd 组和 VRd 组分别有 57.0% 和 49.3% 的患者出现严重不良事件。

结论: 在 VRd 诱导和巩固治疗以及来那度胺维持治疗中添加皮下达雷妥尤单抗对于新诊断的多发性骨髓瘤并符合移植资格的患者的无进展生存期具有显著的益处。

Methods: In this phase III trial (PERSEUS, NCT03710603), 709 transplant-eligible patients with newly diagnosed multiple myeloma received subcutaneous injections of daratumumab (a monoclonal antibody that targets CD38) plus bortezomib, lenalidomide, and dexamethasone (VRd) induction and consolidation therapy and lenalidomide maintenance therapy (D-VRd group) or VRd induction and consolidation therapy plus lenalidomide maintenance therapy alone (VRd group). The primary endpoint was progression-free survival. Key secondary endpoints were a complete response or better and minimal residual disease (MRD) negative status.

Results: The estimated percentage of patients alive without progression at a median follow-up of 48 months was 84.3% in the D-VRd group and 67.7% in the VRd group (hazard ratio for disease progression or death, 0.42; 95% confidence interval, 0.30 to 0.59; P <0.001); the P value crossed the prespecified stopping boundary (P =0.0126). The proportion of patients with complete response or better in the D-VRd group was higher than that in the VRd group (87.9% vs. 70.1%, P <0.001), and the proportion of patients with MRD-negative status was also higher than that in the VRd group (75.2% vs. 47.5%, P <0.001). Thirty-four patients died in the D-VRd group and 44 patients died in the VRd group. Most patients in both groups experienced grade 3 or 4 adverse events; the most common were neutropenia (62.1% in the D-VRd group and 51.0% in the VRd group) and thrombocytopenia (29.1% and 17.3% respectively). Serious adverse events occurred in 57.0% of patients in the D-VRd group and 49.3% in the VRd group.

Conclusions: The addition of subcutaneous daratumumab to VRd induction and consolidation therapy and lenalidomide maintenance therapy has a significant benefit in progression-free survival among transplant-eligible patients with newly diagnosed multiple myeloma.

参考文献 Reference

Sonnevel P et al. N Engl J Med 2024; 390:301

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FLOT 联合或不联合杜瓦鲁单抗用于胃和胃食管交界癌的病理完全缓解 (1/27/2024)

Impact of FLOT +/- durvalumab on pCR rate in gastric/gastroesophageal junctional (GC/GEJ) cancer

背景：在III 期, 随机,  双盲全球 MATTERHORN 研究 (NCT04592913) 第一次中期分析中显示，在胃和胃食管交界癌中，围手术期杜瓦鲁单抗+ 5-氟尿嘧啶, 亚叶酸, 奥沙利铂和多西紫杉醇 (FLOT) 与安慰剂+ FLOT 相比，病理完全响应(pCR)具有统计显著性改善。  

方法： 可切除胃和胃食管交界癌患者按 1:1 随机分配至每4 周的第 1 天接受杜瓦鲁单抗1500 mg 或安慰剂，每2 周的第 1 天和第 15 天接受 FLOT，共 4 个周期（术前和术后2 剂杜瓦鲁单抗 或 安慰剂 4 周期FLOT），然后在每4 周的第 1 天接受杜瓦鲁单抗 1500 mg 或安慰剂，共进行 10 个周期。 随机分组按亚洲与非亚洲进行分层。

结果： 在全球随机分配的 948 名患者中，180 名患者 (19%) 来自亚洲。 全球杜瓦鲁单抗+ FLOT的pCR为19% [91/474;  95% CI (15.7–23.0)],  相比于安慰剂+ FLOT的7% [34/474; 95% CI (5.0–9.9)] 。亚洲 FLOT 的 pCR 结果[19%, 17/90, 95% CI (11.4–28.5)]与全球结果一致。 尽管基线特征存在一些不平衡，并且不同地理位置的 pCR 率存在数值差异，但在所有地区（亚洲、欧洲、北美和南美），杜瓦鲁单抗 + FLOT 与安慰剂+ FLOT 相比，pCR 率均有所提高。在完全和接近完全响应率方面，各区域亚组之间观察到了类似的趋势。

结论： 在 MATTERHORN临床试验 中，在各个地理区域的胃和胃食管交界癌围手术期 FLOT 中添加杜瓦鲁单抗 后，pCR 得到改善。 该研究正在进行中，其主要目标是无事件生存。

Background: In the first interim analysis of the phase III, randomized, double-blind global MATTERHORN study (NCT04592913), perioperative durvalumab + 5-fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) in GC/GEJ cancer showed a statistically significant improvement in pathological complete response (pCR) compared with placebo + FLOT.

Methods: Patients with resectable GC/GEJ cancer were randomly assigned 1:1 to receive durvalumab 1500 mg or placebo on day 1 of every 4 weeks and FLOT on days 1 and 15 of every 2 weeks for 4 cycles (2 doses of durvalumab or placebo and 4 doses of FLOT pre- and post-operative), followed by durvalumab 1500 mg or placebo on day 1 of every 4 weeks for 10 further cycles. Randomization was stratified by Asian versus non-Asian.

Results: Of 948 patients randomized globally, 180 patients (19%) were from Asia. Global pCR for durvalumab + FLOT was 19% [91/474; 95% CI (15.7–23.0)], compared with 7% for placebo + FLOT [34/474; 95% CI (5.0–9.9) )]. The pCR results for FLOT in Asia [19%, 17/90, 95% CI (11.4–28.5)] were consistent with global results. Despite some imbalances in baseline characteristics and numerical differences in pCR rates by geographic location, durvalumab + FLOT had better pCR rates compared with placebo + FLOT in all regions (Asia, Europe, North and South America). Similar trends were observed among regional subgroups in terms of complete and near-complete response rates.

Conclusions: In the MATTERHORN clinical trial, pCR improved with the addition of durvalumab to perioperative FLOT in GC/GEJ cancer across geographic regions. The study is ongoing and its primary goal is event-free survival.

参考文献 Reference

Janjigian YY et al. ASCO GI Cancer Symp 2024; abstr LBA246

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具有分子残留疾病的结直肠癌患者的循环肿瘤 DNA (ctDNA) 动态变化与预后 (1/21/2024)

Correlation of dynamic changes of ctDNA with outcome in colorectal cancer patients with molecular residual disease

背景： 对前瞻性观察性 GALAXY 研究 (UMIN000039205) 数据的分析报告称，无论 BRAF V600E 状态如何，手术后分子残留病 (MRD) 的检测都是患者的预后和复发的最重要风险因素。 在本文中，提出了 GALAXY 研究中 ctDNA 动态与根治性切除的 II-IV 期结直肠癌患者结果的最新分析和相关性。

方法： 采用个性化肿瘤信息检测（Signatera，Natera，Inc.）对手术后 1, 3, 6, 9, 12,18 和 24 个月直至复发期间收集的连续血浆样本中的 ctDNA 进行检测和定量。 每 6 个月进行一次胸部/腹部/骨盆 CT 扫描。 治愈性手术后，患者接受辅助化疗（N = 1,000）或观察（N = 1,518）。 主要终点是无病生存期，定义为手术日期与检测到任何原因导致的复发/死亡日期之间的时间。  

结果： 在 2020 年 5 月至 2022 年 11 月期间入组 GALAXY 研究的 3,034 名结直肠癌患者中，2,518 名患者符合纳入标准并在本次研究中进行了分析。 中位随访时间为 16.3 个月（范围 0.1-37 个月）。 在术后 MRD 窗口期间，有 2,093 名患者获得了 ctDNA 结果，其中 309 名患者 (14.8%) 为 ctDNA+，1,784 名患者 (85.2%) 为 ctDNA阴性。 与 MRD阴性患者相比，在 MRD 窗口期间为 ctDNA+ 的患者 (MRD+) 的无病生存期显著较差。 在 MRD+ 组中，从 MRD 检测到 3 个月时间点的 ctDNA 动态分析显示，与 ctDNA 清除的患者相比，保持 ctDNA+ 的患者复发的可能性高出 5 倍以上（HR: 5.4，95%CI: 3.58-7.67%，p < 0.0001）。

在整个研究人群的 445 名 ctDNA 阳性患者中，240 名患者接受了辅助化疗，其中 66.3% 的 ctDNA 清除。 对于术后 ctDNA 呈阳性且化疗后 ctDNA 转为阴性的患者，58% 的患者持续清除，而最终恢复 ctDNA 阳性状态的患者只有 42%。 持续 ctDNA 清除的患者比暂时实现 ctDNA 清除的患者(ctDNA 阴性转为 ctDNA 阳性)具有更好的无病生存率（24 个月无病生存率 = 90.1% vs 2.3%）。

结论:基于 ctDNA 的 MRD 检测以及辅助化疗响应的 ctDNA 动态可高度预测患者的预后。 CIRCULATE-Japan 正在进行的随机 VEGA 和 ALTAIR 研究将确定 ctDNA 引导辅助治疗的临床效用。

Background: Analysis of data from the prospective observational GALAXY study (UMIN000039205) sowed that detection of molecular residual disease (MRD) after surgery is the most important risk factor for patient prognosis and recurrence, regardless of BRAF V600E status. In this article, an updated analysis and correlation of ctDNA dynamics with outcomes in patients with curatively resected stage II-IV colorectal cancer in the GALAXY study was presented.

Methods: ctDNA was detected and quantified using a personalized tumor informatics assay (Signatera, Natera, Inc.) in serial plasma samples collected at 1, 3, 6, 9, 12,18, and 24 months postoperatively until recurrence. CT scan of chest/abdomen/pelvis was performed every 6 months. After curative surgery, patients received adjuvant chemotherapy (N = 1,000) or observation (N = 1,518). The primary endpoint was disease-free survival, defined as the time between the date of surgery and the date of detection of recurrence/death from any cause.

Results: Of 3,034 colorectal cancer patients enrolled in the GALAXY study between May 2020 and November 2022, 2,518 patients met inclusion criteria and were analyzed in this study. Median follow-up was 16.3 months (range 0.1-37 months). During the postoperative MRD window, ctDNA results were obtained for 2,093 patients, with 309 patients (14.8%) being ctDNA+ and 1,784 patients (85.2%) being ctDNA negative. Patients who were ctDNA+ during the MRD window (MRD+) had significantly worse disease-free survival compared with MRD-negative patients. In the MRD+ group, analysis of ctDNA dynamics from MRD detection to the 3-month time point showed that patients who remained ctDNA+ were greater than 5 times more likely to relapse compared with patients who cleared ctDNA (HR: 5.4, 95% CI: 3.58-7.67%, p < 0.0001). Of the 445 ctDNA-positive patients in the entire study population, 240 patients received adjuvant chemotherapy, with 66.3% having ctDNA clearance. For patients who were ctDNA positive postoperatively and became ctDNA negative after chemotherapy, 58% continued to clear, whereas only 42% of patients ultimately returned to ctDNA-positive status. Patients with sustained ctDNA clearance had better disease-free survival than patients with temporary ctDNA clearance (ctDNA negative to ctDNA positive) (24-month disease-free survival = 90.1% vs 2.3%).

Conclusion: ctDNA-based MRD detection and ctDNA dynamics in response to adjuvant chemotherapy are highly predictive of patient prognosis. The ongoing randomized VEGA and ALTAIR studies of CIRCULATE-Japan will determine the clinical utility of ctDNA-guided adjuvant therapy.    

参考文献 Reference

Yukami H et al. 2024 ASCO Gastrointestinal Cancers Symposium abstr 6

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Histotripsy系统用于治疗肝脏肿瘤 (1/20/2024)

Histotripsy system used to treat liver tumors

Edison 的 Histotripsy 系统使用聚焦超声的非热机械过程对肝脏肿瘤（包括不可切除的肝脏肿瘤）进行非侵入性破坏, 在亚细胞水平上机械破坏和液化肝组织/肿瘤。该系统提供精确且可控的个性化, 可以使治疗部位快速恢复和吸收的能力。

在美国和欧洲 13 个试验中心进行的 #HOPE4LIVER 试验（NCT04573881）, 汇总的数据用于评估Histotripsy摧毁原发性和继发性肝脏肿瘤的临床安全性和有效性, 包括评估了 44 名患者的安全性， 和44 个治疗肿瘤的疗效。试验实现了主要安全性和有效性终点。接受治疗的患者具有异质性，其中 18 名患者患有肝细胞癌，26 名患者患有从结肠、直肠、乳腺和其他原发部位转移到肝脏的肿瘤, 技术成功率达到 95.5%。 Histotripsy后 30 天，在所有 44 名接受治疗的患者中观察到 3 起与手术相关的 ≥ 3 级不良事件（并发症发生率为 6.8%）每个事件通常与肝脏局部治疗相关，而不是Histotripsy所特有的。

Edison 系统和Histotripsy治疗平台获得FDA批准的营销授权， 成为美国第一个使用的Histotripsy平台。

Edison’s Histotripsy system uses the non-thermal mechanical process of focused ultrasound to non-invasively destroy liver tumors, including unresectable liver tumors, to mechanically disrupt and liquefy liver tissue/tumors at the subcellular level. The system provides precise and controlled personalization, allowing for rapid recovery and absorption of the treated area.

Pooled data from the #HOPE4LIVER trial (NCT04573881) conducted at 13 sites in the U.S. and Europe to evaluate the clinical safety and efficacy of Histotripsy in destroying primary and secondary liver tumors. The trial evaluated safety in 44 patients, and the efficacy in 44 tumors. The trial met its primary safety and efficacy endpoints. The patients treated were heterogeneous, with 18 patients having hepatocellular carcinoma and 26 patients having liver metastases tumors from the colon, rectum, breast and other primary sites. The trial achieved a technical success rate of 95.5%. Thirty days after Histotripsy, 3 procedure-related grade ≥ 3 adverse events were observed in all 44 treated patients (complication rate 6.8%). Each event was commonly associated with focal liver therapies and was not specific for Histotripsy.

The Edison system and Histotripsy treatment platform received FDA approval for marketing authorization. It is the first Histotripsy platform to be used in the United States.

参考文献 Reference

https://histosonics.com/news/fda-awards-histosonics-clearance-of-its-first-of-a-kind-edison-histotripsy-system-2/

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立体定向放疗加或不加选择性歧化酶模拟物治疗胰腺癌 (1/14/2024)

Stereotactic body radiotherapy (SBRT) with or without selective dismutase mimetic in pancreatic adenocarcinoma

SBRT具有消融局部胰腺导管腺癌的潜力。选择性歧化酶模拟物使肿瘤敏感，同时降低正常组织毒性。该试验旨在确定avasopasem 与 SBRT 联合治疗局限性胰腺导管腺癌时的疗效和毒性。

方法: 这是一项适应性, 随机, 双盲, 安慰剂对照, Ib/II 期临床试验(NCT03340974)，参加者为 18 岁或以上的边缘性可切除或局部晚期胰腺癌患者接受了至少 3 个月的化疗。 符合条件的患者被随机分配 (1:1)，在SBRT（50、55 或 60 Gy，分五次，根据 90 天安全性和有效性的贝叶斯估计实时自适应分配）之前（即 180 分钟内）接受每日 avasopasem（90 毫克）或安慰剂静脉注射 )患者和医生知道 SBRT 剂量, 但不知道治疗组分配情况。 主要目标是通过晚发 EffTox 方法确定 SBRT 联合 avasopasem 或安慰剂的最佳剂量。 所有分析都是在意向治疗的基础上进行的。  

结果: 2018年1月25日至2020年4月29日期间，筛选了47名患者，其中42名入组（中位年龄为71岁，23名[55%]为男性，19名为女性 ），随机分配至 avasopasem (n =24) 或安慰剂 (n =18)； 安慰剂组因未能达到预先设定的疗效参数而被提前终止。 在数据截止时（2021 年 6 月 28 日），avasopasem 组满足疗效和毒性的界限。 在 avasopasem 组中，18 名接受50 Gy 剂量患者中的 16 名患者 (89%) 观察到晚发 EffTox 疗效反应，6 名接受50 Gy 剂量中的6 名 (100%)观察到晚发 EffTox 疗效反应，在安慰剂组中, 6 名接受50 Gy 剂量患者中的 3 名患者 (50%) 观察到晚发 EffTox 疗效反应, 12名接受55 Gy 剂量患者中的 9 名 (75%)观察到晚发 EffTox 疗效反应，贝叶斯模型建议分 5 次接受 50 Gy 或 55 Gy 加avasopasem进行进一步研究。

安慰剂组 18 名患者中有 3 名 (17%) 报告了任何原因的严重不良事件，avasopasem 组 24 名患者中有 6 名 (25%) 报告了任何原因的严重不良事件。 在安慰剂组中，SBRT 90 天内的 3 级不良事件为腹痛. 急性胆管炎, 发热. 血乳酸升高和脂肪酶升高（各 1 例 [6%]）； 没有发生 4 级事件。 在avasopasem组中，SBRT 90天内的3-4级不良事件包括急性肾损伤, 血液碱性磷酸酶升高, 血肿, 结肠炎, 胃梗阻, 肺部感染, 腹部脓肿, 术后心房颤动和导致呼吸系统疾病的肺炎。 失败（各 1 例 [4%]）。没有与治疗相关的死亡，但 avasopasem 组中的 1 例晚期死亡据报道可能与 SBRT 相关，该死亡是在研究外治疗后十二指肠梗阻的情况下因脓毒症所致。

解释: 对于局限性胰腺导管腺癌患者，SBRT可考虑分五次使用 50 或 55 Gy 。 添加 avasopasem 可能会进一步改善疾病结果。 一项更大规模的 2 期试验（GRECO-2，NCT04698915）正在进行中以验证这些结果。

SBRT has the potential to ablate localized pancreatic ductal adenocarcinoma. Selective dismutase mimetics sensitize tumors while reducing normal tissue toxicity. The trial was designed to determine the efficacy and toxicity of avasopasem in combination with SBRT in localized pancreatic ductal adenocarcinoma.

Methods: This was an adaptive, randomized, double-blind, placebo-controlled, phase Ib/II clinical trial (NCT03340974) in patients 18 years or older with borderline resectable or locally advanced pancreatic cancer who had received at least 3 months of chemotherapy. Eligible patients were randomized (1:1) to receive daily avasopasem (90 mg) or placebo intravenously directly before (ie, within 180 min) . SBRT (50, 55, or 60 Gy in five fractions, adaptively assigned in real time by Bayesian estimates of 90-day safety and efficacy). Patients and physicians were masked to treatment group allocation, but not to SBRT dose.  The primary objective was to determine the optimal dose of SBRT combined with avasopasem or placebo using the late-onset EffTox approach. All analyses were performed on an intention-to-treat basis.

Results: Between January 25, 2018, and April 29, 2020, 47 patients were screened, of whom 42 were enrolled (median age 71 years, 23 [55%] male, 19 [45% ] were women) and randomly assigned to avasopasem (n =24) or placebo (n =18); the placebo group was terminated early due to failure to meet prespecified efficacy parameters. At the time of data cutoff (June 28, 2021), the avasopasem arm met efficacy and toxicity boundaries. In the avasopasem arm, late-onset EffTox efficacy response was observed in 16 of 18 patients (89%) at 50 Gy and in 6 of 6 (100%) at 55 Gy. In the placebo group, late EffTox efficacy response was observed in 3 of 6 patients (50%) at 50 Gy, and nine of 12 patients (75%) at 55 Gy.  Bayesian model recommended further study using avasopasem in 5 fractions to receive 50 Gy or 55 Gy.

Serious adverse events of any cause were reported in 3 of 18 patients (17%) in the placebo group and 6 of 24 patients (25%) in the avasopasem group. In the placebo group, grade 3 adverse events within 90 days of SBRT were abdominal pain, acute cholangitis, pyrexia, increased blood lactate, and increased lipase (1 patient [6%] each); no grade 4 events occurred. In the avasopasem arm, grade 3-4 adverse events within 90 days of SBRT included acute kidney injury, elevated blood alkaline phosphatase, hematoma, colitis, gastric obstruction, pulmonary infection, abdominal abscess, postoperative atrial fibrillation, and pneumonia leading respiratory (one [4%] each). There were no treatment-related deaths, but 1 late death in the avasopasem group was reported to be possibly related to SBRT and was due to sepsis in the setting of duodenal obstruction after off-study treatment.

Interpretation: For patients with localized pancreatic ductal adenocarcinoma, SBRT using 50 or 55 Gy in five fractions may be considered. The addition of avasopasem may further improve disease outcomes. A larger phase 2 trial (GRECO-2, NCT04698915) is ongoing to validate these results.

参考文献 Reference

Taniguchi Cm et al. lancet Onc 2023:24:1387

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Tarlatamab 用于既往治疗过的小细胞肺癌 (1/13/2023)

Tarlatamab therapy in previously treated small cell lung cancer

方法: Tarlatamab 是一种针对 delta样配体 3 和 CD3 的双特异性 T 细胞接合剂免疫疗法。在一项 II 期试验中（NCT05060016），研究者评估了 tarlatamab 对既往接受过治疗的小细胞肺癌患者的抗肿瘤活性和安全性，该药物每 2 周静脉注射一次，剂量为 10 mg 或 100 mg。 主要终点是客观响应（完全或部分响应），通过盲法独立中央审查进行评估。  

结果: 总体而言，220 名患者接受了 tarlatamab 治疗； 患者之前曾接受过两种治疗方案。 在评估抗肿瘤活性和生存率的患者中，10 mg 组的中位随访时间为 10.6 个月，100 mg 组的中位随访时间为 10.3 个月。 10 mg 组中 40%（97.5% CI，29 至 52）的患者出现客观响应，100 mg 组中 32%（97.5% CI，21 至 44）的患者出现客观响应。 在获得客观响应的患者中，59% 的患者响应持续时间至少为 6 个月（68 名患者中的 40 名）。 截至数据截止时，10 mg 组 40 名患者中有 22 名 (55%) 持续出现客观响应，100 mg 组 28 名患者中有 16 名 (57%) 持续出现客观响应。 10 mg 组的中位无进展生存期为 4.9 个月（95% CI，2.9 至 6.7），100 mg 组的中位无进展生存期为 3.9 个月（95% CI，2.6 至 4.4）； 患者 9 个月时的总生存率估计分别为 68% 和 66%。

最常见的不良事件是细胞因子释放综合征（10 mg 组中 51% 的患者和 100 mg 组中 61% 的患者）、食欲下降（分别为 29% 和 44%）、和发热（分别为 35% 和 33%）。 细胞因子释放综合征主要发生在第 1 周期治疗期间，大多数患者的事件严重程度为 1 级或 2 级。 10 mg 组（1% 的患者）发生 3 级细胞因子释放综合征的频率低于 100 mg 组（6%）。 少数患者 (3%) 由于治疗相关的不良事件而停用 tarlatamab。

结论: 每 2 周服用 10 毫克tarlatamab，显示出抗肿瘤活性，具有持久的客观反应，并且对既往接受过治疗的小细胞肺癌患者具有良好的生存结果。 没有发现新的安全信号。

Methods: Tarlatamab is a bispecific T-cell engager immunotherapy targeting delta-like ligand 3 and CD3. In a phase II trial (NCT05060016), investigators evaluated the antitumor activity and safety of tarlatamab at 10 mg or 100 mg intravenously every 2 weeks in patients with previously treated small cell lung cancer. The primary endpoint was objective response (complete or partial response), assessed by blinded independent central review.

Results: Overall, 220 patients received tarlatamab. They had previously received a median of two lines of treatment. Among patients evaluated for antitumor activity and survival, the median follow-up was 10.6 months in the 10 mg group and 10.3 months in the 100 mg group. Objective responses occurred in 40% (97.5% CI, 29 to 52) of patients in the 10 mg group and in 32% (97.5% CI, 21 to 44) of patients in the 100 mg group. Among patients who achieved an objective response, 59% had a response duration of at least 6 months (40 of 68 patients). At the time of data cutoff, an objective response was ongoing in 22 of 40 patients (55%) in the 10 mg group and in 16 of 28 patients (57%) in the 100 mg group. The median progression-free survival was 4.9 months (95% CI, 2.9 to 6.7) in the 10 mg group and 3.9 months (95% CI, 2.6 to 4.4) in the 100 mg group; the overall survival at 6 months was estimated to be 68% and 66% of patients, respectively.

The most common adverse events were cytokine release syndrome (51% of patients in the 10 mg group and 61% of patients in the 100 mg group), decreased appetite (29% and 44%, respectively), and pyrexia (35% and 33%). Cytokine release syndrome occurred primarily during cycle 1 of treatment, with most patients having events of grade 1 or 2 severity. Grade 3 cytokine release syndrome occurred less frequently in the 10 mg group (1% of patients) than in the 100 mg group (6%). A small percentage of patients (3%) discontinued tarlatamab due to treatment-related adverse events.

Conclusions: Tarlatamab, 10 mg every 2 weeks, demonstrated antitumor activity with durable objective responses and favorable survival outcomes in patients with previously treated SCLC. No new safety signals were discovered.

参考文献 Reference

Ahn M-J et al. N Engl J Med 2023; 389:2063

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https://www.prnewswire.com/news-releases/fda-grants-priority-review-to-amgens-tarlatamab-application-for-advanced-small-cell-lung-cancer-302014639.html

MonarchE 试验中探索检测 ctDNA 的试点研究结果 (1/7/2024)

Exploring ctDNA detection using a tumor-informed assay in the monarchE trial

背景: monarchE试验已显示, 在HR+, HER2-,  淋巴结阳性, 高风险早期乳腺癌患者中,两年的辅助 abemaciclib + 内分泌治疗显著改善了无侵袭性疾病生存期 (IDFS) 和无远处复发生存率 (DRFS) 。 Abemaciclib 的益处持续并在 4 年时程度加深。 这项研究使用经过临床验证的 SignateraTM ctDNA 检测,  调查MonarchE 的部分患者ctDNA 检测的技术可行性, 持续率和清除率。

方法: 对选定的患者子集进行样本分析（n=178；84 名来自 abemaciclib + 内分泌治疗 组；94 名来自内分泌治疗组）。样本采集在开始方案治疗前,访视 1（V1,  随机化 + ≤ 3 天）和 2 年治疗即将完成，第 27 次访视（V27；24个月 +/- 5 天）。对选定患者的原发性肿瘤进行全外显子组测序 。选定的样本包括来自具有一系列肿瘤突变负担的患者的样本。从 356 个血浆样本中提取了游离 DNA。 根据每个基线肿瘤样本中检测到的多达 16 个变异, 对于每个患者开发了 Signatera ctDNA 检测方法。

结果: 所选子集 (n=178) 的 IDFS 事件率为 39.3% (abemaciclib + 内分泌治疗组 34.5% [29/84] 和单独内分泌治疗组43.6% [41/94]）。 10 名患者 (5.6%) 最初为 ctDNA+，42 名患者 (23.6%) 为持续ctDNA+ （7 名患者，3.9%）或在 V27 时持续变为（35 名患者，19.7%）ctDNA+。 值得注意的是 70%最初为 ctDNA+ 的患者以及 100% 为持续ctDNA+ 或后来变为 ctDNA+ 的患者出现疾病复发。 相比之下 3 名ctDNA+ 清除的患者都没有出现复发。 在 ctDNA 持续阴性的患者中，28 人 (21.1%) 经历过复发，但她们中位 IDFS 最长（41.7 个月）。 总体而言，10% (7/70) 发生 IDFS 事件的患者最初为 ctDNA+，50% (35/70) 在 V27 时可检测到 ctDNA。  

结论: 完成新辅助化疗后不久检测到 ctDNA 的情况很少见，但也 与复发的高风险相关。 结束2 年abemaciclib治疗时 ctDNA 阳性常见 ，具有高度预后性, 所有患者随后疾病都复发。 重要的是，约 30% 早期 ctDNA 检测阳性的患者在 2 年的治疗期间最终降至检测水平以下，并且没有患者出现复发。 虽然 一些患者在本研究期间持续 ctDNA 阴性并出现复发， 延迟复发可能表明剩余 ctDNA 阴性的纵向益处。 未来 计划对扩大的队列进行分析，包括增加 2 年治疗期内的额外时间点以进一步确定 ctDNA 动态变化, 可以识别复发高风险的患者。

Background: The monarchE trial has shown that two years of adjuvant abemaciclib + endocrine therapy significantly improved invasive disease-free survival (IDFS) and distant recurrence-free survival (DRFS) in patients with HR+, HER2-, node-positive, high-risk early-stage breast cancer. The benefits of abemaciclib persisted and deepened at 4 years. This study investigated the technical feasibility of testing, persistence and clearance of ctDNA in a subset of MonarchE patients using the clinically validated SignateraTM ctDNA assay.

Methods: Samples were analyzed from a selected subset of patients (n=178; 84 from the abemaciclib + endocrine therapy group; 94 from the endocrine therapy group). Samples were collected both before initiating protocol directed therapy, at Visit 1 (V1, randomization + ≤ 3 days) and toward the completion of 2 years of treatment, at Visit 27 (V27; 24 months +/- 5 days). Primary tumors from selected patients were subjected to whole exome sequencing. Selected samples included those from patients with a range of tumor mutation burdens. Cell-free DNA was extracted from 356 plasma samples. The Signatera ctDNA assay was developed for each patient based on up to 16 variants detected in each baseline tumor sample.  

Results: The IDFS event rate in the selected subset (n=178) was 39.3% (34.5% [29/84] in the abemaciclib + endocrine therapy group and 43.6% [41/94] in the endocrine therapy alone group). Ten patients (5.6%) were initially ctDNA+, and 42 patients (23.6%) were persistently ctDNA+ (7 patients, 3.9%) or became ctDNA+  (35 patients, 19.7%) at V27. Of note, 70% of patients who were initially ctDNA+ and 100% of patients who were persistently ctDNA+ or later became ctDNA+ experienced disease recurrence. In contrast, none of the 3 patients that cleared ctDNA+ experienced recurrence. Among patients who were persistently negative for ctDNA, 28 (21.1%) experienced a relapse, but they had the longest median IDFS (41.7 months). Overall, 10% (7/70) of patients with an IDFS event were initially ctDNA+ and 50% (35/70) had detectable ctDNA at V27.

Conclusions: Detection of ctDNA shortly after completion of neoadjuvant chemotherapy was rare but was associated with a high risk of relapse. ctDNA positivity at the end of 2 years of abemaciclib treatment was common and highly prognostic, and all patients subsequently had disease relapse. Importantly, approximately 30% of patients with early ctDNA detection eventually fell below detectable levels during 2 years of treatment, and none developed recurrence. Although some patients remained ctDNA negative and relapsed during this study, delayed relapse may indicate a longitudinal benefit of remaining ctDNA negativity. Future analyses of an expanded cohort are planned, including adding additional time points during the 2-year treatment period to further determine ctDNA dynamics that may identify patients at high risk for relapse.

参考文献 Reference

Loi S. et al. 2023 San Antonio Breast Cancer Symposium. PS06-01

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超加工食品, 肥胖与头颈癌和食管腺癌的风险：欧洲癌症与营养前瞻性调查的中介分析 (1/6/2024)

Ultra-processed foods, adiposity and risk of head and neck cancer and esophageal adenocarcinoma: a mediation analysis in the European Prospective Investigation into Cancer and Nutrition

方法: 这项研究包括 450,111 名参与者。 Cox 回归被用来研究超加工食品*的消费与头颈癌和食管腺癌风险之间的关联。中介分析被用来评估体重指数（BMI）和腰臀比在这些关联中的作用。 在敏感性分析中，意外死亡作为阴性对照结果进行研究。

结果: 在平均 14.13±3.98 年的随访期间, 分别有 910 名和 215 名参与者患上了头颈癌和食管腺癌。超加工食品摄入量每增加 10% 克/天分别与头颈癌风险增加（风险比 [HR] = 1.23，95% 置信区间 [CI] 1.14–1.34）和食管腺癌增加（HR = 1.24，95% CI 1.05– 1.47）相关。腰臀比介导了 5%超加工食品摄入量与头颈癌风险之间的关联 (95% CI 3–10%)，而 BMI 和腰臀比分别介导了 13% (95% CI 6–53%) 和 15% (95% CI) 超加工食品摄入量与食管腺癌风险之间的关联 (95% CI 8–72%)。 在阴性对照分析中，超加工食品消耗与意外死亡呈正相关。    

结论: 在欧洲癌症与营养前瞻性调查中，较高的超加工食品消耗量与较高的头颈癌和食管腺癌风险相关。 通过肥胖介导的比例很小。 需要进一步的研究来调查可能起作用的其他机制。

*有些食品经过高度加工或超加工, 添加了许多成分，如糖, 盐, 脂肪, 人工色素,香料, 防腐剂或稳定剂等。这些食物的例子有冷冻食品、软饮料、热狗和冷盘、快餐、包装饼干、蛋糕和咸味零食。

Methods: This study included 450,111 participants. Cox regression was used to examine the association between ultra-processed food* consumption and risk of head and neck cancer and esophageal adenocarcinoma. A mediation analysis was performed to assess the role of body mass index (BMI) and waist-to-hip ratio in these associations. In sensitivity analyses, accidental death was used as a negative control outcome.

Results: During a mean follow-up period of 14.13±3.98 years, 910 and 215 participants developed head and neck cancer and esophageal adenocarcinoma, respectively. A 10% g/day higher consumption of ultra-processed food intake was associated with an increased risk of head and neck cancer (hazard ratio [HR] = 1.23, 95% confidence interval [CI] 1.14–1.34) and esophageal adenocarcinoma (HR = 1.24, 95 % CI 1.05– 1.47). Waist-to-hip ratio mediated 5% (95% CI 3–10%) of the association between ultra-processed food intake and head and neck cancer risk, while BMI and waist-to-hip ratio each mediated 13% (95% CI 6– 53%) and 15% (95% CI) of the association between ultra-processed food intake and risk of esophageal adenocarcinoma (95% CI 8–72%). In negative control analyses, ultra-processed food consumption was positively associated with accidental death.

Conclusion: In the European Prospective Survey on Cancer and Nutrition, higher consumption of ultra-processed foods was associated with a higher risk of head and neck cancer and esophageal adenocarcinoma. The proportion mediated through obesity was small. Further research is needed to investigate other mechanisms that may be at play.

*Some foods are highly processed or ultra-processed, with many added ingredients such as sugar, salt, fat, artificial colors, flavors, preservatives or stabilizers, etc.Examples of these foods are frozen meals, soft drinks, hot dogs and cold cuts, fast food, packaged cookies, cakes and salty snacks.

参考文献 Reference

Morales-Berstein F et al. Eur J Nutrition 2023; https://doi.org/10.1007/s00394-023-03270-1

http://www.health.harvard.edu/blog/what-are-ultra-processed-foods-and-are-they-bad-for-our-health-2020010918605