Dr André on Nivolumab Plus Ipilimumab in MSI-H/dMMR mCRC

"The [study’s] primary objective was met. The hazard ratio was [0.62], with a statistically significant P value for patients with centrally confirmed MSI-H/dMMR status. The ORR also improved with the combination therapy compared with monotherapy."

Thierry André, MD, professor, medical oncology, University Pierre et Marie Curie; head, the Medical Oncology Department, Saint. Antoine Hospital, discussed findings from the phase 3 CheckMate 8HW trial (NCT04008030), which evaluated nivolumab plus ipilimumab vs nivolumab monotherapy in patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC).

In this randomized study, investigators assessed the efficacy and safety of dual immune checkpoint inhibition compared with anti–PD-1 monotherapy in various lines of therapy. Patients were randomly assigned to receive either nivolumab plus ipilimumab or nivolumab alone. The primary end point was progression-free survival (PFS) by blinded independent central review, with secondary end points including overall response rate (ORR), overall survival (OS), duration of response (DOR), and safety.

Results presented at the 2025 Gastrointestinal Cancers Symposium demonstrated that the combination of nivolumab plus ipilimumab significantly improved PFS compared with nivolumab monotherapy across all lines of therapy (HR, 0.62; 95% CI, 0.48-0.81; P = .0003), Andre reports. The median PFS was not reached in the combination arm (95% CI, 53.8-not evaluable [NE]) vs 39.3 months (95% CI, 22.1-NE) with monotherapy. Two- and 3-year PFS rates with the combination vs monotherapy were 71% vs 56% and 68% vs 51%, respectively.

ORR was also significantly higher with nivolumab plus ipilimumab compared with nivolumab alone, at 71% (95% CI, 65%-76%) vs 58% (95% CI, 52%-64%; P = .0011), respectively, Andre details. The complete response rate was 30% in the combination arm vs 28% in the monotherapy arm, with partial responses observed in 40% and 30% of patients, respectively. The median time to response was 2.8 months in both arms (range, 1.2-44.5; 1.2-29.5).

Treatment-related adverse effects (TRAEs) of grade 3/4 severity were reported in 22% of patients receiving nivolumab plus ipilimumab and 14% of those receiving nivolumab monotherapy. The incidence of serious TRAEs was higher in the combination arm than the monotherapy arm (16% vs 7%). Immune-mediated adverse effects included hypothyroidism (18% with nivolumab plus ipilimumab vs 9% with nivolumab) and adrenal insufficiency (10% vs 3%).

Health-related quality-of-life (HRQoL) improvements were observed in both arms, with a prespecified meaningful change reached at week 21 for the combination group.

Although the combination was associated with a moderate increase in toxicity, the benefit-risk profile supports nivolumab plus ipilimumab as a new standard-of-care treatment for patients with MSI-H/dMMR mCRC, Andre concludes.