Double is better – immunotherapy for metastatic microsatellite-instable colorectal cancer
André T et al, Lancet. 2025;405(10476):383-395
In this phase 3 study in patients with the above-mentioned carcinomas (CheckMATE 8HW), combined treatment with nivolumab and ipilimumab led to superior progression-free survival in all lines of therapy compared to monotherapy with nivolumab.
Background: CheckMate 8HW prespecified dual primary endpoints, assessed in patients with centrally confirmed microsatellite instability-high or mismatch repair-deficient status: progression-free survival with nivolumab plus ipilimumab compared with chemotherapy as first-line therapy and progression-free survival with nivolumab plus ipilimumab compared with nivolumab alone, regardless of previous systemic treatment for metastatic disease. In a previous report, nivolumab plus ipilimumab showed superior progression-free survival versus chemotherapy in first-line microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer in the CheckMate 8HW trial. Here, the authors report results from the prespecified interim analysis for the other primary endpoint of progression-free survival for nivolumab plus ipilimumab versus nivolumab across all treatment lines.
Methods: CheckMate 8HW is a randomised, open-label, international, phase 3 trial at 128 hospitals and cancer centres across 23 countries. Immunotherapy-naive adults with unresectable or metastatic colorectal cancer across different lines of therapy and microsatellite instability-high or mismatch repair-deficient status per local testing were randomly assigned (2:2:1) to nivolumab plus ipilimumab (nivolumab 240 mg, ipilimumab 1 mg/kg, every 3 weeks for 4 doses; then nivolumab 480 mg every 4 weeks; all intravenously), nivolumab (240 mg every 2 weeks for 6 doses, then 480 mg every 4 weeks; all intravenously), or chemotherapy with or without targeted therapies. The dual independent primary endpoints were progression-free survival by blinded independent central review with nivolumab plus ipilimumab versus chemotherapy (first line) and progression-free survival by blinded independent central review with nivolumab plus ipilimumab versus nivolumab (all lines) in patients with centrally confirmed microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer.
Findings: Between August 16, 2019, and April 10, 2023, 707 patients were randomly assigned to nivolumab plus ipilimumab (n = 354) or nivolumab alone (n = 353). 296 of 354 patients (84%) in the nivolumab plus ipilimumab group and 286 of 353 patients (81%) in the nivolumab group were centrally confirmed to have microsatellite instability-high or mismatch repair-deficient status. At the data cutoff on August 28, 2024, median follow-up (from randomisation to data cutoff) was 47.0 months (interquartile range [IQR], 38.4–53.2). Nivolumab plus ipilimumab treatment showed significant and clinically meaningful improvement in progression-free survival versus nivolumab (hazard ratio = 0.62, 95% confidence interval [CI]: 0.48–0.81; p = 0.0003). Median progression-free survival was not reached with nivolumab plus ipilimumab (95% CI: 53.8 to not estimable) and was 39.3 months with nivolumab (22.1 to not estimable). Treatment-related adverse events of any grade occurred in 285 of 352 patients (81%) receiving nivolumab plus ipilimumab and in 249 of 351 patients (71%) receiving nivolumab; grade 3 or 4 treatment-related adverse events occurred in 78 (22%) and 50 (14%) patients, respectively. There were 3 treatment-related deaths: 1 event of myocarditis and pneumonitis each in the nivolumab plus ipilimumab group and 1 pneumonitis event in the nivolumab group.
Interpretation: Nivolumab plus ipilimumab showed superior progression-free survival versus nivolumab across all treatment lines, with a manageable safety profile, in patients with microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. These results, together with the first-line results of superior progression-free survival with nivolumab plus ipilimumab versus chemotherapy, suggest nivolumab plus ipilimumab as a potential new standard of care for patients with microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer.