As reported in The New England Journal of Medicine by Andre et al, interim analysis of the phase III CheckMate 8HW trial has shown that nivolumab plus ipilimumab prolonged progression-free survival vs chemotherapy with or without targeted agents in patients with microsatellite instability–high (MSI-H) or mismatch repair–deficient (dMMR) metastatic colorectal cancer who have had no previous systemic therapy for metastatic disease.
Study Details
In the open-label trial, patients with MSI-H or dMMR tumors from sites in 23 countries were randomly assigned 2:2:1 between August 2019 and April 2023 to receive nivolumab plus ipilimumab, nivolumab alone, or chemotherapy. The current interim analysis of the first primary endpoint compared progression-free survival between patients in the nivolumab/ipilimumab group (n = 202) vs patients in the chemotherapy group (n = 101) who had centrally confirmed MSI-H or dMMR tumors.
The nivolumab/ipilimumab regimen consisted of nivolumab at 240 mg and ipilimumab at 1 mg/kg every 3 weeks for the first 12 weeks, followed by nivolumab at 480 mg every 4 weeks. Chemotherapy consisted of investigator’s choice of mFOLFOX6 (modified leucovorin, fluorouracil, and oxaliplatin) or FOLFIRI (leucovorin, fluorouracil, and irinotecan) with or without bevacizumab or cetuximab.
Key Findings
A total of 255 patents had centrally confirmed MSI-H or dMMR tumors, including 171 in the nivolumab/ipilimumab group vs 84 in the chemotherapy group. At a median follow-up of 31.5 months (range = 6.1–48.4 months), median progression-free survival was not reached (95% confidence interval [CI] = 38.4 months to not evaluable) in the nivolumab/ipilimumab group vs 5.9 months (95% CI = 4.4–7.8 months) in the chemotherapy group (P < .001). Rates at 2 years were 72% vs 14%. At 24 months, restricted mean survival time was 10.6 months longer with nivolumab/ipilimumab vs chemotherapy. Among all randomly assigned patients, median progression-free survival was not reached (95% CI = 34.3 months to not evaluable) vs 6.2 months (95% CI = 4.7–9.0 months), and 2-year rates were 63% vs 15%.
Grade 3 or 4 treatment-related adverse events occurred in 23% of the nivolumab/ipilimumab group, most commonly adrenal insufficiency (3%) and increased alanine aminotransferase (2%), and in 48% of the chemotherapy group, most commonly neutropenia (10%) and asthenia (6%). Treatment-related serious events occurred in 19% vs 19% of patients.
Treatment-related adverse events led to discontinuation of any study drug in 16% vs 32% of patients. Treatment-related death occurred in two patients in the nivolumab/ipilimumab group, due to myocarditis and pneumonitis.
The investigators concluded: “Progression-free survival was longer with nivolumab plus ipilimumab than with chemotherapy among patients who had not previously received systemic treatment for MSI-H or dMMR metastatic colorectal cancer.”
Thierry Andre, MD, Department of Medical Oncology, Hopital Saint Antoine, Assistance Publique–Hopitaux de Paris, is the corresponding author for The New England Journal of Medicine article.
Disclosure: The study was funded by Bristol Myers Squibb and Ono Pharmaceutical. For full disclosures of the study authors, visit nejm.org.
