FDA Approves Opdivo Plus Yervoy® for Untreated MSI-H or dMMR Metastatic Colorectal Cancer
Bristol Myers Squibb today announced a major milestone in cancer immunotherapy with the U.S. Food and Drug Administration (FDA) granting approval for the combination of Opdivo® (nivolumab) and Yervoy® (ipilimumab) as a first-line treatment for adults and pediatric patients aged 12 years and older diagnosed with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer (CRC). The approval marks a significant advancement in addressing a highly aggressive and historically difficult-to-treat subset of colorectal cancer.
This regulatory decision was driven by compelling data from the pivotal Phase 3 CheckMate-8HW trial (NCT04008030), the largest and most comprehensive immunotherapy study conducted to date in MSI-H/dMMR metastatic CRC (mCRC). The trial enrolled a total of 839 patients and evaluated the efficacy and safety of dual checkpoint blockade using Opdivo plus Yervoy versus two comparators: Opdivo monotherapy and investigator’s choice chemotherapy regimens in different settings.
A Paradigm Shift: Dual Immunotherapy Achieves Superior Outcomes
CheckMate-8HW assessed Opdivo and Yervoy in both all-line and first-line treatment settings. In one key arm of the trial, 354 patients received the combination therapy, while 353 received Opdivo monotherapy. In another critical arm designed to evaluate first-line treatment specifically, 202 patients were administered Opdivo plus Yervoy, compared with 101 patients who received standard chemotherapy regimens, including mFOLFOX-6 or FOLFIRI, with or without the addition of bevacizumab or cetuximab.
The study met both of its dual primary endpoints—progression-free survival (PFS) across all lines of therapy compared to Opdivo alone, and PFS in the first-line setting compared to chemotherapy. These endpoints were evaluated using Blinded Independent Central Review (BICR), an objective and rigorous methodology.
“This approval provides much-needed hope to patients facing a diagnosis of MSI-H/dMMR metastatic colorectal cancer, particularly those who have not yet received systemic treatment,” said Dr. Heinz-Josef Lenz, a principal investigator on the CheckMate-8HW study and Deputy Director for Research Programs at USC Norris Comprehensive Cancer Center. “The results demonstrate that beginning treatment with the dual immunotherapy combination can offer a significant and sustained survival advantage, changing the way we approach this challenging disease.”
Unprecedented Efficacy: Reduction in Disease Progression and Long-Term Survival Benefits
The data from CheckMate-8HW reveals that Opdivo plus Yervoy led to a 38% reduction in the risk of disease progression or death when compared to Opdivo monotherapy among immunotherapy-naïve patients (Hazard Ratio [HR] = 0.62; 95% Confidence Interval [CI]: 0.48–0.81; P=0.0003). In terms of median PFS, the benefit of dual immunotherapy was so pronounced that the median was not reached (95% CI: 53.8 months–Not Estimable), compared with 39.3 months for Opdivo monotherapy (95% CI: 22.1–NE).
Additionally, PFS rates at 12, 24, and 36 months were consistently higher for the combination arm: 76%, 71%, and 68%, respectively, compared to 63%, 56%, and 51% for monotherapy. Kaplan-Meier curves showed an early separation in survival probability beginning around two months, which remained durable through the three-year mark.
The trial also demonstrated a significantly higher overall response rate (ORR) with the combination regimen—71% versus 58% with Opdivo alone (P=0.0011). These results underline the potential of dual checkpoint inhibition to induce deeper and more durable responses in patients whose tumors exhibit MSI-H/dMMR molecular characteristics.
First-Line Comparison: Dual Immunotherapy Outperforms Chemotherapy by a Wide Margin
Perhaps most striking were the results from the first-line treatment comparison between Opdivo plus Yervoy and chemotherapy. In this arm, the combination reduced the risk of disease progression or death by an extraordinary 79% (HR = 0.21; 95% CI: 0.14–0.32; P<0.0001). Median PFS was again not reached for the combination (95% CI: 38.4–NE), while the chemotherapy arm had a median PFS of just 5.8 months (95% CI: 4.4–7.8).
PFS rates at 12 and 24 months further emphasized the superiority of the dual immunotherapy: 79% and 72%, respectively, compared with just 21% and 14% for chemotherapy. The early separation of Kaplan-Meier survival curves was evident at three months and remained consistent over the two-year follow-up.
These results make Opdivo plus Yervoy the first dual immune checkpoint inhibitor regimen to outperform both a single-agent PD-1 inhibitor and traditional chemotherapy in this specific patient population.
Safety Profile: Manageable and Consistent with Prior Experience
The safety findings from CheckMate-8HW were consistent with the well-established profiles of both Opdivo and Yervoy. Among the most frequently reported adverse reactions (ARs) occurring in ≥10% of patients, grade 3-4 ARs were comparable between the combination therapy and monotherapy groups. No new safety signals were detected, and adverse events were generally manageable through standard treatment algorithms and established monitoring protocols.
The combination was not associated with a significant increase in immune-mediated toxicities beyond what is already known. Importantly, the safety outcomes offer reassurance that the increased efficacy does not come at the expense of tolerability—a key consideration when treating patients with advanced malignancies.
Accelerated Approval: A Reflection of Unmet Need and Strong Clinical Evidence
This FDA approval arrives more than two months ahead of the original Prescription Drug User Fee Act (PDUFA) target action date of June 23, 2025, a reflection of the agency’s recognition of the therapy’s clinical importance. The application was granted Breakthrough Therapy Designation and Priority Review, both of which are regulatory pathways intended to expedite the development and review of drugs that address unmet medical needs in serious or life-threatening conditions.
“By advancing this dual immunotherapy regimen ahead of schedule, the FDA is acknowledging the pressing need for innovative treatments in the MSI-H/dMMR mCRC patient population,” said a spokesperson from Bristol Myers Squibb. “We are committed to continued research and development in immuno-oncology to expand the benefits of this approach to even more patients.”
Important Safety Information
Opdivo and Yervoy are associated with a number of serious immune-mediated adverse events. These include but are not limited to:
- Pneumonitis
- Colitis
- Hepatitis and hepatotoxicity
- Endocrinopathies (including hypothyroidism, hyperthyroidism, adrenal insufficiency, and diabetes mellitus)
- Nephritis with renal dysfunction
- Severe dermatologic adverse reactions
- Infusion-related reactions
- Graft-vs-host disease in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT)
- Embryo-fetal toxicity
Use of Opdivo in combination with a thalidomide analogue and dexamethasone for multiple myeloma is associated with increased mortality and is not recommended outside of controlled clinical trials.
Healthcare professionals should consult the full Prescribing Information for detailed guidance on managing these risks.
