The phase 1b KEYNOTE-651 study evaluated pembrolizumab plus chemotherapy in microsatellite stable or mismatch repair-proficient metastatic colorectal cancer. Patients with microsatellite stable or mismatch repair-proficient metastatic colorectal cancer received pembrolizumab 200 mg every 3 weeks plus 5-fluorouracil, leucovorin, oxaliplatin (previously untreated; cohort B) or 5-fluorouracil, leucovorin, irinotecan (previously treated with fluoropyrimidine plus oxaliplatin; cohort D) every 2 weeks. Primary end point was safety; investigator-assessed objective response rate per RECIST v1.1 was secondary and biomarker analysis was exploratory. Thirty-one patients were enrolled in cohort B and 32 in cohort D; median follow-up was 30.2 and 33.5 months, respectively. One dose-limiting toxicity (grade 3 small intestine obstruction) occurred in cohort D. In cohort B, grade 3/4 treatment-related adverse events (AEs) occurred in 18 patients (58%), most commonly neutropenia and decreased neutrophil count (n = 5 each). In cohort D, grade 3/4 treatment-related AEs occurred in 17 patients (53%), most commonly neutropenia (n = 7). No grade 5 treatment-related AEs occurred. Objective response rate was 61% in cohort B ( wildtype: 71%; mutant: 53%) and 25% in cohort D ( wildtype: 47%; mutant: 6%). In both cohorts, programmed cell death protein 1 combined positive score and T-cell-inflamed gene expression profiles were higher and human epidermal growth factor receptor 2 expression was lower in responders than nonresponders. No association between tumor mutational burden and response was observed. Pembrolizumab plus 5-fluorouracil, leucovorin, oxaliplatin/5-fluorouracil, leucovorin, irinotecan demonstrated an acceptable AE profile. Efficacy data appeared comparable with current standard of care (including by mutation status). Biomarker analyses were hypothesis-generating, warranting further exploration. ClinicalTrials.gov; NCT03374254

中文翻译：

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Pembrolizumab 加 mFOLFOX7 或 FOLFIRI 用于微卫星稳定/错配修复 – 有效的转移性结直肠癌：KEYNOTE-651 队列 B 和 D

1b 期 KEYNOTE-651 研究评估了派姆单抗联合化疗治疗微卫星稳定或错配修复良好的转移性结直肠癌。微卫星稳定或错配修复良好的转移性结直肠癌患者每 3 周接受 200 mg 派姆单抗加 5-氟尿嘧啶、亚叶酸、奥沙利铂（之前未经治疗；队列 B）或 5-氟尿嘧啶、亚叶酸、伊立替康（之前接受过氟嘧啶加奥沙利铂治疗；队列 B）。队列 D) 每两周一次。主要终点是安全性；研究者根据 RECIST v1.1 评估的客观缓解率是次要的，生物标志物分析是探索性的。 B 组有 31 名患者入组，D 组有 32 名患者入组；中位随访时间分别为 30.2 个月和 33.5 个月。 D 组中发生了一种剂量限制性毒性（3 级小肠梗阻）。B 组中，18 名患者（58%）发生了 3/4 级治疗相关不良事件（AE），最常见的是中性粒细胞减少症和中性粒细胞计数减少（每个 n = 5)。在队列 D 中，17 名患者 (53%) 发生了 3/4 级治疗相关 AE，最常见的是中性粒细胞减少症 (n = 7)。没有发生 5 级治疗相关 AE。 B 组的客观缓解率为 61%（野生型：71%；突变型：53%），D 组的客观缓解率为 25%（野生型：47%；突变型：6%）。在这两个队列中，应答者中的程序性细胞死亡蛋白 1 综合阳性评分和 T 细胞炎症基因表达谱均较高，而人表皮生长因子受体 2 表达低于无应答者。没有观察到肿瘤突变负荷和反应之间的关联。派姆单抗加 5-氟尿嘧啶、亚叶酸、奥沙利铂/5-氟尿嘧啶、亚叶酸、伊立替康显示出可接受的 AE 特征。功效数据似乎与当前的护理标准相当（包括突变状态）。生物标志物分析是假设生成的，值得进一步探索。临床试验.gov； NCT03374254