Risk Factors and Comparative Safety of Anti <scp>‐PD</scp> ‐1 Combination Therapies in Advanced Melanoma: A Nationwide Real‐World Cohort Study From China

BACKGROUD: Different anti-PD-1 combination therapies are used to improve response rate and combat drug resistance for melanoma in the real world of China. While the reported safety data has remained scarce, especially for the controversial use of interferon. Identification of risk factors and comparative safety of different therapies will be beneficial for physicians to make decisions on rational usage of immunotherapy. METHODS: A nationwide retrospective cohort study consecutively collected advanced melanoma patients treated by anti-PD-1 based therapies between July 1, 2018 and June 30, 2023. Univariate and multivariable logistic regression analysis was performed to identify the association between the potential risk factors and the occurrence of immune-related adverse events (irAEs). RESULTS: A total of 508 advanced melanoma patients receiving PD-1 monotherapy (n = 181), PD-1 + tyrosine kinase inhibitors (TKI, n = 131), PD-1 + anti-vascular endothelial growth factor (anti-VEGF, n = 56), PD-1 + interferon Alfa-1b (IFN-α1b, n = 99) and PD-1 + IFN-α1b + TKI (n = 41) were included. There was no significant difference in irAEs across subtypes of melanoma. While for patients with autoimmune disease of psoriasis and lichen planus, recurrence was observed after immunotherapy. Baseline renal or hepatic dysfunction and prior TKI therapy were risk factors for grade 3-5 irAEs. Multivariate logistic regression model found that compared with PD-1 monotherapy therapy, PD-1 based combination therapies had greater toxicity but were tolerated, except PD-1 + IFN-α1b + TKI group. Notably, the triple therapy was associated with the highest risk of grade 3-5 irAEs (OR, 3.1; 95% CI: 1.2-8.1; p = 0.019), which led to a high rate of hospitalization and permanent treatment discontinuation. CONCLUSION: Our results suggested that PD-1 + TKI, PD-1 + anti-VEGF, PD-1 + IFN-α1b combination therapies have some adverse events but are generally tolerated sufficiently for continuation of treatment. While the triple therapy PD-1 + IFN-α1b + TKI is not recommended because the benefits do not outweigh the risks.