Dr Lenz on the FDA Approval of Nivolumab Plus Ipilimumab for dMMR/MSI-H mCRC

Heinz-Josef Lenz, MD, a professor of medicine and cancer biology, and the J. Terrence Lanni Chair in Gastrointestinal Cancer Research at the Keck School of Medicine of the University of the University of Southern California (USC); as well as the co-director of the USC Center for Molecular Pathway and Drug Discovery and the co-director of the USC Norris Center for Cancer Drug Development, discussed the significance of the FDA approval of nivolumab (Opdivo) plus ipilimumab (Yervoy) for the treatment of patients with mismatch repair–deficient (dMMR) or microsatellite instability–high (MSI-H) unresectable or metastatic colorectal cancer (CRC).

On April 8, 2025, the FDA approved the combination of nivolumab plus ipilimumab for the treatment of adult and pediatric patients 12 years of age and older with dMMR/MSI-H unresectable or metastatic CRC. This regulatory decision was based on findings from the phase 3 CheckMate 8HW trial (NCT04008030).

This approval marks a significant advancement in the treatment paradigm for patients with dMMR/MSI-H metastatic CRC, Lenz began. Data from CheckMate 8HW published in The New England Journal of Medicine in November 2024 established the superiority of this regimen over standard chemotherapy in the first-line setting, with nivolumab plus ipilimumab reducing the risk of disease progression or death by 79% (HR, 0.21; 95% CI, 0.14-0.32; P < .0001).

However, until recently, questions remained regarding the efficacy of this dual immune checkpoint blockade regimen compared with nivolumab monotherapy, he said. This knowledge gap was addressed in data from CheckMate 8HW presented at the 2025 Gastrointestinal Cancers Symposium, which demonstrated that nivolumab plus ipilimumab was superior to nivolumab monotherapy in regard to progression-free survival (PFS; HR, 0.62; 95% CI, 0.48-0.81; P = .0003). In this analysis, the 2-year PFS rate was 71% with the combination vs 56% with nivolumab alone. The overall response rate also favored the combination vs nivolumab alone, at 71% (95% CI, 65%-76%) vs 58% (95% CI, 52%-63%; P = .0011).

Concerns regarding immune-related toxicities, which are commonly associated with dual immune checkpoint blockade, were also addressed in this trial, Lenz added. The rate of graded 3/4 adverse effects was 22% with the combination vs 14% with nivolumab monotherapy. Importantly, health-related quality of life outcomes also favored the combination starting at week 21, he concluded.