Binimetinib in combination with nivolumab or nivolumab and ipilimumab in patients with previously treated microsatellite-stable metastatic colorectal cancer with RAS mutations in an open-label phase 1b/2 study

Elez, E; Cubillo, A; Alfonso, PG; Middleton, MR; Chau, I; Alkuzweny, B; Alcasid, A; Zhang, X; Van Cutsem, E

Journal article

Binimetinib in combination with nivolumab or nivolumab and ipilimumab in patients with previously treated microsatellite-stable metastatic colorectal cancer with RAS mutations in an open-label phase 1b/2 study

Abstract:: Binimetinib; Colorectal cancer; IpilimumabBinimetinib; Càncer colorectal; IpilimumabBinimetinib; Cáncer colorrectal; IpilimumabBackground In patients with previously treated RAS-mutated microsatellite-stable (MSS) metastatic colorectal cancer (mCRC), a multicenter open-label phase 1b/2 trial was conducted to define the safety and efficacy of the MEK1/MEK2 inhibitor binimetinib in combination with the immune checkpoint inhibitor (ICI) nivolumab (anti–PD-1) or nivolumab and another ICI, ipilimumab (anti-CTLA4). Methods In phase 1b, participants were randomly assigned to Arm 1A (binimetinib 45 mg twice daily [BID] plus nivolumab 480 mg once every 4 weeks [Q4W]) or Arm 1B (binimetinib 45 mg BID plus nivolumab 480 mg Q4W and ipilimumab 1 mg/kg once every 8 weeks [Q8W]) to determine the maximum tolerable dose (MTD) and recommended phase 2 dose (RP2D) of binimetinib. The MTD/RP2D was defined as the highest dosage combination that did not cause medically unacceptable dose-limiting toxicities in more than 35% of treated participants in Cycle 1. During phase 2, participants were randomly assigned to Arm 2A (binimetinib MTD/RP2D plus nivolumab) or Arm 2B (binimetinib MTD/RP2D plus nivolumab and ipilimumab) to assess the safety and clinical activity of these combinations. Results In phase 1b, 21 participants were randomized to Arm 1A or Arm 1B; during phase 2, 54 participants were randomized to Arm 2A or Arm 2B. The binimetinib MTD/RP2D was determined to be 45 mg BID. In phase 2, no participants receiving binimetinib plus nivolumab achieved a response. Of the 27 participants receiving binimetinib, nivolumab, and ipilimumab, the overall response rate was 7.4% (90% CI: 1.3, 21.5). Out of 75 participants overall, 74 (98.7%) reported treatment-related adverse events (AEs), of whom 17 (22.7%) reported treatment-related serious AEs. Conclusions The RP2D binimetinib regimen had a safety profile similar to previous binimetinib studies or nivolumab and ipilimumab combination studies. There was a lack of clinical benefit with either drug combination. Therefore, these data do not support further development of binimetinib in combination with nivolumab or nivolumab and ipilimumab in RAS-mutated MSS mCRC.This study was sponsored by Array BioPharma, which was acquired by Pfizer in July 2019, in collaboration with Bristol Myers Squibb

Publication status:: Published

Peer review status:: Peer reviewed

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APA Style

Elez, E., Cubillo, A., Alfonso, P. G., Middleton, M. R., Chau, I., Alkuzweny, B., Alcasid, A., Zhang, X., & Van Cutsem, E. (2024). Binimetinib in combination with nivolumab or nivolumab and ipilimumab in patients with previously treated microsatellite-stable metastatic colorectal cancer with RAS mutations in an open-label phase 1b/2 study. BMC Cancer, 24(1), 446–446.

MLA Style

Elez, E, et al. “Binimetinib in Combination with Nivolumab or Nivolumab and Ipilimumab in Patients with Previously Treated Microsatellite-Stable Metastatic Colorectal Cancer with RAS Mutations in an Open-Label Phase 1b/2 Study.” BMC Cancer, vol. 24, no. 1, 2024, pp. 446–46.

Chicago Style

Elez, E, A Cubillo, PG Alfonso, et al. 2024. “Binimetinib in Combination with Nivolumab or Nivolumab and Ipilimumab in Patients with Previously Treated Microsatellite-Stable Metastatic Colorectal Cancer with RAS Mutations in an Open-Label Phase 1b/2 Study.” BMC Cancer 24 (1): 446–46.
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