FDA

Nivolumab plus ipilimumab approved for MSI-H/dMMR metastatic CRC

April 11, 2025

FDA approved nivolumab (Opdivo) with ipilimumab (Yervoy) for adult and pediatric patients ≥12 years of age with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer (CRC).

The agency also converted the accelerated approval to regular approval for single agent nivolumab for adult and pediatric patients ≥12 years of age with MSI-H or dMMR metastatic CRC, that’s progressed following fluoropyrimidine, oxaliplatin, and irinotecan.

Efficacy

Efficacy of nivolumab with ipilimumab was evaluated in CHECKMATE-8HW (NCT04008030), a randomized, three-arm, open-label trial in immunotherapy-naïve patients with unresectable or metastatic CRC with known MSI-H or dMMR status. Patients were randomized to receive one of the following treatments:

• nivolumab 240 mg q3wks and ipilimumab 1 mg/kg q3wks for a maximum of 4 doses, then nivolumab 480 mg q4wks,
• nivolumab 240 mg q2wks for 6 doses, then nivolumab 480 mg q4wks, or
• investigator’s choice chemotherapy.

The major efficacy outcome measure was progression-free survival (PFS) in the following pre-specified settings:

• First-line: nivolumab + ipilimumab vs. chemotherapy
• All lines: nivolumab + ipilimumab vs. nivolumab alone

The analysis of nivolumab + ipilimumab vs. chemotherapy in the first-line setting was conducted in 255 patients with centrally confirmed MSI-H/dMMR status of 303 patients based on local testing. Median PFS was not reached (NR) (95% confidence interval [CI], 38.4, not estimable [NE]) in the nivolumab + ipilimumab arm and 5.8 months (95% CI, 4.4, 7.8) in the chemotherapy arm (hazard ratio [HR], 0.21; 95% CI, 0.14, 0.32; p-value <0.0001). Comparative results of overall response rate (ORR) and overall survival (OS) between arms weren’t available at the time of the interim PFS analysis due to statistical testing strategy.

The analysis of nivolumab + ipilimumab vs. nivolumab (all lines) was conducted in 582 patients with centrally confirmed MSI-H/dMMR status of 707 patients based on local testing. Median PFS was NR (95% CI, 53.8, NE) in the nivolumab + ipilimumab arm and 39.3 months (95% CI, 22.1, NE) in the nivolumab arm (HR, 0.62; 95% CI, 0.48, 0.81; p-value 0.0003). ORR was 71% (95% CI, 65, 76) in the nivolumab + ipilimumab arm and 58% (95% CI, 52, 63) in the nivolumab arm (p-value 0.0011). The comparative results of OS between arms weren’t available at the interim PFS analysis due to statistical testing strategy.

Safety

The most common adverse reactions reported in ≥20% of patients treated with nivolumab with ipilimumab were fatigue, diarrhea, pruritus, abdominal pain, musculoskeletal pain, and nausea. The most common adverse reactions reported in ≥20% of patients treated with nivolumab as a single agent were fatigue, diarrhea, abdominal pain, pruritus, and musculoskeletal pain.

Sources:

FDA approves nivolumab with ipilimumab for unresectable or metastatic MSI-H or dMMR colorectal cancer. [News release]. 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-ipilimumab-unresectable-or-metastatic-msi-h-or-dmmr-colorectal-cancer

US Food and Drug Administration approves Opdivo® (nivolumab) plus Yervoy® (ipilimumab) as a treatment for patients with previously untreated microsatellite instability-high or mismatch repair deficient unresectable or metastatic colorectal cancer. [News release]. 2025. https://news.bms.com/news/corporate-financial/2025/U-S--Food-and-Drug-Administration-Approves-Opdivo-nivolumab-plus-Yervoy-ipilimumab-as-a-Treatment-for-Patients-with-Previously-Untreated-Microsatellite-Instability-High-or-Mismatch-Repair-Deficient-Unresectable-or-Metastatic-Colorectal-Cancer1/default.aspx