FDA approves nivolumab with ipilimumab for unresectable or metastatic MSI-H or dMMR colorectal cancer

Regulatory approval: On April 8, 2025, the FDA granted accelerated approval to nivolumab plus ipilimumab for adult and pediatric patients ≥12 years with unresectable or metastatic MSI-H or dMMR colorectal cancer. The FDA also converted prior accelerated approval to regular approval for single-agent nivolumab in adult and pediatric patients ≥12 years with MSI-H/dMMR metastatic CRC that progressed after fluoropyrimidine, oxaliplatin, and irinotecan. The approvals were supported by CHECKMATE-8HW PFS and response data; OS comparisons were not yet available at interim analysis.

FDA action (regulatory approval)

On April 8, 2025, the FDA granted accelerated approval to nivolumab (Opdivo) plus ipilimumab (Yervoy) for adult and pediatric patients (≥12 years) with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC). The FDA also converted accelerated approval to regular approval for single-agent nivolumab for adult and pediatric patients (≥12 years) with MSI-H/dMMR metastatic CRC that has progressed following fluoropyrimidine, oxaliplatin, and irinotecan.

Supporting trial evidence

Efficacy and safety were evaluated in CHECKMATE-8HW (NCT04008030), a randomized, three-arm, open-label trial in immunotherapy-naïve unresectable/metastatic CRC with known MSI-H/dMMR status.

Primary endpoint: PFS by blinded independent central review (RECIST v1.1) in centrally confirmed MSI-H/dMMR populations.

  • First-line setting (n=255 centrally confirmed of 303 locally tested):

    • Median PFS NR (95% CI 38.4, NE) with nivolumab+ipilimumab vs 5.8 months (95% CI 4.4–7.8) with chemotherapy; HR 0.21 (95% CI 0.14–0.32), p<0.0001.
    • Comparative ORR/OS were not available at interim PFS analysis due to the statistical testing strategy.

  • All lines (n=582 centrally confirmed of 707 locally tested):

    • Median PFS NR (95% CI 53.8, NE) with combination vs 39.3 months (95% CI 22.1, NE) with nivolumab; HR 0.62 (95% CI 0.48–0.81), p=0.0003.
    • ORR: 71% vs 58% (p=0.0011). OS comparisons were not available at interim analysis.

Safety (≥20% incidence)

With nivolumab+ipilimumab: fatigue, diarrhea, pruritus, abdominal pain, musculoskeletal pain, nausea. With nivolumab alone: fatigue, diarrhea, abdominal pain, pruritis, musculoskeletal pain.

Regulatory notes

Reviewed under Project Orbis with collaboration from ANVISA (Brazil), IMoH (Israel), and Health Canada (reviews ongoing). The application received priority review, breakthrough therapy designation, and orphan drug designation.

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