Efficacy and safety of anti-PD-1-based therapies in advanced melanoma across acral and mucosal subtypes: a nationwide retrospective cohort study

BACKGROUND: Acral melanoma (AM) and mucosal melanoma (MM) respond poorly to anti-PD-1 monotherapy. Therefore, there is an urgent need to explore safe and effective anti-PD-1-based combined therapies. METHODS: A nationwide real-world cohort study consecutively included patients with advanced melanoma treated with anti-PD-1 in China between July 1, 2018, and June 30, 2023. The Research Electronic Data Capture (REDCap) system was used across all centers. The primary endpoints were progression-free survival (PFS), overall survival (OS), and immune-related adverse events (irAEs), with a secondary endpoints of objective response rate (ORR). Multivariable Cox and logistic regression models were conducted to compare the efficacy and safety of different anti-PD-1-based combination therapies with anti-PD-1 monotherapy. Stratified analyses were performed to evaluate the effect of therapies in cutaneous, acral, mucosal, and unknown primary subtypes. RESULTS: A total of 431 advanced melanoma patients comprising 22% cutaneous, 39% acral, 32% mucosal, and 7% unknown primary subtypes were included. Multivariable Cox analysis indicated that compared with anti-PD-1 monotherapy, anti-PD-1 + anti-VEGF + chemotherapy (HR, 0.4 [0.2, 0.7], P = 0.005) and anti-PD-1 + anti-VEGF therapy (HR, 0.4 [0.2, 0.9], P = 0.018) showed significant PFS benefit in AM and MM, respectively. Notably, anti-PD-1 + IFN-α1b showed a nonsignificantly longer PFS and OS in AM. A multivariate logistic regression model found that anti-PD-1-based combination therapies were significantly associated with grade 1-2 irAEs, while only anti-PD-1 + IFN-α1b + anti-VEGF therapy was significantly associated with high risk of grade 3-5 irAEs (OR, 4.4 [1.3-14.7], p = 0.017), without a significant survival benefit. CONCLUSIONS: Our results provide evidence for anti-PD-1 + anti-VEGF + chemotherapy and anti-PD-1 + IFN-α1b in AM and anti-PD-1 + anti-VEGF therapy in MM, as the long-term benefit and acceptable toxicity. However, for the patients who received anti-PD-1 + IFN-α1b + anti-VEGF, cautionary notes and awareness of drug safety should be raised, as the triple therapy with multiple mechanisms may increase the potential risk of toxicity.