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On April 8, 2025, the Food and Drug Administration approved nivolumab (Opdivo, Bristol Myers Squibb Company) with ipilimumab (Yervoy, Bristol Myers Squibb Company) for adult and pediatric patients 12 years of age and older with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer (CRC). The FDA also converted the accelerated approval to regular approval for single agent nivolumab for adult and pediatric patients 12 years of age and older with MSI-H or dMMR metastatic CRC, that has progressed following fluoropyrimidine, oxaliplatin, and irinotecan.
Full prescribing information for Opdivo and Yervoy will be posted on Drugs@FDA.
Efficacy and Safety
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 every 3 weeks and ipilimumab 1 mg/kg every 3 weeks for a maximum of 4 doses, then nivolumab 480 mg every 4 weeks,
- nivolumab 240 mg every 2 weeks for 6 doses, then nivolumab 480 mg every 4 weeks, or
- investigator’s choice chemotherapy:
The major efficacy outcome measure was progression-free survival (PFS) assessed by blinded independent central review (BICR) per RECIST v1.1 in patients with centrally confirmed MSI-H/dMMR status in the following pre-specified settings:
- First-line setting: nivolumab + ipilimumab versus chemotherapy,
- All lines: nivolumab + ipilimumab versus nivolumab alone.
The analysis of nivolumab + ipilimumab versus 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% 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 0.21 [95% CI: 0.14, 0.32] p-value <0.0001). Comparative results of ORR and OS between arms were not available at the time of the interim PFS analysis due to statistical testing strategy.
The analysis of nivolumab + ipilimumab versus 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 (Hazard ratio 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 were not available at the interim PFS analysis due to statistical testing strategy.
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, pruritis, and musculoskeletal pain.
See the prescribing information for the recommended doses of nivolumab and ipilimumab.
Expedited Programs
This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, FDA collaborated with the Brazilian Health Regulatory Agency (ANVISA), the Israel Ministry of Health (IMoH), and Health Canada (HC). The application reviews are ongoing at the other regulatory agencies.
This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment. The FDA approved this application 10 weeks ahead of the FDA goal date.
This application was granted priority review, breakthrough designation, and orphan drug designation. FDA expedited programs are described in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.
For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact OCE’s Project Facilitate at 240-402-0004 or email OncProjectFacilitate@fda.hhs.gov.