P-12 A phase 3 study of nivolumab (NIVO), NIVO + ipilimumab (IPI), or chemotherapy for microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) metastatic colorectal cancer (mCRC): CheckMate 8HW

Patients with MSI-H/dMMR mCRC treated with chemotherapy have poorer outcomes than patients with microsatellite stable/MMR proficient mCRC. Pembrolizumab monotherapy is approved in multiple countries as first-line therapy for patients with MSI-H/dMMR mCRC; however, despite observed clinical benefit vs chemotherapy, the 24-month progression-free survival (PFS) rate was 48% (Andre et al. NEJM 2020). NIVO (anti–programmed death 1 [PD-1]) and IPI (anti–cytotoxic T lymphocyte antigen-4 [CTLA-4]) are immune checkpoint inhibitors with distinct but complementary mechanisms. NIVO±IPI is approved in previously treated patients with MSI-H/dMMR mCRC in the US, EU, and Japan, based on findings from the phase 2, non-randomized, multicohort CheckMate 142 study. Indirect comparisons suggest that NIVO (3 mg/kg) + IPI (1 mg/kg) provides improved clinical benefit vs NIVO (investigator-assessed [INV] objective response rate [ORR] 55% vs 31%; 12-month INV PFS rate 71% vs 50%; 12-month overall survival [OS] rate 85% vs 73%) with a favorable benefit-risk profile for previously treated MSI-H/dMMR mCRC (Overman et al. JCO 2018). NIVO+IPI also demonstrated robust and durable clinical benefit and was well tolerated for the first-line treatment of MSI-H/dMMR mCRC (INV ORR 69%; 24-month INV PFS rate 74%; 24-month OS rate 79%; Lenz et al. JCO 2022). To date, no prospective phase 3 studies have reported results for anti–PD-1 + anti–CTLA-4 vs chemotherapy or anti–PD-1/programmed death ligand 1 (PD-L1) monotherapy in MSI-H/dMMR mCRC. CheckMate 8HW (NCT04008030) is an international, multicenter, open-label, randomized, phase 3 study designed to compare the efficacy and safety of NIVO+IPI to chemotherapy or NIVO in patients with MSI-H/dMMR mCRC. Approximately 748 patients across 23 countries aged ≥18 years with histologically confirmed recurrent or mCRC that is not amenable to surgery, irrespective of prior treatment with chemotherapy and/or targeted agents, with known tumor MSI-H or dMMR status and ECOG performance status ≤1 will be randomized to receive NIVO, NIVO+IPI, or investigator’s choice chemotherapy (patients in the chemotherapy arm can receive NIVO+IPI upon progression). The dual primary endpoints are PFS, assessed by blinded independent central review (BICR), for NIVO+IPI vs NIVO across all lines and NIVO+IPI vs chemotherapy in the first-line setting in patients with centrally confirmed MSI-H/dMMR mCRC. Other key endpoints include PFS by BICR for NIVO+IPI vs NIVO in the first-line setting, PFS by INV, ORR by BICR, OS, and safety. Recruitment of patients in the first-line setting is ongoing. NCT04008030. All authors contributed to and approved the abstract; writing and editorial assistance was provided by Andrew Scott, PharmD, of Parexel International, funded by Bristol Myers Squibb . Bristol Myers Squibb. The study was supported by Bristol Myers Squibb.