Anti-LAG-3: A change in the paradigm of advanced melanoma treatment

Melanoma is the deadliest skin cancer globally. It arises from the malignant transformation of melanocytes through multiple complex pathways. While cutaneous melanoma, originating from the epidermis, is the most common form, other rarer subtypes also exist. The complex physiopathology of melanoma, characterized by a high mutational load and metastatic potential, when correlated with the hallmarks of cancer, clearly demonstrates its predisposition to immunotherapy. Immunotherapy has significantly improved clinical outcomes, with the median survival of patients with advanced melanoma increasing from 6 months to 6 years following treatment with immune checkpoint inhibitors. However, the high risk of toxicity, particularly with the current standard combination therapies, and problems related to relapse or resistance to treatment, remain a major concern, with some mechanisms yet to be fully elucidated. Therefore, the discovery of new molecules targeting alternative immune checkpoints (ICs) has become one of the leading approaches. This review, focusing on lymphocyte-activation gene 3 (LAG-3), characterizes this novel IC at the structural and molecular level, as well as describes its mechanism of action. Moreover, it highlights key clinical trials involving anti-LAG-3 molecules, including the landmark RELATIVITY-047 study, which led to the approval of relatlimab, the first anti-LAG-3 monoclonal antibody, in combination with nivolumab, as a first-line treatment for advanced melanoma. By reporting these promising clinical results, which demonstrate that this novel combination therapy is safer and as effective as other first-line therapies, this review points to a paradigm shift in the treatment of advanced melanoma.Keywords: melanoma, immunotherapy, anti-LAG-3, relatlimab, clinical trials.