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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
Background
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.
Trial design
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.
Clinical trial identification
NCT04008030.
Editorial acknowledgement
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.
Legal entity responsible for the study
Bristol Myers Squibb.
Funding
The study was supported by Bristol Myers Squibb.
Disclosures
T. André: Honoraria (self): Amgen, Astra-Zeneca, Bristol-Myers Squibb, Gritstone Oncology, GlaxoSmithKline, Haliodx, Kaleido Biosciences, Merck & Co., Inc., Pierre Fabre, Sanofi, Servier et, Merck & Co., Inc, Servier; Advisory / Consultancy: Astellas Pharma, BMS, Gritstone Oncology, Transgène, Roche/Ventana, Seagen, Merck & Co., Inc, Sevier; Research grant / Funding (institution): BMS, Seagen, GSK; Travel / Accommodation / Expenses: BMS, Merck & Co., Inc. E. Van Cutsem: Advisory / Consultancy: Abbvie, Array, Astellas, Astrazeneca, Bayer, Beigene, Biocartis, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Daiichi, Halozyme, GSK, Helsinn, Incyte, Ipsen, Janssen Research, Lilly, Merck Sharp & Dohme, Merck KGaA, Mirati, Novartis, Pierre Fabre, Roche, Seattle Genetics, Servier, Sirtex, Terumo, Taiho, TRIGR, Zymeworks; Research grant / Funding (institution): Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche, Servier. J. Bennouna: Honoraria (self): Bristol Myers Squibb; Advisory / Consultancy: Bristol Myers Squibb. T. Yoshino: Honoraria (self): Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Merck Biopharma, Bayer Yakuhin, Ono Pharmaceutical and MSD; Research grant / Funding (institution): Ono Pharmaceutical, Sanofi, Daiichi Sankyo, PAREXEL International, Pfizer Japan, Taiho Pharmaceutical, MSD, Amgen, Genomedia, Sysmex, Chugai Pharmaceutical and Nippon Boehringer Ingelheim. L. Jensen: Research grant / Funding (institution): Clinical trial, MSD, Clinical trial, BMS, Clinical trial, INCYTE. S. Abdullaev: Shareholder / Stockholder / Stock options: Bristol Myers Squibb; Full / Part-time employment: Bristol Myers Squibb. T. Chen: Full / Part-time employment: Bristol Myers Squibb, Bristol Myers Squibb, Bristol Myers Squibb. M. Lei: Full / Part-time employment: Bristol Myers Squibb. All other authors have declared no conflicts of interest.
