FDA Accepts sBLA for Opdivo® + Yervoy® in MSI-High/dMMR Cancers
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
Bristol Myers Squibb (NYSE: BMY) has announced that the U.S. Food and Drug Administration (FDA) has accepted its supplemental Biologics License Application (sBLA) for Opdivo® (nivolumab) plus Yervoy® (ipilimumab) as a potential first-line treatment for adult and pediatric patients (12 years and older) with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer (mCRC). The FDA granted Breakthrough Therapy Designation and Priority Review status to the application, with a Prescription Drug User Fee Act (PDUFA) goal date set for June 23, 2025.
Dana Walker, M.D., M.S.C.E., vice president and Opdivo global program lead at Bristol Myers Squibb, highlighted the importance of this milestone, stating, “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. We look forward to potentially bringing a new standard of care treatment option to this patient population.”
Clinical Trial Basis for the sBLA
The application is supported by data from the Phase 3 CheckMate -8HW study, which evaluated the efficacy and safety of Opdivo plus Yervoy compared to the investigator’s choice of chemotherapy in the first-line setting and against Opdivo monotherapy across all lines of therapy. The dual primary endpoints of progression-free survival (PFS) were assessed by Blinded Independent Central Review (BICR).
Initial findings from the CheckMate -8HW trial were first unveiled at the 2024 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium. Further insights and expanded data were subsequently presented at the 2025 ASCO Gastrointestinal Cancers Symposium. The trial demonstrated that the combination of Opdivo and Yervoy significantly improved PFS compared to chemotherapy and Opdivo alone.
Safety evaluations confirmed that the combination’s safety profile remained consistent with previous findings and was manageable using established protocols, with no new safety signals identified. The trial is ongoing to assess secondary endpoints, including overall survival (OS).
Regulatory History and Prior Approvals
Opdivo plus Yervoy received prior approval from the U.S. FDA in July 2018 for the treatment of adult and pediatric patients (12 years and older) with MSI-H or dMMR mCRC that had progressed following prior treatments with fluoropyrimidine, oxaliplatin, and irinotecan. Additionally, in December 2024, the European Union granted approval for Opdivo plus Yervoy as a first-line treatment for adult patients with MSI-H or dMMR unresectable or metastatic colorectal cancer. In October 2024, China’s National Medical Products Administration (NMPA) approved the combination for the same indication.
Bristol Myers Squibb has expressed gratitude to all patients and investigators who participated in the CheckMate -8HW clinical trial, emphasizing the vital role clinical research plays in advancing treatment options for challenging cancers.
About CheckMate -8HW Trial
The CheckMate -8HW (NCT04008030) study is a Phase 3 randomized, open-label clinical trial designed to evaluate Opdivo plus Yervoy versus Opdivo alone or the investigator’s choice of chemotherapy. The trial enrolled patients with MSI-H or dMMR unresectable or metastatic colorectal cancer.
A total of 839 patients were randomized into three study arms:
- Opdivo Monotherapy: Patients received Opdivo 240 mg every two weeks for six doses, followed by Opdivo 480 mg every four weeks.
- Opdivo plus Yervoy Combination Therapy: Patients received Opdivo 240 mg plus Yervoy 1 mg/kg every three weeks for four doses, followed by Opdivo 480 mg every four weeks.
- Investigator’s Choice of Chemotherapy: Patients were treated with modified FOLFOX-6 (mFOLFOX-6) or FOLFIRI with or without bevacizumab or cetuximab.
The trial’s dual primary endpoints were PFS per BICR for Opdivo plus Yervoy versus chemotherapy in the first-line setting and PFS per BICR for Opdivo plus Yervoy compared to Opdivo alone across all lines of therapy. Additional secondary endpoints, including overall survival (OS), are still being analyzed.
The Role of Dual Immunotherapy in MSI-H/dMMR Colorectal Cancer
Colorectal cancer (CRC) remains one of the most common and deadly cancers worldwide. Microsatellite instability-high (MSI-H) and mismatch repair deficient (dMMR) colorectal cancers represent a distinct molecular subtype, accounting for approximately 15% of all colorectal cancers. These tumors typically exhibit a higher mutational burden and greater immunogenicity, making them prime candidates for immune checkpoint inhibitor therapy.
The combination of Opdivo and Yervoy leverages two distinct immune pathways to enhance the body’s immune response against tumors. Opdivo, a PD-1 checkpoint inhibitor, helps restore T-cell activity, while Yervoy, a CTLA-4 inhibitor, amplifies the immune response by priming T cells for activation. Together, these therapies work synergistically to produce a more robust and sustained anti-tumor immune response compared to monotherapy or traditional chemotherapy.
Future Implications of the sBLA Acceptance
If approved, this expanded indication for Opdivo plus Yervoy would represent a significant advancement in first-line treatment options for MSI-H/dMMR metastatic colorectal cancer. Current first-line treatment options for these patients typically involve chemotherapy regimens, which may be associated with significant toxicities and variable efficacy.
The FDA’s Breakthrough Therapy Designation and Priority Review status underscore the potential of Opdivo plus Yervoy to offer a meaningful clinical benefit over existing therapies. Breakthrough Therapy Designation is granted to treatments demonstrating substantial improvement over available therapies for serious or life-threatening conditions. Priority Review accelerates the standard FDA review timeline from ten months to six months, signaling the agency’s recognition of the treatment’s potential impact.
With a PDUFA goal date of June 23, 2025, a regulatory decision on this expanded indication is expected within the coming months. If granted approval, Opdivo plus Yervoy could redefine the standard of care for MSI-H/dMMR metastatic colorectal cancer, offering patients a chemotherapy-free first-line treatment option with durable clinical benefits.
