Simple SummaryIn the era of immunotherapy, advanced melanoma patients have unprecedentedly higher survival rates. However, the application of immunotherapy may lead to immune-related adverse events (irAEs), which are often managed with steroids. The potential negative impact of steroids on the effectiveness of immunotherapy remains uncertain, as studies often report contradictory results. This retrospective analysis of 415 first-line immunotherapy patients showed that steroid exposure increased progression-free survival (PFS) compared to no exposure, but early initiation (within four weeks) was linked to a shorter PFS compared to late or no exposure. This suggests that administering steroids during the immunotherapy priming phase may hinder the establishment of an effective immunotherapy-induced immune response. The implications of these findings are significant for managing irAEs, indicating a need for the cautious use of steroids in the initial stages of treatment.AbstractBackground: Successful treatment with Immune Checkpoint Inhibitors (ICI) requires the balanced activation of the immune system. Over-activation may result in immune-related adverse events (irAEs), which often require steroidal treatment. This study examined the possible impact of steroids on treatment efficacy in melanoma patients concerning initiation timing and dosage. Methods: A retrospective, single-center analysis of patients with advanced melanoma who underwent first-line ICI therapy during 2014–2020 was conducted. Results: Among the 415 patients, two-hundred patients (48.3%) were exposed to steroids during the first line, most of them due to irAEs (n= 169, 84.5%). Nearly a quarter of them were exposed to steroids within the first four weeks of treatment. Surprisingly, steroidal exposure was associated with better progression-free survival (PFS; HR = 0.74,p= 0.015); however, early exposure (within four weeks of treatment) resulted in a significantly shorter PFS compared to late exposure (adjusted HR 3.2,p< 0.001). Conclusions: Early exposure to corticosteroids during the priming phase of ICI therapy could impede the establishment of an effective immune response. These results suggest that caution should be exercised when considering the use of steroids for the management of early-onset irAEs.