FDA Grants Priority Review to Nivolumab/Ipilimumab in MSI-H/dMMR CRC

Phase 3 CheckMate-8HW trial results evaluating the combination in microsatellite instability–high or mismatch repair deficient CRC supported the decision.

The FDA has accepted and granted priority review to a supplemental biologics license application (BLA) for nivolumab (Opdivo) plus ipilimumab (Yervoy) as a frontline treatment for patients 12 years or older with unresectable or metastatic microsatellite instability–high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer (CRC), according to a news release from the drug’s developer, Bristol Myers Squibb.1

The FDA has assigned a target action date of June 23, 2025.

Acceptance for the application was based on results from the phase 3 CheckMate-8HW study (NCT04008030), which found that the combination therapy met the primary end points of progression-free survival (PFS) compared with investigator’s choice of chemotherapy or nivolumab alone via blinded independent central review (BICR). The most recent update was presented the 2025 ASCO Gastrointestinal Cancer Symposium.2

Findings revealed that among patients with MSI-H or dMMR disease, the median PFS was not reached (NR, 95% CI, 53.8 months to not evaluable [NE]) with the combination therapy vs 39.3 months (95% CI, 22.1-NE) with nivolumab alone (HR, 0.62; 95% CI, 0.48-0.81; P = .0003). In the respective arms, the 12-, 24-, and 36-month PFS rates were 76% vs 63%, 71% vs 56%, and 68% vs 51%. Furthermore, among all-comers in each respective arm, the median PFS was 54.1 months vs 18.4 months (HR, 0.64; 95% CI, 0.52-0.79).

Among those with confirmed MSI-H/dMMR status, the objective response rate (ORR) was 71% (95% CI, 65%-76%) with the investigational therapy vs 58% (95% CI, 52%-64%) with nivolumab monotherapy (P = .0011), with complete responses (CRs) occurring in 30% and 28% of the respective arms and partial responses occurring in 40% and 30% of each. The median time to response (TTR) was 2.8 months (range, 1.2-44.5) vs 2.8 months (range, 1.2-29.5), respectively, with a median duration of response (DOR) of NR (95% CI, NE-NE) in both arms.

“Today’s milestone brings us one step closer to providing an effective dual immunotherapy treatment option to adult and pediatric patients with [MSI-H] or [dMMR] metastatic [CRC],” Dana Walker, MD, MSCE, vice president and the nivolumab global program lead at Bristol Myers Squibb, stated in the news release on the BLA acceptance.1 “We look forward to potentially bringing a new standard-of-care treatment option to this patient population.”

Patients were randomly assigned 2:2:1 to receive nivolumab monotherapy (n = 353), nivolumab plus ipilimumab (n = 354), or investigator’s choice of modified folinic acid plus fluorouracil and oxaliplatin (mFOLFOX6) or folinic acid plus fluorouracil and irinotecan (FOLFIRI) with or without bevacizumab (Avastin) or cetuximab (Erbitux; n = 132). In the monotherapy arm, patients received 240 mg of nivolumab once every 2 weeks for 6 doses followed by 480 mg once every 4 weeks. In the combination arm, patients received 240 mg of nivolumab plus 1 mg/kg of ipilimumab every 3 weeks for 4 doses followed by 480 mg of nivolumab every 4 weeks.

The trial’s primary end points were PFS per BICR for nivolumab/ipilimumab vs chemotherapy in the first-line setting and PFS for nivolumab vs nivolumab/ipilimumab across all lines of treatment.3 Secondary end points included ORR, health-related quality of life, and safety.

Treatment-related adverse effects (TRAEs) of any grade occurred in 81% vs 71% of patients who received the combination therapy vs nivolumab alone. In the respective arms, the most common any-grade TRAEs included pruritus (26% vs 18%), diarrhea (20% vs 17%), and hypothyroidism (17% vs 9%).

References

1. U.S. Food and Drug Administration accepts Bristol Myers Squibb’s supplemental biologics license application for Opdivo® Plus Yervoy® for patients with unresectable or metastatic microsatellite instability-high or mismatch repair deficient colorectal cancer. News release. Bristol Myers Squibb. February 24, 2025. Accessed February 24, 2025. https://tinyurl.com/nhnrvhys
2. Andre T, Elez E, Lenz H-J, et al. First results of nivolumab (NIVO) plus ipilimumab (IPI) vs NIVO monotherapy for microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) from CheckMate 8HW. J Clin Oncol. 2025;43(suppl 4):LBA143. doi:10.1200/JCO.2025.43.4_suppl.LBA143
3. Andre T, Elez E, Van Cutsem E, et al. Nivolumab (NIVO) plus ipilimumab (IPI) vs chemotherapy (chemo) as first-line (1L) treatment for microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): First results of the CheckMate 8HW study. J Clin Oncol. 2024;42(suppl 3):LBA768. doi:10.1200/JCO.2024.42.3_suppl.LBA768