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