The combination of nivolumab (Opdivo) and ipilimumab (Yervoy) has emerged as a promising first-line treatment for patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) metastatic colorectal cancer (mCRC). Data from the phase 3 CheckMate-8HW trial demonstrate a significant improvement in progression-free survival (PFS) compared to chemotherapy, marking a potential shift in the standard of care for this patient population. The study, the findings of which were published in The New England Journal of Medicine, highlights the clinical benefit and manageable safety profile of this dual immunotherapy approach.
CheckMate-8HW Trial: Key Findings
The CheckMate-8HW trial, a phase 3, open-label study, randomized patients with previously untreated MSI-H/dMMR mCRC to receive either nivolumab plus ipilimumab, nivolumab monotherapy, or chemotherapy. The primary endpoint was PFS, assessed by blinded independent central review. The results showed a statistically significant improvement in PFS with the combination therapy compared to chemotherapy (P < .001).
Specifically, the estimated 12- and 24-month PFS rates were 79% (95% CI, 72%-84%) and 72% (95% CI, 64%-79%) with nivolumab/ipilimumab, respectively, compared to 21% (95% CI, 11%-32%) and 14% (95% CI, 6%-25%) in the chemotherapy arm. These findings underscore the durable benefit of the immunotherapy combination in delaying disease progression.
Clinical Significance and Expert Commentary
Thierry Andre, MD, professor of medical oncology at Sorbonne Université and head of the Medical Oncology Department at Saint Antoine Hospital, Paris, France, emphasized the superiority of nivolumab plus ipilimumab over chemotherapy in the first-line treatment of MSI-H or dMMR mCRC. He also noted that the observed grade 3/4 treatment-related toxic effects were consistent with the established profiles of each individual drug, with no new safety concerns identified.
Further analysis presented at the 2025 ASCO Gastrointestinal Cancers Symposium compared nivolumab plus ipilimumab vs nivolumab monotherapy. With a median follow-up of 47 months in patients with centrally confirmed MSI-H/dMMR colorectal cancer (n = 582), median progression-free survival had not been reached in the dual-immunotherapy arm, whereas the single-agent nivolumab arm had a median progression-free survival of 39.3 months. In the overall population (n = 707), the median progression-free survival was 54.1 months with the combination vs 18.4 months with single-agent nivolumab. Nivolumab plus ipilimumab conferred a statistically significant hazard ratio of 0.62, representing a 38% lower risk of disease progression or death.
Safety and Tolerability
While the combination therapy was associated with a higher incidence of adverse events (AEs), the safety profile was generally manageable. Any-grade AEs occurred in 99% of patients in the combination arm and 98% in the chemotherapy arm, with grade 3/4 AEs occurring in 48% and 67%, respectively. Treatment-related AEs leading to drug discontinuation were less frequent in the combination arm (16%) compared to the chemotherapy arm (32%).
Regulatory and Market Impact
The European Commission (EC) approved nivolumab plus ipilimumab for the first-line treatment of adult patients with MSI-H/dMMR unresectable or metastatic colorectal cancer (mCRC). This decision underscores the growing recognition of immunotherapy's role in treating this specific subset of colorectal cancer patients. The FDA had previously granted accelerated approval to ipilimumab for MSI-H/dMMR mCRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan since 2018.
Implications for Clinical Practice
The CheckMate-8HW trial provides compelling evidence for the use of nivolumab plus ipilimumab as a first-line treatment option for patients with MSI-H/dMMR mCRC. The combination therapy offers a significant improvement in PFS compared to chemotherapy, with a manageable safety profile. These findings are expected to influence clinical practice, leading to a greater adoption of dual immunotherapy in this patient population.
