Nivolumab Plus Ipilimumab FDA Approved for MSI-H, dMMR Colorectal Cancer

The FDA has approved nivolumab (Opdivo; Bristol Myers Squibb Company) with ipilimumab (Yervoy; Bristol Myers Squibb Company) for adult and pediatric patients aged 12 years and older with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer (CRC).¹

Nivolumab with ipilimumab FDA approved for MSI-H, dMMR CRC. | Image Credit: Pawel - stock.adobe.com

Additionally, the FDA 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 (mCRC) that has progressed following fluoropyrimidine, oxaliplatin, and irinotecan.

The approval is based on the efficacy and safety findings from CHECKMATE-8HW (NCT04008030), a randomized, 3-arm, open-label trial in immunotherapy-naive patients with unresectable or mCRC with known MSI-H or dMMR status.

A total of 839 immunotherapy-naive patients with histologically confirmed MSI-H/dMMR mCRC and an Eastern Cooperative Oncology Group performance status of 0 or 1 were randomized to 1 of 3 treatment arms: nivolumab monotherapy (240 mg every 2 weeks for 6 doses, then 480 mg every 4 weeks), nivolumab plus ipilimumab (nivolumab 240 mg plus ipilimumab 1 mg/kg every 3 weeks for 4 doses, followed by nivolumab 480 mg every 4 weeks), or investigator’s choice chemotherapy.²

The dual primary end points were progression-free survival (PFS) assessed by blinded independent central review in the first-line setting (nivolumab/ipilimumab vs chemotherapy) and across all lines of therapy (nivolumab/ipilimumab vs nivolumab alone).

In the first-line setting, the combination therapy demonstrated a significant improvement in PFS compared with chemotherapy, with median PFS not reached vs 5.8 months, respectively (HR, 0.21; P < .0001).¹ In the broader population across all lines of therapy, nivolumab plus ipilimumab also outperformed nivolumab monotherapy, with a higher median PFS (not reached vs 39.3 months; HR, 0.62; P = .0003) and objective response rate (71% vs 58%; P = .0011).

While overall survival data were not available at the time of interim analysis, the combination regimen showed a strong efficacy signal. Common adverse reactions included fatigue, diarrhea, and abdominal or musculoskeletal pain, with similar profiles observed across treatment arms.

These findings support the clinical benefit of dual checkpoint inhibition in MSI-H/dMMR metastatic CRC.

This review was conducted as part of Project Orbis, an initiative of the FDA’s Oncology Center of Excellence that enables concurrent submission and review of oncology therapies across international regulatory authorities. For this application, the FDA collaborated with the Brazilian Health Regulatory Agency, the Israel Ministry of Health, and Health Canada. Review processes are still underway at the participating international agencies.

References

1. FDA approves nivolumab with ipilimumab for unresectable or metastatic MSI-H or dMMR colorectal cancer. FDA. News release. 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?utm_medium=email&utm_source=govdelivery

2. Sava J. FDA accepts sBLA for nivolumab/ipilimumab combo in dMMR/MSI-H CRC. Targeted Oncology^®. February 24, 2025. Accessed April 8, 2025. https://www.targetedonc.com/view/fda-accepts-sbla-for-nivolumab-ipilimumab-combo-in-dmmr-msi-h-crc