Systemic therapies for advanced melanoma after immunotherapy failure: Efficacy and safety insights.

Abstract

e21552 Background: Immune checkpoint inhibitors (ICIs) and targeted therapies have significantly improved clinical outcomes in advanced melanoma. However, resistance to ICIs lead to relapse in a substantial proportion of patients, creating a critical need for effective treatment strategies after ICI failure. Tumor-infiltrating lymphocyte (TIL) therapy and oncolytic virus therapies like Talimogenelaherparepvec (TVEC), have emerged as promising approaches alongside other systemic therapies. This study systematically evaluates the efficacy and safety of systemic therapies after ICI failure to guide sequencing new treatment modalities in relapsed advanced melanoma. Methods: A systematic search of PubMed, Cochrane, and Ovid databases from January 2012 to December 2024 was conducted to identify studies on systemic therapies for advanced melanoma following ICI failure. Data were extracted on study design, treatment sequences, progression-free survival (PFS), overall survival (OS), and response rates (RR), including complete response (CR) and partial response (PR) rates that collectively contribute to the objective response rate (ORR). The data were summarized descriptively to capture treatment efficacy and safety outcomes across different therapeutic approaches. Results: From 145 studies identified, 31 (n = 3,462) met inclusion criteria. OS data were available on 2,407 patients, and PFS for 2,342 patients. For ICI/PD-1 retreatment (anti-CTLA-4 with nivolumab or pembrolizumab), the ORR ranged from 11% to 34%, with a median PFS of 2.5 to 8.5 months and OS of 14.3 months. In BRAF positive patients, MEK/BRAF inhibitors post-ICI therapy showed similar results (ORR 32%, PFS 7.5 months, OS 12.8 months). Sequential anti-CTLA-4/anti-PD-1 or anti-PD-1/anti-LAG-3 therapies yielded lower ORRs (8% to 14%) and shorter PFS (2.8 months). TIL/HD IL2 therapy achieved the highest efficacy, with an ORR of 37.5% and OS not reached among responders. TVEC therapy showed promising results (ORR 55%, PFS 37 months). Chemotherapy exhibited the lowest efficacy (ORR 11%, PFS 2.5 months). Grade 3-4 immune-mediated adverse events were noted in 5-57% of patients, with cytopenia affecting up to 100% of TIL therapy recipients. Conclusions: Therapeutic options for advanced melanoma after PD-1 failure are expanding, with TIL therapy, anti-LAG-3 inhibitors, TVEC, and targeted agents. Heterogeneity of study designs, response rates, and toxicity profiles complicate direct comparisons. Given the high efficacy, TIL therapy and TVEC should be considered as second line treatment options. Further research to establish optimal treatment algorithms and combination strategies with acceptable toxicity profile is warranted in relapsed melanoma.