Pembrolizumab Plus mFOLFOX7 or FOLFIRI for Microsatellite Stable/Mismatch Repair-Proficient Metastatic Colorectal Cancer: KEYNOTE-651 Cohorts B and D

IF 4.3 3区材料科学 Q1 ENGINEERING, ELECTRICAL & ELECTRONIC ACS Applied Electronic Materials Pub Date : 2024-06-01 DOI:10.1016/j.clcc.2024.03.001

Richard Kim , Mustapha Tehfe , Petr Kavan , Jorge Chaves , Jeremy S. Kortmansky , Eric X. Chen , Christopher H. Lieu , Lucas Wong , Marwan Fakih , Kristen Spencer , Qing Zhao , Raluca Predoiu , Chenxiang Li , Pierre Leconte , David Adelberg , E. Gabriela Chiorean

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Abstract

Background

The phase 1b KEYNOTE-651 study evaluated pembrolizumab plus chemotherapy in microsatellite stable or mismatch repair-proficient metastatic colorectal cancer.

Patients and Methods

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.

Results

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 or 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 or 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 (KRAS wildtype: 71%; KRAS mutant: 53%) and 25% in cohort D (KRAS wildtype: 47%; KRAS mutant: 6%). In both cohorts, PD-L1 combined positive score and T-cell-inflamed gene expression profiles were higher and HER2 expression was lower in responders than nonresponders. No association between tumor mutational burden and response was observed.

Conclusion

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 KRAS mutation status). Biomarker analyses were hypothesis-generating, warranting further exploration.

ClinicalTrials.gov Identifier

ClinicalTrials.gov; NCT03374254

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Pembrolizumab 联合 mFOLFOX7 或 FOLFIRI 治疗微卫星稳定/错配修复缺陷转移性结直肠癌：KEYNOTE-651 B组和D组

KEYNOTE-651 1b 期研究评估了 pembrolizumab 加化疗治疗微卫星稳定或错配修复功能良好的转移性结直肠癌的效果。微卫星稳定或错配修复功能良好的转移性结直肠癌患者每 3 周接受一次 pembrolizumab 200 毫克，外加 5-氟尿嘧啶、亮菌素、奥沙利铂（既往未接受过治疗；B 组）或 5-氟尿嘧啶、亮菌素、伊立替康（既往接受过氟嘧啶加奥沙利铂治疗；D 组），每 2 周一次。主要终点为安全性；研究者根据 RECIST v1.1 评估的客观反应率为次要终点，生物标志物分析为探索性终点。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组出现了一种剂量限制性毒性（3级小肠梗阻）。B组有18名患者（58%）出现了3/4级治疗相关不良事件（AEs），最常见的是中性粒细胞减少和中性粒细胞计数减少（各5例）。在队列D中，17名患者（53%）出现了3/4级治疗相关不良事件，最常见的是中性粒细胞减少（7例）。未出现 5 级治疗相关不良反应。B组客观反应率为61%（野生型：71%；突变型：53%），D组为25%（野生型：47%；突变型：6%）。与无应答者相比，两组患者的程序性细胞死亡蛋白 1 合并阳性评分和 T 细胞炎症基因表达谱均较高，而人表皮生长因子受体 2 的表达较低。未观察到肿瘤突变负荷与应答之间存在关联。Pembrolizumab联合5-氟尿嘧啶、亮菌素、奥沙利铂/5-氟尿嘧啶、亮菌素、伊立替康的AE谱可接受。疗效数据似乎与目前的标准疗法相当（包括按突变状态）。生物标志物分析提出了一些假设，值得进一步探讨。ClinicalTrials.gov; NCT03374254

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