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

• The FDA accepted the supplemental biologics license application (sBLA) for the combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) as a potential first-line treatment option 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 (mCRC).
• Results from the phase 3 CheckMate 8HW study (NCT04008030) serve as the basis for this application.
• A Prescription Drug User Fee Act (PDUFA) action date of June 23, 2025, has been set.

The FDA has accepted the sBLA for nivolumab and ipilimumab as a first-line therapy for unresectable or metastatic MSI-H/dMMR colorectal cancer in both adult and pediatric patients aged 12 years and older.¹

Findings from the 3-arm phase 3 CheckMate 8HW study support this application, as the combination of nivolumab and ipilimumab in the first-line setting met the study’s dual primary end points of progression-free survival (PFS) vs investigator’s choice of chemotherapy. The same was true when the combination was compared with nivolumab monotherapy across all lines of therapy, as assessed by blinded independent central review (BICR).^1,2

Initial results from the study were presented at the 2024 American Society of Clinical Oncology Gastrointestinal Cancers Symposium (ASCO GI). Final ASCO GI data presented in 2025 confirmed the manageable and consistent safety profile of the dual immunotherapy combination, with no new safety signals identified since the first presentation.

“CheckMate 8HW has been looking for several years now as we have gotten updates from the study's maturation, at the combination of nivolumab and ipilimumab. It drives home the point of knowing biomarkers as early as possible, because if you can save a patient from chemotherapy, that is a wonderful thing to do,” said Mark A. Lewis, MD, director of gastrointestinal oncology at Intermountain Health, in an interview with Targeted Oncology^TM.

“Today’s milestone brings us one step closer to providing an effective dual immunotherapy treatment option to adult and pediatric patients with microsatellite instability-high or mismatch repair deficient metastatic colorectal cancer,” said Dana Walker, MD, MSCE, vice president, nivolumab global program lead, Bristol Myers Squibb, in a press release. “We look forward to potentially bringing a new standard of care treatment option to this patient population.”

Previously in July 2018, the combination of nivolumab and ipilimumab was granted FDA approval for adult and pediatric patients 12 years and older with MSI-H or dMMR mCRC who have progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan.

In December 2024, the European Union approved this combination for the first-line treatment of adult patients with MSI-H or dMMR unresectable or mCRC. In October 2024,the China National Medical Products Administration also approved this combination for the same indication.

With this sBLA application accepted, a PDUFA target action date has been set for June 23, 2025.

Microscopic, photorealistic image of colorectal cancer cells - Generated with Adobe Firefly

About the CheckMate 8HW Trial

CheckMate 8HW is a randomized, open-label, phase 3 study evaluating the combination of nivolumab and ipilimumab vs nivolumab alone or the investigator’s choice of chemotherapy for the treatment of patients with MSI-H or dMMR unresectable or mCRC.³

A total of 839 patients were randomly assigned to receive either nivolumab as monotherapy at a dose of 240 mg once every 2 weeks for 6 doses, followed by nivolumab 480 mg once every 4 weeks (Q4W), the combination of nivolumab 240 mg and ipilimumab 1 mg/kg once every 3 weeks for 4 doses, followed by nivolumab 480 mg Q4W, or investigator’s choice of chemotherapy.

Enrollment was open to patients with histologically confirmed unresectable or metastatic CRC, MSI-H or dMMR status per local testing, those who had no prior treatment with immunotherapy, and those with an ECOG performance status of 0 or 1.

PFS per BICR for the nivolumab/ipilimumab combination vs investigator’s choice of chemotherapy in the first-line setting and PFS per BICR for the combination vs nivolumab alone across all lines of therapy served as the dual primary end points of the trial. The study is ongoing to assess secondary end points, including overall survival. Other secondary end points being evaluated are overall response rate (ORR), health-related quality of life, and safety.²

Updated Safety and Efficacy Data

According to updated results from the 2025 ASCO GI meeting, the combination of nivolumab with ipilimumab significantly improved PFS in this patient population.² Among patients with centrally confirmed MSI-H or dMMR status, the median PFS was not reached (NR; 95% CI, 53.8 months to not evaluable [NE]) in the nivolumab/ipilimumab arm vs 39.3 months (95% CI, 22.1-NE) in the nivolumab monotherapy arm (HR, 0.62; 95% CI, 0.48-0.81; P = .0003). In each respective arm across this population, the PFS rates were 76% vs 63% at 12 months, 71% vs 56% at 24 months, and 68% vs 51% at 36 months. The median PFS was 54.1 months vs 18.4 months across all randomly assigned patients, respectively (HR, 0.64; 95% CI, 0.52-0.79).

In the MSI-H/dMMR tumor population, the ORR was 71% (95% CI, 65%-76%) with nivolumab plus ipilimumab vs 58% (95% CI, 52%-64%) with nivolumab alone (P = .0011). Complete responses and partial responses were seen in 30% and 40% of the nivolumab/ipilimumab arm and 28% and 30% of the ipilimumab monotherapy arm, respectively. Additionally, the median time to response in each arm was 2.8 months (range, 1.2-44.5) vs 2.8 months (range, 1.2-29.5), and the median duration of response was NR (95% CI, NE-NE) vs NR (95% CI, NE-NE).

For safety, treatment-related adverse events (TRAEs) of any grade were seen in 81% and 71% of patients treated with the combination of nivolumab and ipilimumab and nivolumab monotherapy, respectively. The most common any-grade TRAEs in each arm were pruritus (26% vs 18%), diarrhea (20% vs 17%), and hypothyroidism (17% vs 9%). Grade 3 or higher TRAEs were also seen in each arm, with the most common being adrenal insufficiency (2% vs less than 1%).

The most common any-grade non-endocrine events in the combination and monotherapy arms were rash (7% vs 6%), diarrhea or colitis (6% vs 4%), and hepatitis (4% vs 1%), respectively. Further, the most common endocrine events in each arm included hypothyroidism or thyroiditis (18% vs 9%), hyperthyroidism (12% vs 5%), and adrenal insufficiency (10% vs 3%).

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://tinyurl.com/3emw343x

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. 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 (mCRC) (CheckMate 8HW). ClinicalTrials.gov. Updated December 18, 2024. Accessed February 24, 2025. https://www.clinicaltrials.gov/study/NCT04008030