Cancer immunology, immunotherapy : CII · 2026
Efficacy and safety of anti-PD-1-based therapies in advanced melanoma across acral and mucosal subtypes: a nationwide retrospective cohort study.
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Qiao Yuan, Fu Xiao, Hussain Iltaf, Ge Weihong, Yang Wei, Jiang Renbin, Dai Xiaoyan, Chen Haisheng, Zhao Jinyi, Tang Meng, Mu Fei, Wang Hao, Wu Qiuhui, Xia Xing, Zhang Yunnan, Ji Suzhi, Xu Ying, Cao Xinrui, Wang Jiexin, Gao Le, Wang Jingwen, Yao Yu, Fang Yu
Аннотация
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.
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.