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A prespecified interim analysis from the Phase III CheckMate 8HW trial (NCT04008030) found that the combination of Opdivo (nivolumab) plus Yervoy (ipilimumab) significantly improved progression-free survival (PFS) over chemotherapy in the first-line treatment of microsatellite-instability–high (MSI-H) or mismatch-repair–deficient (dMMR) metastatic colorectal cancer.1,2 Results of the analysis, published by The New England Journal of Medicine, also showed fewer severe treatment-related adverse events (TRAEs) with consistent benefits across patient subgroups, according to the trial investigators.
“Historically, patients with MSI-H or dMMR metastatic colorectal cancer have poor outcomes when treated with standard chemotherapy with or without targeted therapies,” the study authors wrote. “[PFS] was longer with the programmed death 1 (PD-1) inhibitor pembrolizumab than with chemotherapy among previously untreated patients with MSI-H or dMMR metastatic colorectal cancer in the KEYNOTE-177 trial. However, 29% of the patients treated with pembrolizumab had progressive disease as the best overall response, and 48% were alive and did not have progressive disease at 2 years of follow-up.”1
Opdivo plus Yervoy was the first immune-oncology combination approved by the FDA for metastatic melanoma. The combination is also indicated 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.
The multinational, open-label, randomized CheckMate 8HW trial enrolled patients with unresectable or metastatic colorectal cancer and MSI-H or dMMR status, who were randomly assigned in a 2:2:1 ratio to receive Opdivo plus Yervoy, Opdivo monotherpay, or chemotherapy with or without targeted therapies. The trial’s dual primary endpoints were PFS with first-line Opdivo plus Yervoy compared to chemotherapy and PFS with Opdivo plus Yervoy compared to 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 patients had centrally confirmed MSI-H or dMMR tumors.
Results show that at a median follow-up of 31.5 months (range, 6.1 to 48.4), PFS outcomes were significantly superior in patients administered Opdivo plus Yervoycompared to chemotherapy (P<0.001), with 24-month PFS of 72% (95% confidence interval [CI], 64 to 79) with the combination vs. 14% (95% CI, 6 to 25) with chemotherapy. Further, 24-month restricted mean survival time was 10.6 months (95% CI, 8.4 to 12.9) longer in the Opdivo plus Yervoy cohort compared to chemotherapy, which investigators said is consistent with the primary analysis of PFS.
In terms of safety, grade 3 and 4 TRAEs were reported by 23% of the patients in the Opdivo plus Yervoy cohort compared to 48% of patients in the chemotherapy cohort, which is consistent with the established profiles of the individual drugs, and no new safety signals were reported.
“Nivolumab plus ipilimumab also led to better progression-free survival outcomes than chemotherapy among all patients who underwent randomization,” the study authors concluded. “These progression-free survival results from the CheckMate 8HW trial are consistent with previous data of first-line nivolumab plus ipilimumab from the nonrandomized CheckMate 142 study, and they support the use of nivolumab plus ipilimumab in MSI-H or dMMR metastatic colorectal cancer.”1
References
1. Andre T., et al. Nivolumab plus Ipilimumab in Microsatellite-Instability–High Metastatic Colorectal Cancer. N Engl J Med 2024;391:2014-2026. DOI: 10.1056/NEJMoa2402141. Vol. 391 No. 21.
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 September 19, 2024. Accessed December 2, 2024. 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. December 2, 2024. 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
3. Opdivo. Prescribing information. Bristol Myers Squibb; 2021. Accessed December 2, 2024. https://packageinserts.bms.com/pi/pi_opdivo.pdf
4. FDA approves first immunotherapy for initial treatment of gastric cancer. News release. FDA. April 16, 2021. Accessed December 2, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-immunotherapy-initial-treatment-gastric-cancer