Sex-disparities in survival after anti-PD-1 monotherapy for advanced melanoma in Norway: a population-based cohort study

Background and objective During the last decade, immune checkpoint inhibitor therapy, including anti-PD-1 monotherapy, has revolutionized the prognosis of advanced cutaneous melanoma. Nonetheless, it remains unclear whether anti-PD-1 monotherapy perpetuates or mitigates long-standing sex-based survival disparities that favour female melanoma patients. Moreover, observational research regarding factors that could potentially modify any such survival disparities is sparce. This study aims to determine whether there is a difference in melanoma-specific survival between females and males treated with first-line palliative anti-PD-1 monotherapy for cutaneous melanoma in Norway and how methodological choices can affect observed disparities. Methods This cohort study will include population-based information about melanoma diagnoses and treatment captured by the Cancer Registry of Norway (including the Norwegian Melanoma Registry), the Norwegian Patient Registry, the Norwegian Prescribed Drug Registry, and Statistics Norway. Unadjusted and adjusted sex-based disparities in net survival for patients treated with first line anti-PD-1 monotherapy for advanced melanoma will be assessed using relative survival. We will additionally investigate the effects of treatment period (pre/post immunotherapy era), estrogen exposure via menopausal hormone therapy, and age at treatment initiation on sex-based survival disparities. Results and discussion This study will add to emerging real-world evidence about sex-based survival disparities among patients treated with anti-PD-1 monotherapy for advanced melanoma. Moreover, our study has the potential to identify important patient subpopulations who experience a greater or lesser survival benefit from this treatment and thereby identify potentially fruitful areas for mechanistic research on treatment efficacy. Plain language summary Females diagnosed with melanoma have historically lived longer than males with the same diagnosis. A newer treatment called immune checkpoint inhibitor (ICI) therapy could increase or decrease the gap in survival between females and males, but we need more evidence before we can say for certain how ICI therapy affects this survival gap. This registered report presents a plan to evaluate differences in survival between females and males treated with a specific type of ICI therapy for melanoma. We will use high-quality data from Norway to show how certain decisions for data analysis can potentially lead to different results. This may help explain why some research studies have made differing conclusions about the survival gap between females and males treated with ICI therapy for melanoma.