FDA Accepts sBLA for Nivolumab/Ipilimumab in Unresectable/Metastatic MSI-H/dMMR CRC

The FDA has accepted a supplemental biologics license application (sBLA) seeking the approval of nivolumab (Opdivo) plus ipilimumab (Yervoy) for the first-line treatment of adult and pediatric patients at least 12 years of age with unresectable or metastatic microsatellite instability–high (MSI-H) or mismatch repair–deficient (dMMR) colorectal cancer (CRC).1

The FDA has granted the sBLA breakthrough therapy designation and priority review status. The Prescription Drug User Fee Act target action date is June 23, 2025.

The sBLA is supported by findings from the 3-arm, phase 3 CheckMate 8HW trial (NCT04008030), in which the combination generated superior progression-free survival (PFS) outcomes as assessed by blinded independent central review (BICR) in the frontline setting compared with investigator’s choice of chemotherapy, as well as across all lines of therapy compared with nivolumab monotherapy. Initial findings from the trial, which were presented at the 2024 Gastrointestinal Cancers Symposium, demonstrated that at a data cutoff date of October 12, 2023, and a median follow-up of 24.3 months, among patients with first-line, centrally confirmed MSI-H/dMMR metastatic CRC (mCRC), the median PFS with nivolumab plus ipilimumab (n = 171) was not reached (NR; 95% CI, 38.4 months-not evaluable [NE]) vs 5.9 months (95% CI, 4.4-7.8) with chemotherapy (n = 84; HR, 0.21; 95% CI, 0.13-0.35; P < .0001).2 The respective 12- and 24-month PFS rates were 79% and 72% in the nivolumab/ipilimumab arm vs 21% and 14% in the chemotherapy arm.

Updated findings from the trial, which were presented at the 2025 Gastrointestinal Cancers Symposium, showed that at a data cutoff date of August 28, 2024, and a median follow-up of 47.0 months (range, 16.7-60.5), among patients with centrally confirmed MSI-H/dMMR mCRC treated across all lines of therapy, the median PFS with nivolumab plus ipilimumab (n = 296) was NR (95% CI, 53.8 months-NE) vs 39.3 months (95% CI, 22.1-NE) with nivolumab alone (n = 286; HR, 0.62; 95% CI, 0.48-0.81; P = .0003).3 The respective 12-, 24-, and 36-month PFS rates were 76%, 71%, and 68% in the combination arm vs 63%, 56%, and 51% in the monotherapy arm.

“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 mCRC,” Dana Walker, MD, MSCE, vice president and Opdivo global program lead at Bristol Myers Squibb, stated in a news release.1 “We look forward to potentially bringing a new standard-of-care treatment option to this patient population.”

The open-label CheckMate-8HW trial enrolled patients with histologically confirmed, unresectable or metastatic CRC with MSI-H/dMMR status confirmed by local testing and an ECOG performance status of 0 or 1.2 A total of 839 patients were randomly assigned to receive nivolumab monotherapy (nivolumab at 240 mg every 2 weeks for 6 doses, then at 480 mg every 4 weeks), nivolumab plus ipilimumab (nivolumab at 240 mg plus ipilimumab at 1 mg/kg every 3 weeks for 4 doses, followed by nivolumab monotherapy at 480 mg every 4 weeks), or investigator’s choice of mFOLFOX6 (5-fluorouracil, leucovorin, and oxaliplatin) or FOLFIRI (folinic acid, fluorouracil, and irinotecan) with or without bevacizumab (Avastin) or cetuximab (Erbitux).1,2 Treatment in all arms continued until disease progression, unacceptable toxicity, or withdrawal of consent. Patients in the nivolumab/ipilimumab and nivolumab monotherapy arms had a maximum treatment duration of 2 years.2

The dual primary end points of the trial were PFS per BICR for nivolumab plus ipilimumab compared with chemotherapy in the frontline setting, and nivolumab plus ipilimumab compared with nivolumab monotherapy across all lines of therapy. Other select end points included safety, overall survival, objective response rate by BICR, and patient-reported outcomes.

Notably, the safety profile of nivolumab plus ipilimumab in CheckMate-8HW was consistent with previously reported safety data, and investigators identified no new safety signals.1

CheckMate-8HW is ongoing to evaluate secondary end points.

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... News release. Bristol Myers Squibb. February 24, 2025. Accessed February 24, 2025. https://news.bms.com/news/corporate-financial/2025/U.S.-Food-and-Drug-Administration-Accepts-Bristol-Myers-Squibbs-Supplemental-Biologics-License-Application-for-Opdivo-Plus-Yervoy-for-Patients-with-Unresectable-or-Metastatic-Microsatellite-Instability-High-or-Mismatch-Repair-Deficient/default.aspx
2. 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
3. Andre T, Elez E, Lenz H, 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 Onol. 2025;43(suppl 4):LBA143. doi:10.1200/JCO.2025.43.4_suppl.LBA143