Updated CheckMate -8HW Trial Results Show Significant Survival Benefit with Opdivo Plus Yervoy in MSI-H/dMMR Colorectal Cancer

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Data released from the ongoing Phase III CheckMate -8HW trial (NCT04008030) showed a significantly improved progression-free survival (PFS) and overall response rate (ORR) in patients administered Opdivo (nivolumab) plus Yervoy (ipilimumab) compared to Opdivo monotherapy in the first-line treatment of microsatellite-instability–high (MSI-H) or mismatch-repair–deficient (dMMR) metastatic colorectal cancer.^1,2 Study investigators concluded that the dual immunotherapy approach holds promise as a new standard of care for patients with this deadly form of the disease.

“The data presented today confirm nivolumab plus ipilimumab as a new standard treatment for people living with metastatic colorectal cancer given the evidence observed in both disease-free survival and response rate,” Thierry Andre, MD, Medical Oncology Department head, Sorbonne University and Hospital Saint-Antoine, Paris, France, said in a press release. “Importantly, no new safety signals were identified, with a moderate increase of treatment-related adverse events, mostly grade 1 or 2, observed with the combination. Together, these data reaffirm the benefit of dual immunotherapy with [Opdivo] plus [Yervoy] for this population of patients who urgently need improved treatment options.”¹

The combination of Opdivo and Yervoy was the first immune-oncology combination approved by the FDA for metastatic melanoma. The combination is also approved 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 Opdivo 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 is a negative T-cell activity regulator. By attaching to CTLA-4, Yervoy inhibits the interaction between CTLA-4 and its CD80/CD86 ligands. This action has been found to increase T-cell activation and proliferation, including tumor-infiltrating T-effector cells.

Trial Design

CheckMate -8HW is a multinational, open-label, randomized trial that enrolled patients with unresectable or metastatic colorectal cancer and MSI-H or dMMR. Participants were randomly assigned in a 2:2:1 ratio to receive Opdivo plus Yervoy, Opdivo monotherapy, or investigator’s choice of chemotherapy consisting of mFOLFOX-6 or FOLFIRI with or without bevacizumab or cetuximab.

The dual primary endpoints of the trial are a comparison of PFS with first-line Opdivo plus Yervoy vs. chemotherapy and PFS with Opdivo plus Yervoy vs. Opdivo monotherapy in patients regardless of prior systemic treatment for metastatic disease. Investigators randomly assigned 303 patients who had not received prior systemic treatment for metastatic disease to Opdivo plus Yervoy or chemotherapy, of whom 255 had centrally confirmed MSI-H or dMMR tumors.

A prespecified interim analysis released in December show that at a median follow-up of 31.5 months (range, 6.1 to 48.4), the 24-month PFS was 72% (95% confidence interval [CI], 64 to 79) with Opdivo plus Yervoy compared to 14% (95% CI, 6 to 25) with chemotherapy. Results also showed that compared to chemotherapy, 24-month restricted mean survival time was 10.6 months (95% CI, 8.4 to 12.9) longer in patients administered Opdivo plus Yervoy.

The latest results from the trial show that at a median follow-up of 47 months, patients with MSI-H/dMMR mCRC administered Opdivo plus Yervoy achieved a 38% decrease 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, in the monotherapy cohort. For the secondary endpoint, ORR as per BICR was 71% with the combination compared to 58% in the monotherapy cohort.

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.

“The benefit of dual inhibition of PD-1 and CTLA-4 has been well established in Phase III trials of Opdivo plus Yervoy across a broad range of tumor types, including in MSI-H/dMMR mCRC compared to chemotherapy,” Dana Walker, MD, MSCE, vice president, global program lead, late development, oncology, Bristol Myers Squibb, said in the release. “The results from this analysis of the CheckMate -8HW trial answer affirmatively an important question about whether dual I/O therapy with Opdivo plus Yervoy can also improve outcomes for patients with MSI-H/dMMR mCRC compared with Opdivo alone.”¹

References

1. Bristol Myers Squibb Presents Results from CheckMate -8HW Analysis Evaluating Opdivo® (nivolumab) plus Yervoy® (ipilimumab) Compared to Opdivo Monotherapy...News release. Bristol Myers Squibb. January 25, 2025. Accessed January 27, 2025. https://news.bms.com/news/corporate-financial/2025/Bristol-Myers-Squibb-Presents-Results-from-CheckMate--8HW-Analysis-Evaluating-Opdivo-nivolumab-plus-Yervoy-ipilimumab-Compared-to-Opdivo-Monotherapy/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 January 27, 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 January 27, 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 January 27, 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 January 27, 2025. https://www.fda.gov/news-events/press-announcements/fda-approves-first-immunotherapy-initial-treatment-gastric-cancer