SUMMARY: The American Cancer Society estimates that in 2024, about 100,640 new cases of melanoma were diagnosed in the United States and 8,290 people died of the disease. The rates of melanoma have been rising rapidly over the past few decades, but this has varied by age.
A better understanding of Immune checkpoints has opened the doors for the discovery of novel immune targets. Immune checkpoints are cell surface inhibitory proteins/receptors that harness the immune system and prevent uncontrolled immune reactions. Survival of cancer cells in the human body may be related to their ability to escape immune surveillance, by inhibiting T lymphocyte activation. Under normal circumstances, inhibition of an intense immune response and switching off the T cells of the immune system is accomplished by Immune checkpoints or gate keepers. With the recognition of Immune checkpoint proteins and their role in suppressing antitumor immunity, antibodies have been developed that target the membrane bound inhibitory Immune checkpoint proteins/receptors such as CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152), PD-1(Programmed cell Death 1), etc. By blocking the Immune checkpoint proteins, T cells are unleashed, resulting in T cell proliferation, activation and a therapeutic response.
YERVOY® (Ipilimumab) is a fully human immunoglobulin G1 monoclonal antibody that blocks Immune checkpoint protein/receptor CTLA-4, and was the first systemic therapy in randomized Phase III trials, to show prolonged Overall Survival (OS) in patients with advanced melanoma. YERVOY® in a pooled analysis of data from 12 studies showed a 3-year Overall Survival of 26% among treatment naive patients, and survival up to 10 years in approximately 20% of all patients, with advanced melanoma. The two PD-1 inhibitors of interest are OPDIVO® (Nivolumab) and KEYTRUDA® (Pembrolizumab), which are fully human, Immunoglobulin G4, anti-PD-1 targeted monoclonal antibodies that bind to the PD-1 receptor, and block its interaction with ligands PD-L1 and PD-L2, following which the tumor-specific effector T cells are unleashed. They are thus able to undo PD-1 pathway-mediated inhibition of the immune response. When compared with YERVOY® in patients with advanced melanoma, PD-1 inhibitors, both OPDIVO® and KEYTRUDA® have demonstrated superior Overall Survival (OS), Progression Free Survival (PFS), and Objective Response Rate (ORR), with a better safety profile. OPDIVO® in combination with YERVOY® in a Phase I study resulted in an Overall Survival of 68% at 3 years among patients with advanced melanoma, regardless of prior therapies.
CheckMate 067 is a double-blind Phase III study in which patients with previously untreated advanced melanoma were randomly assigned in a 1:1:1 ratio to receive one of the three regimens: OPDIVO® 1 mg/kg every 3 weeks plus YERVOY® 3 mg/kg every 3 weeks for four doses, followed by OPDIVO® 3 mg/kg every 2 weeks (N=314); OPDIVO® 3 mg/kg every 2 weeks plus placebo (N=316); or YERVOY® 3 mg/kg every 3 weeks for four doses plus placebo (N=315). Randomization was stratified according to BRAF mutation status, metastasis stage, and Programmed cell Death Ligand 1 (PD-L1) status. Treatment was continued until disease progression or unacceptable toxicities. The two Primary end points were PFS and OS in the OPDIVO® plus YERVOY® group, and in the OPDIVO® group versus the YERVOY® group.
The researchers had previously reported the results from the 6.5 year analysis, which showed durable improved outcomes with OPDIVO® plus YERVOY®, and OPDIVO® alone, when compared to single agent YERVOY®, among patients with advanced melanoma. The authors in this publication reported the final 10-year results for the CheckMate 067 trial, including results for Overall Survival and Melanoma-Specific Survival, as well as Durability of Response.
With a minimum follow-up of 10 years, median Overall Survival for patients treated with OPDIVO® plus YERVOY® combination therapy was 71.9 months, for those treated with single agent OPDIVO® was 36.9 months, and 19.9 months with single agent YERVOY®. The Hazard Ratio for death was 0.53 for OPDIVO® plus YERVOY® as compared with YERVOY® and was 0.63 for single agent OPDIVO® as compared with YERVOY®. Median Melanoma-Specific Survival was more than 120 months with OPDIVO® plus YERVOY® combination therapy (Not Reached, with 37% of the patients alive at the end of the trial), 49.4 months with single agent OPDIVO®, and 21.9 months with YERVOY®. Among patients who had been alive and progression free at 3 years, 10-year Melanoma-Specific Survival was 96% with OPDIVO® plus YERVOY®, 97% with single agent OPDIVO®, and 88% with YERVOY®.
In conclusion, these 10-year data have shown ongoing survival benefits with OPDIVO® plus YERVOY® and with single agent OPDIVO®, as compared with YERVOY® monotherapy, in patients with advanced melanoma, potentially offering a curative therapy for responding patients.
Final, 10-Year Outcomes with Nivolumab plus Ipilimumab in Advanced Melanoma. Wolchok JD, Chiarion-Sileni V, Rutkowsk P, et al. for the CheckMate 067 Investigators. N Engl J Med 2025;392:11-22.
