Positive Results from CheckMate -8HW Trial Lead to Priority Review, Breakthrough Therapy Designation for Opdivo Plus Yervoy in MSI-H/dMMR Colorectal Cancer
The combination of Opdivo plus Yervoy produced significant Phase III trial results in the first-line treatment of patients aged 12 and older with unresectable or metastatic MSI-H/dMMR colorectal cancer.
Credit: Sebastian Kaulitzki | stock.adobe.com
Positive findings from the ongoing Phase III CheckMate -8HW trial (NCT04008030) resulted in the FDA granting Breakthrough Therapy Designation and Priority Review status to a supplemental biologics license application (sBLA) for Opdivo (nivolumab) plus Yervoy (ipilimumab) for the first-line treatment of patients aged 12 years and older with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer (mCRC).1,2 The FDA granted the sBLA with a Prescription Drug User Fee Act target action date of June 23, 2025.
“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,” Dana Walker, MD, MSCE, vice president, Opdivo global program lead, Bristol Myers Squibb, said in a press release.1
Opdivo plus Yervoy was the first immune-oncology combination granted FDA approval for metastatic melanoma. It has also received FDA approval for the first-line treatment of adults with unresectable advanced or metastatic esophageal squamous cell carcinoma; hepatocellular carcinoma; intermediate or poor risk advanced renal cell carcinoma (RCC); unresectable malignant pleural mesothelioma; and non-small cell lung cancer (NSCLC).3
Opdivo is a monoclonal antibody that binds to the PD-1 receptor and inhibits tumor growth by improving T-cell function.4,5 The medication has been approved across an array of indications, both as a single agent and in combination therapy, including for patients with unresectable or metastatic melanoma; metastatic NSCLC; advanced RCC; classical Hodgkin lymphoma; recurrent or metastatic squamous cell carcinoma of the head and neck; locally advanced or metastatic urothelial carcinoma; microsatellite instability-high or mismatch repair deficient metastatic colorectal cancer; and hepatocellular carcinoma.4
Yervoy is a recombinant, human monoclonal antibody that attaches to the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), which inhibits the interaction between CTLA-4 and its CD80/CD86 ligands, prompting to increase in T-cell activation and proliferation, including tumor-infiltrating T-effector cells.
Trial Design
The multinational, open-label, randomized CheckMate -8HW included patients with unresectable or metastatic colorectal cancer and MSI-H or dMMR. Patients were randomly assigned in a 2:2:1 ratio to receive Opdivo combined with Yervoy; Opdivo monotherapy; or investigator’s choice of chemotherapy of mFOLFOX-6 or FOLFIRI with or without bevacizumab or cetuximab.
The trial’s primary endpoints are a PFS comparison with first line Opdivo plus Yervoy versus chemotherapy; and PFS with Opdivo plus Yervoy versus Opdivo monotherapy in patients who may or may not have received prior systemic treatment for metastatic disease. Investigators randomly assigned 303 patients were not previously administered systemic treatment for metastatic disease to receive Opdivo plus Yervoy or chemotherapy, of whom 255 had centrally confirmed MSI-H or dMMR tumors.
A prespecified interim analysis released in December demonstarted that at a median follow-up of 31.5 months (range, 6.1 to 48.4), 24-month PFS was 72% (95% confidence interval [CI], 64 to 79) in patients administered Opdivo plus Yervoy versus 14% (95% CI, 6 to 25) in the chemotherapy group. Compared to chemotherapy, 24-month restricted mean survival time was 10.6 months (95% CI, 8.4 to 12.9) longer in the Opdivo plus Yervoy cohort.
At a median follow-up of 47 months, patients with MSI-H/dMMR mCRC in the Opdivo plus Yervoy cohort experienced a 38% reduction in the risk of disease progression or death compared to Opdivo monotherapy [HR 0.62; 95% CI 0.48–0.81; P = 0.0003]. PFS rates at 12-, 24-, and 36-months with the combination were 76%, 71%, and 68%, respectively, compared to 63%, 56%, and 51%, respectively, with Opdivo monotherapy. ORR as determined by BICR was 71% with Opdivo plus Yervoy versus 58% with Opdivo monotherapy.
In terms of safety, the profile for the combination was consistent with prior adverse event (AE) reporting and deemed manageable with established protocols. Grade 3/4 treatment-related AEs occurred in 22% of patients in the Opdivo plus Yervoy cohort compared to 14% of patients in the Opdivo monotherapy cohort and no new safety signals were identified.
“We look forward to potentially bringing a new standard of care treatment option to this patient population,” Walker added.1
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 25, 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. 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 25, 2025. https://clinicaltrials.gov/study/NCT04008030
3. Opdivo (nivolumab) Plus Yervoy (ipilimumab) Reduced the Risk of Disease Progression or Death by 79% Versus Chemotherapy in Patients with Microsatellite Instability-High or Mismatch Repair Deficient Metastatic Colorectal Cancer in CheckMate -8HW Trial. Bristol Myers Squibb. January 20, 2024. Accessed February 25, 2025. https://news.bms.com/news/corporate-financial/2024/Opdivo-nivolumab-Plus-Yervoy-ipilimumab-Reduced-the-Risk-of-Disease-Progression-or-Death-by-79-Versus-Chemotherapy-in-Patients-with-Microsatellite-Instability-High-or-Mismatch-Repair-Deficient-Metastatic-Colorectal-Cancer-in-CheckMate--8HW-Trial/default.aspx
4. Opdivo. Prescribing information. Bristol Myers Squibb; 2021. Accessed February 25, 2025. https://packageinserts.bms.com/pi/pi_opdivo.pdf
5. FDA approves first immunotherapy for initial treatment of gastric cancer. News release. FDA. April 16, 2021. Accessed February 25, 2025. https://www.fda.gov/news-events/press-announcements/fda-approves-first-immunotherapy-initial-treatment-gastric-cancer
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