FDA Approves Nivolumab Plus Ipilimumab for dMMR/MSI-H Metastatic CRC

US FDA

The FDA has granted approval to the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) for the treatment of adult and pediatric patients at least 12 years of age with mismatch repair–deficient (dMMR) or microsatellite instability–high (MSI-H) unresectable or metastatic colorectal cancer (CRC).1 The FDA has also converted the accelerated approval of nivolumab monotherapy to a regular approval for the treatment of adult and pediatric patients at least 12 years of age with MSI-H or dMMR metastatic CRC who have progressed after fluoropyrimidine, oxaliplatin, and irinotecan.

The efficacy of nivolumab plus chemotherapy was evaluated in the phase 3 CheckMate 8HW trial (NCT04008030), in which first-line nivolumab plus ipilimumab generated a median progression-free survival (PFS) that was not reached (NR; 95% CI, 38.4-not estimable [NE]) vs 5.8 months (95% CI, 4.4-7.8) with chemotherapy (HR, 0.21; 95% CI, 0.14-0.32; P < .0001) among patients with dMMR/MSI-H metastatic CRC (mCRC).

"The combination of nivolumab plus ipilimumab is a very important step forward for better treatment for MSI-H mCRC," Heinz-Josef Lenz, MD, a CheckMate 8HW investigator, said to OncLive®. "There is no doubt that this is the most effective treatment we have for this MSI-H patient cohort without having significant increased toxicity."

Lenz is 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) in Los Angeles. He is also 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.

The multicenter, open-label CheckMate 8HW trial included patients who were randomly assigned in a 2:2:1 ratio to receive nivolumab monotherapy (n = 353), nivolumab plus ipilimumab (n = 354), or investigator’s choice of mFOLFOX6 (modified folinic acid plus fluorouracil and oxaliplatin) or FOLFIRI (folinic acid plus fluorouracil and irinotecan) with or without bevacizumab (Avastin) or cetuximab (Erbitux; n = 132).2 Patients in the monotherapy arm received nivolumab at 240 mg every 2 weeks for 6 doses, then at 480 mg every 4 weeks thereafter. In the combination arm, patients received nivolumab at 240 mg plus ipilimumab at 1 mg/kg every 3 weeks for 4 doses, followed by nivolumab at 480 mg every 4 weeks.

Eligible patients had histologically confirmed unresectable or metastatic CRC, MSI-H or dMMR status per local testing, no prior treatment with immunotherapy, and an ECOG performance status of 0 or 1.

The primary end points of the trial were PFS per blinded independent central review for nivolumab plus ipilimumab vs chemotherapy in the first-line setting and PFS for nivolumab monotherapy vs nivolumab plus ipilimumab across all lines of treatment. Secondary end points included ORR, health-related quality of life (HRQOL), and safety.

Additional data from CheckMate 8HW, which were presented at the 2025 Gastrointestinal Cancers Symposium, demonstrated early and sustained PFS benefit with the combination regimen compared with nivolumab monotherapy. Among patients with centrally confirmed MSI-H or dMMR status, the median PFS was NR (95% CI, 53.8 months-NE) with nivolumab plus ipilimumab compared with 39.3 months (95% CI, 22.1-NE) with nivolumab alone (HR, 0.62; 95% CI, 0.48-0.81; P = .0003).1,2 The respective PFS rates at 12, 24, and 36 months were 76% vs 63%, 71% vs 56%, and 68% vs 51%.2

Furthermore, at the time of analysis, 6% of patients in the nivolumab/ipilimumab arm and 4% of those in the monotherapy arm remained on treatment. The discontinuation rates due to disease progression were 23% in the combination arm vs 39% in the monotherapy arm. The median duration of treatment was 20.5 months (range, 0-35.9) in the combination arm vs 16.4 months (range, 0-36.0) in the monotherapy arm. Deaths occurred in 29% and 42% of patients in these respective arms.

In the overall randomized population, the median PFS was 54.1 months with nivolumab plus ipilimumab vs 18.4 months with nivolumab alone (HR, 0.64; 95% CI, 0.52-0.79).

The objective response rate (ORR) among MSI-H/dMMR patients was higher in the combination arm, at 71% (95% CI, 65%-76%) compared with 58% (95% CI, 52%-63%) in the monotherapy arm (P = .0011).1,2 Complete responses (CRs) and partial responses (PRs), respectively, were observed in 30% and 40% of patients in the nivolumab/ipilimumab arm compared with 28% and 30% of patients in the monotherapy arm.2 The median time to response (TTR) was 2.8 months in both arms, and the median duration of response (DOR) was NR (95% CI, NE-NE) in both groups.

HRQOL improvements were noted in the nivolumab/ipilimumab arm, with EORTC QLQ-C30 Health Status subscale scores meeting the prespecified threshold for meaningful change from baseline at week 21.

Any-grade treatment-related adverse effects (TRAEs) were reported in 81% of patients receiving nivolumab plus ipilimumab and 71% of those receiving nivolumab alone. The most common TRAEs in the combination vs monotherapy arms were pruritus (26% vs 18%), diarrhea (20% vs 17%), and hypothyroidism (17% vs 9%). The most frequently observed grade 3 or higher TRAE was adrenal insufficiency (2% vs < 1%).

Regarding immune-mediated AEs, the most common any-grade non-endocrine events in the combination vs monotherapy arms were rash (7% vs 6%), diarrhea or colitis (6% vs 4%), and hepatitis (4% vs 1%). The most common endocrine-related AEs included hypothyroidism or thyroiditis (18% vs 9%), hyperthyroidism (12% vs 5%), and adrenal insufficiency (10% vs 3%).

References

1. FDA approves nivolumab with ipilimumab for unresectable or metastatic MSI-H or dMMR colorectal cancer. FDA. April 8, 2025. Accessed April 8, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-ipilimumab-unresectable-or-metastatic-msi-h-or-dmmr-colorectal-cancer
2. Andre T, Elez E, Lenz H-J, et al. First results of nivolumab (NIVO) plus ipilimumab (IPI) vs NIVO monotherapy for microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) from CheckMate 8HW. J Clin Oncol. 2025;43(suppl 4):LBA143. doi:10.1200/JCO.2025.43.4_suppl.LBA143