Nivolumab and Ipilimumab Approved for MSI-H/dMMR Colorectal Cancer
Expert Perspectives · Lyn Brook · 2025-04-09
The FDA has granted approval to nivolumab (Opdivo®, Bristol Myers Squibb) plus ipilimumab (Yervoy®, Bristol Myers Squibb) for the treatment of 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).
In addition, this approval converts the accelerated approval of single-agent nivolumab for MSI-H or dMMR metastatic CRC into a traditional approval. The single-agent indication applies to patients whose disease has progressed following prior treatment with fluoropyrimidine, oxaliplatin, and irinotecan.
Wondering how to discuss this trial with patients? Hear how from Dr. Christopher Lieu!
Why This Approval Matters
The approval of nivolumab in combination with ipilimumab provides a new immunotherapy-based treatment option for patients with MSI-H or dMMR metastatic CRC. This combination offers significant improvements in progression-free survival (PFS) compared to chemotherapy or nivolumab monotherapy, solidifying its role as a first-line treatment option for this patient population.
Breaking Down the CHECKMATE-8HW Trial
The efficacy of nivolumab plus ipilimumab was evaluated in the CHECKMATE-8HW trial (NCT04008030), a phase 3, three-arm, open-label study. The trial enrolled immunotherapy-naïve patients with unresectable or metastatic CRC and confirmed MSI-H or dMMR status. Patients were randomized to one of three treatment arms:
- Nivolumab + ipilimumab combination therapy: Nivolumab 240 mg every three weeks with ipilimumab 1 mg/kg every three weeks for up to four doses, followed by nivolumab 480 mg every four weeks
- Nivolumab monotherapy: Nivolumab 240 mg every two weeks for six doses, followed by nivolumab 480 mg every four weeks
- Investigator’s choice chemotherapy
Key efficacy endpoints included PFS as assessed by blinded independent central review (BICR) per RECIST v1.1, overall response rate (ORR), and overall survival (OS).
First-Line Setting
In the first-line setting, 255 patients with centrally confirmed MSI-H/dMMR status were analyzed. The median PFS was not reached in the nivolumab plus ipilimumab arm compared with 5.8 months in the chemotherapy arm. The hazard ratio (HR) for disease progression or death was 0.21, demonstrating a significant improvement with the combination therapy. At the time of interim PFS analysis, comparative results of ORR and OS between arms were not available due to statistical testing strategy.
All Lines of Therapy
In the all-lines analysis, 582 patients with centrally confirmed MSI-H/dMMR status were evaluated. The median PFS was not reached in the nivolumab plus ipilimumab arm, compared with 39.3 months in the nivolumab monotherapy arm. The HR for disease progression or death was 0.62. The ORR was 71% (95% CI: 65, 76) in the combination arm versus 58% in the monotherapy arm. At the time of interim PFS analysis, comparative results of OS between arms were not available due to statistical testing strategy.
Managing Adverse Events
The most common adverse reactions experienced by ≥20% of patients treated with nivolumab plus ipilimumab were fatigue, diarrhea, pruritus, abdominal pain, musculoskeletal pain, and nausea. The most common adverse reactions experienced in ≥20% of patients treated with nivolumab as a single agent were fatigue, diarrhea, abdominal pain, pruritus, and musculoskeletal pain.
Clinical Implications and Future Outlook
“Nivolumab plus ipilimumab showed superior PFS versus nivolumab across all treatment lines, with a manageable safety profile, in patients with MSI-H or dMMR metastatic CRC,” concluded Thierry André, MD, a Professor of Medical Oncology at the Sorbonne University in Paris, France, and colleagues, in their published results of the CHECKMATE-8HW trial, on which approval was based. “These results, together with the first-line results of superior PFS with nivolumab plus ipilimumab versus chemotherapy, suggest nivolumab plus ipilimumab as a potential new standard of care for patients with MSI-H or dMMR metastatic CRC.”
Dosing and Administration
Refer to the prescribing information for the recommended dosages of nivolumab and ipilimumab.
Resources
Clinicaltrials.gov (2025). A study of nivolumab, nivolumab plus ipilimumab, or investigator’s choice chemotherapy for the treatment of participants with deficient mismatch repair (dMMR)/microsatellite instability high (MSI-H) metastatic colorectal cancer. NLM identifier: NCT04008030