Efficacy and safety of anti-PD-1 combined with IFN-α1b with or without anlotinib as the first-line therapy in patients with unresectable advanced melanoma: a real-world cohort study

The prognosis of advanced melanoma remains poor, and immune checkpoint inhibitor monotherapy often shows limited efficacy, especially in acral and mucosal subtypes. This challenge is particularly relevant for Chinese patients. We conducted this retrospective cohort study to evaluate outcomes associated with the addition of anlotinib to anti-PD-1 plus IFN-α1b as first-line treatment for advanced melanoma. A total of 211 patients with stage Ⅲ-IV unresectable melanoma treated between June 2020 and June 2024 were included, of whom 179 received the doublet and 32 received the triplet therapy. Propensity score overlap weighting was applied to substantially improve the balance of measured baseline characteristics between the two groups. After weighting, triplet therapy was associated with longer overall survival than doublet therapy, with a median overall survival of 35.8 versus 16.2 months, respectively (HR, 0.42; 95% CI, 0.24–0.72; P = 0.002). Progression-free survival was also longer with triplet therapy, with a median progression-free survival of 9.4 versus 5.2 months (HR, 0.52; 95% CI, 0.34–0.80; P = 0.003). The weighted objective response rates were 45.1% in the triplet group and 38.1% in the doublet group, with no statistically significant between-group difference ( P = 0.165). Exploratory subgroup analyses with false discovery rate adjustment yielded signals favoring triplet therapy in several patient subsets, particularly those with PD-L1 expression < 1% and mucosal melanoma. Given the limited sample sizes within individual subgroups, these observations are hypothesis-generating and require validation. Grade 3–4 adverse events occurred in 21.9% of patients receiving triplet therapy and 8.9% of those receiving doublet therapy, with no treatment-related deaths. In this retrospective real-world cohort, triplet therapy was associated with longer overlap-weighted overall and progression-free survival than doublet therapy, with manageable toxicity. These findings require confirmation in adequately powered prospective randomized studies.