Background: The incidence of melanoma is increasing in patients of both sexes. It is known that women and men have differences in their innate and acquired immune systems. Knowing these differences, it is reasonable to hypothesize that the reagibility of the immune system and hereby the efficacy of tumor therapies might be dependent on sex. This study assessed sex-based differences in the outcome to different treatment strategies in metastatic melanoma. Methods: Patients with advanced (stage IV, AJCCv8) metastatic melanoma who were first-line treated with either PD-1-based immune checkpoint inhibition (ICI) as monotherapy or combination, or targeted therapy (TT) with BRAF plus MEK inhibitors were identified from the prospective multicenter skin cancer registry ADOREG. The study endpoints were best overall response (BOR), progression-free survival (PFS), and overall survival (OS); all endpoints were evaluated univariately and multivariately with focus on sex differences. Results: 2032 evaluable patients were identified who were treated with ICI or TT. Of those, 1274 (62.7%) were male and 758 (37.3%) were female. Median age was 66 years (range: 20-96) in the ICI cohort, and 60 years (range: 20-90) in the TT cohort. Most patients (n=1484 (73%); m: 941, f: 534) received ICI therapy; 548 patients (27%; m: 333, f: 215) were treated with TT. There were no sex-specific differences in BOR (ICI: p=0.83; TT: p=0.52), PFS (ICI: p=0.46; TT: p=0.21), and OS (ICI: p=0.20; TT: p=0.30). There were also no significant sex-specific differences in OS when patients were separately investigated by serum LDH (normal LDH: p=0.41; elevated LDH: p=0.39) or BRAF status (BRAF wt: p=0.15; BRAF mut: p=0.82). The multivariate analyses likewise showed no sex-specific differences in BOR, PFS and OS. However, LDH and ECOG were confirmed as independent influencing variables in terms of PFS and LDH, ECOG and type of therapy in terms of OS. Conclusions: There were no sex differences in first-line treatment outcomes in terms of response and survival in patients with advanced metastatic melanoma, irrespective of whether they received ICI or TT. There were also no sex differences in treatment response when BRAF status or LDH levels were measured.

Sex differences and its impact on treatment outcomes of advanced melanoma in Germany – a DeCOG study on 2032 patients of the multicenter prospective skin cancer registry ADOREG