Simple SummaryWith the common use of immune checkpoint inhibitors (ICIs) as a standard therapy for many tumor entities, the number of immune-related adverse events (irAEs) has increased. Side effect management for irAEs includes the administration of corticosteroids which are mostly very effective. However, a subgroup of patients with checkpoint inhibitor-induced side effects do not adequately respond to steroids with so-called steroid-refractory side effects (sr-irAEs) or cannot be tapered off steroids without the recurrence of side effects, the so-called steroid-dependent side effects (sd-irAEs). Since little is known about the incidence and management of sr/sd-irAEs, we investigated the occurrence and management of these difficult-to-treat side effects. This is the first study to report on the incidence rate of steroid-refractory or steroid-dependent irAEs in patients with skin cancer.AbstractThe occurrence, second-line management and outcome of sr/sd-irAEs was investigated in patients with skin cancer. All skin cancer patients treated with immune checkpoint inhibitors (ICIs) between 2013 and 2021 at a tertiary care center were analyzed retrospectively. Adverse events were coded by CTCAE version 5.0. The course and frequency of irAEs were summarized using descriptive statistics. A total of 406 patients were included in the study. In 44.6% (n = 181) of patients, 229 irAEs were documented. Out of those, 146 irAEs (63.8%) were treated with systemic steroids. Sr-irAEs and sd-irAEs (n = 25) were detected in 10.9% of all irAEs, and in 6.2% of ICI-treated patients. In this cohort, infliximab (48%) and mycophenolate mofetil (28%) were most often administered as second-line immunosuppressants. The type of irAE was the most important factor associated with the choice of second-line immunosuppression. The Sd/sr-irAEs resolved in 60% of cases, had permanent sequelae in 28% of cases, and required third-line therapy in 12%. None of the irAEs were fatal. Although these side effects manifest in only 6.2% of patients under ICI therapy, they impose difficult therapy decisions, especially since there are few data to determine the optimal second-line immunosuppression.