Eric X. Chen , Petr Kavan , Mustapha Tehfe , Jeremy S. Kortmansky , Michael B. Sawyer , E. Gabriela Chiorean , Christopher H. Lieu , Blase Polite , Lucas Wong , Marwan Fakih , Kristen Spencer , Jorge Chaves , Chenxiang Li , Pierre Leconte , David Adelberg , Richard Kim
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Lieu , Blase Polite , Lucas Wong , Marwan Fakih , Kristen Spencer , Jorge Chaves , Chenxiang Li , Pierre Leconte , David Adelberg , Richard Kim","doi":"10.1016/j.clcc.2024.03.002","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><p>Cohorts A, C, and E of the phase Ib KEYNOTE-651 study evaluated pembrolizumab + binimetinib ± chemotherapy in microsatellite stable/mismatch repair-proficient metastatic colorectal cancer.</p></div><div><h3>Patients and Methods</h3><p>Patients received pembrolizumab 200 mg every 3 weeks plus binimetinib 30 mg twice daily alone (cohort A; previously treated with any chemotherapy) or with 5-fluorouracil, leucovorin, oxaliplatin (cohort C; previously untreated) or 5-fluorouracil, leucovorin, irinotecan (cohort E; previously treated with 1 line of therapy including fluoropyrimidine + oxaliplatin-based regimen) every 2 weeks. Binimetinib dose-escalation to 45 mg twice daily was planned in all cohorts using a modified toxicity probability interval design (target dose-limiting toxicity [DLT], 30%). The primary endpoint was safety; investigator-assessed objective response rate was secondary.</p></div><div><h3>Results</h3><p>In cohort A, 1/6 patients (17%) had DLTs with binimetinib 30 mg; none occurred in 14 patients with 45 mg. In cohort C, 3/9 patients (33%) had DLTs with binimetinib 30 mg; dose was not escalated to 45 mg. In cohort E, 1/5 patients (20%) had DLTs with binimetinib 30 mg; 5/10 patients (50%) had DLTs with 45 mg. Enrollment was stopped in cohort E binimetinib 45 mg and deescalated to 30 mg; 2/4 additional patients (50%) had DLTs with binimetinib 30 mg (total 3/9 [33%] had DLTs with binimetinib 30 mg). Objective response rate was 0% in cohort A, 9% in cohort C, and 15% in cohort E.</p></div><div><h3>Conclusion</h3><p>Per DLT criteria, binimetinib + pembrolizumab (cohort A) was tolerable, binimetinib + pembrolizumab + 5-fluorouracil, leucovorin, oxaliplatin (cohort C) did not qualify for binimetinib dose escalation to 45 mg, and binimetinib + pembrolizumab + 5-fluorouracil, leucovorin, irinotecan (cohort E) required binimetinib dose reduction from 45 to 30 mg. No new safety findings were observed across cohorts. There was no apparent additive efficacy when binimetinib + pembrolizumab was added to chemotherapy. 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Binimetinib dose-escalation to 45 mg twice daily was planned in all cohorts using a modified toxicity probability interval design (target dose-limiting toxicity [DLT], 30%). The primary endpoint was safety; investigator-assessed objective response rate was secondary.</p></div><div><h3>Results</h3><p>In cohort A, 1/6 patients (17%) had DLTs with binimetinib 30 mg; none occurred in 14 patients with 45 mg. In cohort C, 3/9 patients (33%) had DLTs with binimetinib 30 mg; dose was not escalated to 45 mg. In cohort E, 1/5 patients (20%) had DLTs with binimetinib 30 mg; 5/10 patients (50%) had DLTs with 45 mg. Enrollment was stopped in cohort E binimetinib 45 mg and deescalated to 30 mg; 2/4 additional patients (50%) had DLTs with binimetinib 30 mg (total 3/9 [33%] had DLTs with binimetinib 30 mg). 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引用次数: 0
摘要
Ib期KEYNOTE-651研究的A、C和E组评估了微卫星稳定/错配修复功能良好的转移性结直肠癌患者接受pembrolizumab + binimetinib ±化疗的情况。患者接受pembrolizumab 200毫克，每3周一次，另加binimetinib 30毫克，每日两次，单独治疗（队列A；既往接受过任何化疗），或与5-氟尿嘧啶、亮菌素、奥沙利铂（队列C；既往未接受过化疗）或5-氟尿嘧啶、亮菌素、伊立替康（队列E；既往接受过1线治疗，包括氟嘧啶+奥沙利铂方案），每2周一次。所有队列均采用改良毒性概率区间设计（目标剂量限制性毒性[DLT]为30%），计划将比尼替尼剂量递增至45毫克，每天两次。主要终点为安全性；研究者评估的客观反应率为次要终点。在队列 A 中，1/6 的患者（17%）在服用 30 毫克的替米替尼后出现了 DLT；14 名患者在服用 45 毫克的替米替尼后未出现任何 DLT。在队列 C 中，3/9（33%）名患者在服用替米替尼 30 毫克后出现了 DLT；服用 45 毫克时剂量未升级。在队列 E 中，1/5 的患者（20%）在服用替米替尼 30 毫克后出现 DLT；5/10 的患者（50%）在服用 45 毫克后出现 DLT。队列E中的替尼米替尼45毫克停止入组，降级为30毫克；另外2/4名患者（50%）服用替尼米替尼30毫克出现DLT（总共3/9名患者[33%]服用替尼米替尼30毫克出现DLT）。客观反应率在 A 组为 0%，C 组为 9%，E 组为 15%。根据DLT标准，宾尼美替尼+彭博利珠单抗（A组）可以耐受，宾尼美替尼+彭博利珠单抗+5-氟尿嘧啶、亮霉素、奥沙利铂（C组）不符合宾尼美替尼剂量升级至45毫克的条件，宾尼美替尼+彭博利珠单抗+5-氟尿嘧啶、亮霉素、伊立替康（E组）需要将宾尼美替尼剂量从45毫克降至30毫克。各组群未发现新的安全性问题。在化疗的基础上加用替尼米替尼+pembrolizumab没有明显的增效作用。数据不支持C组和E组继续入组。
Pembrolizumab Plus Binimetinib With or Without Chemotherapy for MSS/pMMR Metastatic Colorectal Cancer: Outcomes From KEYNOTE-651 Cohorts A, C, and E
Background
Cohorts A, C, and E of the phase Ib KEYNOTE-651 study evaluated pembrolizumab + binimetinib ± chemotherapy in microsatellite stable/mismatch repair-proficient metastatic colorectal cancer.
Patients and Methods
Patients received pembrolizumab 200 mg every 3 weeks plus binimetinib 30 mg twice daily alone (cohort A; previously treated with any chemotherapy) or with 5-fluorouracil, leucovorin, oxaliplatin (cohort C; previously untreated) or 5-fluorouracil, leucovorin, irinotecan (cohort E; previously treated with 1 line of therapy including fluoropyrimidine + oxaliplatin-based regimen) every 2 weeks. Binimetinib dose-escalation to 45 mg twice daily was planned in all cohorts using a modified toxicity probability interval design (target dose-limiting toxicity [DLT], 30%). The primary endpoint was safety; investigator-assessed objective response rate was secondary.
Results
In cohort A, 1/6 patients (17%) had DLTs with binimetinib 30 mg; none occurred in 14 patients with 45 mg. In cohort C, 3/9 patients (33%) had DLTs with binimetinib 30 mg; dose was not escalated to 45 mg. In cohort E, 1/5 patients (20%) had DLTs with binimetinib 30 mg; 5/10 patients (50%) had DLTs with 45 mg. Enrollment was stopped in cohort E binimetinib 45 mg and deescalated to 30 mg; 2/4 additional patients (50%) had DLTs with binimetinib 30 mg (total 3/9 [33%] had DLTs with binimetinib 30 mg). Objective response rate was 0% in cohort A, 9% in cohort C, and 15% in cohort E.
Conclusion
Per DLT criteria, binimetinib + pembrolizumab (cohort A) was tolerable, binimetinib + pembrolizumab + 5-fluorouracil, leucovorin, oxaliplatin (cohort C) did not qualify for binimetinib dose escalation to 45 mg, and binimetinib + pembrolizumab + 5-fluorouracil, leucovorin, irinotecan (cohort E) required binimetinib dose reduction from 45 to 30 mg. No new safety findings were observed across cohorts. There was no apparent additive efficacy when binimetinib + pembrolizumab was added to chemotherapy. Data did not support continued enrollment in cohorts C and E.
期刊介绍：
Clinical Colorectal Cancer is a peer-reviewed, quarterly journal that publishes original articles describing various aspects of clinical and translational research of gastrointestinal cancers. Clinical Colorectal Cancer is devoted to articles on detection, diagnosis, prevention, and treatment of colorectal, pancreatic, liver, and other gastrointestinal cancers. The main emphasis is on recent scientific developments in all areas related to gastrointestinal cancers. Specific areas of interest include clinical research and mechanistic approaches; drug sensitivity and resistance; gene and antisense therapy; pathology, markers, and prognostic indicators; chemoprevention strategies; multimodality therapy; and integration of various approaches.
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