In a multinational, randomised, phase III CheckMate 8HW study, progression-free survival (PFS) outcomes were significantly better with nivolumab plus ipilimumab than with chemotherapy among patients with centrally confirmed microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) metastatic colorectal cancer (mCRC) who had not previously received systemic treatment for metastatic disease.
Health-related quality-of-life benefit was observed with nivolumab plus ipilimumab as compared with chemotherapy. The findings were reported by Dr. Thierry Andre of the Department of Medical Oncology, Hôpital Saint Antoine, Assistance Publique–Hôpitaux de Paris in Paris, France, and colleagues on 27 November 2024 in The New England Journal of Medicine.
Patients with MSI-H or dMMR mCRC have poor outcomes when treated with standard chemotherapy with or without targeted therapies. PFS was longer with the PD1 inhibitor pembrolizumab than with chemotherapy among previously untreated patients with MSI-H or dMMR mCRC in the KEYNOTE-177 study. However, 29% of the patients treated with pembrolizumab had progressive disease as the best overall response, and 48% were alive and did not have progressive disease at 2 years of follow-up.
The authors wrote in the background that a combination of nivolumab and ipilimumab has shown favourable efficacy outcomes relative to single agent immunotherapy in several cancer types, including MSI-H or dMMR mCRC. In the phase II CheckMate 142 study, nivolumab plus ipilimumab led to deep and durable responses, survival rates that are promising, and manageable safety profiles in patients with MSI-H or dMMR mCRC.
The CheckMate 8HW is an ongoing, phase III, multinational, randomised study evaluating nivolumab plus ipilimumab as compared with nivolumab alone or chemotherapy in patients with MSI-H or dMMR mCRC. In the latest article, the authors reported the results from the prespecified interim analysis of first-line nivolumab plus ipilimumab as compared with chemotherapy.
The study team randomly assigned patients with unresectable or mCRC and MSI-H or dMMR status according to local testing to receive, in a 2:2:1 ratio, nivolumab plus ipilimumab, nivolumab alone, or chemotherapy with or without targeted therapies. The dual primary endpoints, assessed in patients with centrally confirmed MSI-H or dMMR status, were PFS with nivolumab plus ipilimumab as compared with chemotherapy as first-line therapy and PFS with nivolumab plus ipilimumab as compared with nivolumab alone in patients regardless of previous systemic treatment for metastatic disease. At this prespecified interim analysis, the first primary endpoint (involving nivolumab plus ipilimumab versus chemotherapy) was assessed.
A total of 303 patients who had not previously received systemic treatment for metastatic disease were randomly assigned to receive nivolumab plus ipilimumab or chemotherapy; 255 patients had centrally confirmed MSI-H or dMMR tumours. At a median follow-up of 31.5 months (range, 6.1 to 48.4), PFS outcomes (the primary analysis) were significantly better with nivolumab plus ipilimumab than with chemotherapy (p < 0.001 for the between-group difference in PFS, calculated with the use of a two-sided stratified log-rank test); 24-month PFS was 72% (95% confidence interval [CI] 64 to 79) with nivolumab plus ipilimumab as compared with 14% (95% CI 6 to 25) with chemotherapy.
Because of the violation of the proportional hazards assumption, analyses of the restricted mean survival time at 24 months were conducted to facilitate the interpretation of the PFS results from the primary analysis; these additional analyses showed a difference of 10.6 months (95% CI 8.4 to 12.9) in the restricted mean survival time in favour of nivolumab plus ipilimumab, a finding consistent with the primary analysis of PFS.
Furthermore, the prespecified subgroup analyses consistently favoured nivolumab plus ipilimumab over chemotherapy, as indicated by numerically higher PFS at 12 months in all subgroups. Nivolumab plus ipilimumab also led to better PFS outcomes than chemotherapy among all patients who underwent randomisation.
Grade 3 and 4 treatment-related side effects were consistent with the established profiles of each individual drug, and no new safety concerns were identified. Grade 3 or 4 treatment-related adverse events occurred in 23% of the patients in the nivolumab plus ipilimumab group and in 48% of the patients in the chemotherapy group.
The changes from baseline in health-related quality-of-life, as measured by the European Organisation for Research and Treatment of Cancer quality-of-life core questionnaire (the Global Health Status subscale), surpassed the prespecified threshold for meaningful improvements starting at week 13 in the nivolumab plus ipilimumab group. Changes from baseline remained stable in the chemotherapy group until week 29, when the health-related quality-of-life declined to a value lower than the prespecified threshold.
The authors concluded that PFS results from the CheckMate 8HW study are consistent with previous data of first-line nivolumab plus ipilimumab from the non-randomised CheckMate 142 study, and support the use of nivolumab plus ipilimumab in patients with MSI-H or dMMR mCRC.
Reference
Andre T, Elez E, Van Cutsem E, et al. for the CheckMate 8HW Investigators. Nivolumab plus Ipilimumab in Microsatellite-Instability–High Metastatic Colorectal Cancer. N Engl J Med 2024;391:2014-2026.