SUMMARY: The American Cancer Society estimates that for 2025, about 104,960 new cases of melanoma of the skin will be diagnosed in the United States and 8430 people are expected to die 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), a fully human immunoglobulin G1 monoclonal antibody that blocks immune checkpoint protein/receptor CTLA-4 was compared with PD-1 inhibitors, OPDIVO® (Nivolumab) and KEYTRUDA® (Pembrolizumab) in patients with advanced melanoma, and both OPDIVO® and KEYTRUDA® have demonstrated superior Overall Survival (OS), Progression Free Survival (PFS), and Objective Response Rate (ORR), and with a better safety profile. In the CheckMate 067, which is a double-blind Phase III study, results from the 6.5 year analysis showed that a combination of OPDIVO® plus YERVOY® demonstrated significant improvement in OS and PFS, when compared to single agent OPDIVO® or single agent YERVOY®.
In an attempt to improve outcomes and enhance the risk-benefit profiles of immunotherapy combinations, alternate immune checkpoints are being explored. LAG-3 (Lymphocyte-Activation Gene 3 (LAG-3), is a cell-surface receptor expressed on immune cells including activated CD4+ T cells, and negatively regulates T-cell proliferation, inhibits T-cell activation and effector T-cell function. LAG-3 is upregulated in several tumor types, including malignant melanoma.
Relatlimab is a first-in-class human IgG4 LAG-3–blocking antibody that binds to LAG-3 and restores the effector function of exhausted T cells, resulting in T cell proliferation, activation and a therapeutic response. In preclinical studies, dual inhibition of LAG-3 and PD-1 showed synergistic antitumor activity, and in a Phase I/II trial, the combination of Relatlimab and OPDIVO®, demonstrated durable Objective Responses in patients with Relapsed/Refractory melanoma following treatment with PD-1 inhibitors.
RELATIVITY-047 is a Phase II/III, global, multicenter, double-blind, randomized trial in which a fixed-dose combination of Relatlimab and OPDIVO® (OPDUALAG®) was compared with OPDIVO® alone, in patients with previously untreated metastatic or unresectable melanoma. In this study, 714 patients were randomly assigned 1:1 to receive OPDUALAG® (Relatlimab 160 mg and OPDIVO® 480 mg in a fixed-dose combination) (N=355) or single agent OPDIVO® 480 mg (N=359). Both regimens were administered as an IV infusion over 60 minutes every 4 weeks, and treatment was continued until disease progression, unacceptable toxicities, or withdrawal of consent. Both treatment groups were well balanced and patients were stratified according to LAG-3 expression (1% or more versus less than 1%), PD-L1 expression (1% or more versus less than 1%), BRAF V600 mutation status, and metastasis stage (M0 or M1 with normal LDH levels versus M1 with elevated LDH levels). More patients in the OPDUALAG® group had Stage M1c disease, and a larger proportion had three or more sites with at least one metastatic lesion. The Primary end point was Progression Free Survival (PFS) as assessed by blinded Independent Central Review. Secondary end points included Overall Survival and Objective Response Rate (ORR).
At a median follow up was 13.2 months there was a statistically significant improvement in progression-free survival (PFS), as well as a numerically higher objective response rate (ORR) with a fixed-dose combination of OPDUALAG®, compared with OPDIVO® alone. This led to the approval of this combination by the FDA in 2022.
The researchers herein reported updated descriptive efficacy and safety results from RELATIVITY-047 with a median follow-up of 33.8 months, which confirmed the sustained efficacy benefit of OPDUALAG®, compared with OPDIVO® alone.
The median PFS was 10.2 months with OPDUALAG® as compared with 4.6 months with OPDIVO® (HR=0.79; [95% CI, 0.66-0.95]).The 3-year PFS rates were 31.8% and 26.9% respectively. The median OS was 51.0 months and 34.1 months, respectively (HR, 0.80 [95% CI, 0.66 to 0.99]). The ORR was 43.7% (95% CI, 38.4 to 49.0) with OPDUALAG® versus 33.7% (95% CI, 28.8 to 38.9) with OPDIVO®.
The PFS benefit was more so with OPDUALAG® across key prespecified subgroups, compared to single agent OPDIVO®. Patients with poor prognosis characteristics, such as visceral metastases, high tumor burden, elevated levels of serum LDH, or mucosal or acral melanoma, had better outcomes with OPDUALAG®, than with single agent OPDIVO®. Further, a benefit with OPDUALAG® was also noted across BRAF mutant and wild-type subgroups, compared to single agent OPDIVO®. Expression of LAG-3 or PD-L1 was not useful in predicting a benefit of OPDUALAG® over single agent OPDIVO® and appears to NOT have a clear role in treatment selection.
Subsequent systemic therapy was received by 38% in the OPDUALAG® group and 39.3% in the OPDIVO® alone group. The median PFS2 was 29.6 months with OPDUALAG® and 20.3 months with OPDIVO® alone, further supporting the long-term benefits of OPDUALAG®.
Grade 3 or 4 toxicities occurred in 18.9% of patients in the OPDUALAG® group and in 9.7% of patients in the single agent OPDIVO® group. The Safety profile of OPDUALAG® appeared favorable, when compared with dual checkpoint inhibition with a CTLA-4 inhibitor and PD-1 inhibitor combination (YERVOY® plus OPDIVO®) in the CheckMate 067 trial, in which adverse events were noted in 59% of patients.
The researchers concluded that RELATIVITY-047 is the first study to show a statistically significant improvement in Progression Free Survival for an immunotherapy combination versus PD-1 monotherapy, in patients with previously untreated metastatic or unresectable melanoma. This is believed to be the first analysis demonstrating that a combination immunotherapy significantly improves Overall Survival compared to anti-PD-1 monotherapy (evidenced by an Overall Survival HR 95% CI upper bound now <1). The authors added that these results validate blocking LAG-3 in combination with PD-1 as a therapeutic strategy for patients with melanoma, and establishes LAG-3 as the third immune checkpoint pathway, thus providing more treatment options for patients with advanced melanoma.
Three-Year Overall Survival With Nivolumab Plus Relatlimab in Advanced Melanoma From RELATIVITY-047. Tawbi HA, Hodi FS, Lipson EJ, et al. J Clin Oncol 2024;43:1546-1552
