Nivolumab with ipilimumab is approved by the USFDA for unresectable or metastatic MSI-H or dMMR colorectal cancer

On April 8, 2025, the Food and Drug Administration approved nivolumab (Opdivo, Bristol Myers Squibb Company) and ipilimumab (Yervoy, Bristol Myers Squibb Company) for adults and children 12 years and older with colorectal cancer (CRC) that cannot be surgically removed or has spread, and is either microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).

The FDA has switched nivolumab’s fast-track approval for use alone to regular approval for adults and kids aged 12 and older with MSI-H or dMMR metastatic CRC that has gotten worse after treatment with fluoropyrimidine, oxaliplatin, and irinotecan.

Effectiveness and Safety

The effectiveness of nivolumab with ipilimumab was evaluated in CHECKMATE-8HW (NCT04008030), a study where patients with advanced colorectal cancer who had not received immunotherapy before and had known MSI-H or dMMR status were randomly assigned to one of three treatment groups. We randomly assigned patients to receive one of the following treatments:

Nivolumab 240 mg is administered every 3 weeks, and ipilimumab 1 mg/kg every 3 weeks for a maximum of 4 doses, followed by nivolumab 480 mg every 4 weeks, or nivolumab 240 mg every 2 weeks for 6 doses; thereafter, nivolumab 480 mg every 4 weeks, or chemotherapy at the investigator’s discretion.

The main goal of the study was to measure how long patients with confirmed MSI-H/dMMR status lived without their disease getting worse, as assessed by an independent review team using RECIST v1.1.

First treatment: nivolumab with ipilimumab compared to chemotherapy; later treatments: nivolumab with ipilimumab versus nivolumab alone.

The study compared nivolumab + ipilimumab to chemotherapy in the first treatment line using 255 patients who had their MSI-H/dMMR status confirmed, out of a total of 303 patients assessed locally. The median progression-free survival (PFS) was not reached (NR) (95% CI: 38.4, not estimable [NE]) in the nivolumab + ipilimumab cohort, while it was 5.8 months (95% CI: 4.4, 7.8) in the chemotherapy cohort (Hazard ratio 0.21 [95% CI: 0.14, 0.32], p-value <0.0001). Comparative data on the overall response rate (ORR) and overall survival (OS) between the arms were unavailable during the interim progression-free survival (PFS) analysis due to the statistical testing approach employed.

The study compared nivolumab with ipilimumab to nivolumab by itself in 582 people who had their MSI-H/dMMR status confirmed, out of 707 patients tested locally. The average time without the disease getting worse (PFS) was not reached (NR) in the nivolumab + ipilimumab group and was 39.3 months in the nivolumab group, with a hazard ratio of 0.62 and a p-value of 0.0003.

The overall response rate (ORR) was 71% (95% CI: 65, 76) for the nivolumab + ipilimumab group and 58% (95% CI: 52, 63) for the nivolumab group (p-value 0.0011). The overall survival results between the groups could not be accessed during the early analysis of progression-free survival because of the way the statistical tests were done.

The predominant adverse events observed in ≥20% of individuals receiving nivolumab in conjunction with ipilimumab included fatigue, diarrhea, pruritus, stomach discomfort, musculoskeletal pain, and nausea. The predominant adverse responses observed in ≥20% of individuals administered nivolumab as a monotherapy included fatigue, diarrhea, abdominal pain, pruritus, and musculoskeletal pain.