Citation: Kudura, K.; Basler, L.; Nussbaumer, L.; Foerster, R. Sex-Related Differences in Metastatic Melanoma Patients Treated with Immune Checkpoint Inhibition. Cancers 2022, 14, 5145. https:// doi.org/10.3390/cancers14205145 Academic Editor: Adam C. Berger Received: 27 September 2022 Accepted: 19 October 2022 Published: 20 October 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). cancers Article Sex-Related Differences in Metastatic Melanoma Patients Treated with Immune Checkpoint Inhibition Ken Kudura 1, *, Lucas Basler 2 , Lukas Nussbaumer 3 and Robert Foerster 4 1 Department of Nuclear Medicine, University Hospital Zurich, 8091 Zurich, Switzerland 2 Institute of Radiooncology, Cantonal Hospital Aarau, 5001 Aarau, Switzerland 3 Faculty of Medicine, University of Zurich, 8091 Zurich, Switzerland 4 Institute of Radiooncology, Cantonal Hospital Winterthur, 8400 Winterthur, Switzerland * Correspondence: kenkudura@yahoo.de Simple Summary: Immune checkpoint inhibitors, ICI, have revolutionized the treatment of advanced melanoma. However, given the small number of patients responding to immunotherapy and the high risk for immune-related adverse events, there has been a rising interest in recent publications to identify factors that influence response to immunotherapies, including sex. We aimed at investigating sex-related differences in patients with advanced melanoma treated with ICI by linking the assessment of inflammatory response in peripheral blood, onset of IRAEs during therapy and treatment response in short- and long-term. Men with advanced melanoma showed a significantly better response to immunotherapy in short- and long-term than women. Higher immune activation in peripheral blood before and after initiation ICI might be linked to favorable treatment response during and after ICI in favor of men and decoupled from the onset of IRAEs. Given the significantly higher immunotoxicity and worse outcome experienced by women compared to men the use of ICI should be chosen carefully in women with advanced melanoma. Abstract: Objectives: We aimed to investigate sex-related differences in patients with advanced melanoma treated with ICI by linking the assessment of inflammatory response in peripheral blood, onset of immune-related adverse events IRAEs during therapy and treatment response in short- and long-term. Methods: For the purpose of this single-center retrospective study metastatic melanoma patients treated with ICI were included. Baseline patient characteristics, blood sample tests and the onset of immune-related adverse events IRAEs were documented based on clinical records. The short-term treatment response was assessed with 18 F-2-Fluor-2-desoxy-D-glucose Positron Emission Tomography/Computed Tomography FDG-PET/CT scans performed six months after initiation of ICI. The overall survival OS and progression-free survival PFS were used as endpoints to assess the long-term response to immunotherapy. Results: In total, 103 patients with advanced melanoma (mean age 68 ± 13.83 years) were included, 29 women (mean age 60.41 ± 14.57 years) and 74 men (mean age 65.66 ± 13.34 years). The primary tumor was located on a lower extremity in one out of three women and on the head/neck in one out of three men (p < 0.001). While the superficial spreading (41%) and nodular (36%) melanoma subtypes represented together 77% of the cases in male population, women showed a more heterogenous distribution of melanoma subtypes with the superficial spreading (35%), nodular (23%), acral lentiginous (19%) and mucosal (12%) melanoma subtypes being most frequent in female population (p < 0.001). Most differences between women and men with regards to inflammatory parameters were observed six months after initiation of ICI with a higher median NLR (p = 0.038), lower counts of lymphocytes (p = 0.004) and thrombocytes (p = 0.089) in addition to lower counts of erythrocytes (p < 0.001) and monocytes (p < 0.001) in women towards men. IRAEs were more frequent in women towards men (p = 0.013). Women were more likely to display endocrinological IRAEs, such as thyroiditis being the most frequent adverse event in women. Interestingly IRAEs of the gastrointestinal tract were the most frequent ones in men. Finally, men with advanced melanoma showed a significantly better response to immunotherapy in short- (p = 0.015) and long-term (OS p = 0.015 and PFS p < 0.001) than women. In fact, every fourth man died during the course of the disease, while every second woman did not survive. (p = 0.001). Cancers 2022, 14, 5145. https://doi.org/10.3390/cancers14205145 https://www.mdpi.com/journal/cancers