Treatment Options for Relapsed Metastatic Cutaneous Melanoma

After frontline therapy for melanoma, treatment options continue to expand but are not yet fully defined. For patients with clear molecular targets, such as BRAF mutations, the preferred next step after progression on checkpoint inhibitors is often dual targeted therapy with BRAF and MEK inhibitors. For those who have only received PD-1 inhibitors initially, combination checkpoint blockade targeting CTLA-4 and PD-1 pathways may be considered. Other mutations, such as KIT or NRAS, have fewer targeted options, making immunotherapy or enrollment in clinical trials important considerations. For select patients with limited, injectable disease without visceral metastases, oncolytic virus therapy remains a valuable tool, although long-term cures are rare. Additionally, adoptive cell therapy (TIL) is increasingly discussed for eligible patients based on performance status and disease burden.

The overarching clinical goal beyond frontline treatment is achieving durable disease control or cure, despite diminishing prospects with successive lines of therapy. Patients often accept higher toxicity levels in pursuit of long-term remission, emphasizing the importance of balancing efficacy with quality of life. Although regulatory agencies focus on end points such as progression-free survival and objective response rate to evaluate new therapies, clinicians prioritize patient-centered outcomes and overall survival. This can create tension between trial design and real-world treatment decisions, as responses and disease stabilization significantly impact patient experiences even if they do not always meet formal regulatory thresholds.

Practical challenges remain, including insurance coverage barriers for reusing certain immunotherapy combinations in the second line after frontline exposure. Nonetheless, evidence supports that some patients derive meaningful benefit from these sequences. Clinical judgment often guides off-label use based on individual patient response and tolerance. Continued research, clinical trials, and the development of novel agents remain critical to improving outcomes in later lines of melanoma therapy and addressing the evolving needs of this patient population.