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. Data did not support continued enrollment in cohorts C and E.</p></div>","PeriodicalId":3,"journal":{"name":"ACS Applied Electronic Materials","volume":null,"pages":null},"PeriodicalIF":4.3000,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Pembrolizumab Plus Binimetinib With or Without Chemotherapy for MSS/pMMR Metastatic Colorectal Cancer: Outcomes From KEYNOTE-651 Cohorts A, C, and E\",\"authors\":\"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\",\"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). 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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.
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