Severe Late-Onset Grade III-IV Adverse Events under Immunotherapy: A Retrospective Study of 79 Cases

SIMPLE SUMMARY: PD-1 inhibitors (nivolumab, pembrolizumab) and anti-CTLA-4 (CD152) (ipilimumab) are widely used in metastatic melanoma. Immunotherapy leads to prolonged lymphocyte effects, which explains the cytotoxicity underlying immune-reaction-based adverse events. Most adverse events (irAEs) occur in the first cycle of treatment at a median of 40 days, but some occur later, over 2 years after immunotherapy is initiated. IrAEs of any grade have been observed in 68.2% of patients and 10% of patients experienced severe grade III/IV irAEs. Data on late-onset irAEs are lacking. We aim to investigate late-onset grade III-IV irAEs and patient characteristics in the context of anti-PD-1 antibody treatment or combination therapy in real-life settings. ABSTRACT: Background: For several decades, PD-1 has been a target in malignant melanoma (MM). PD-1 inhibitors (nivolumab, pembrolizumab) and anti-CTLA-4 (CD152) (ipilimumab) have revolutionized cancer therapy. PD-1 and CTLA-4 inhibition leads to prolonged lymphocyte effects, which explains the cytotoxicity underlying immune-reaction-based adverse events (irAEs). Most irAEs occur in the first cycle of treatment at a median of 40 days. IrAEs of any grade have been observed in 68.2% of patients, with 10% of patients experiencing severe grade III/IV irAEs. Data on late-onset irAEs are lacking. Methods: Data on patients with advanced melanoma (N = 1862) from March 2016 to March 2021 were obtained from the RicMel database, a French national multicentric biobank dedicated to the follow-up of MM patients. Patients who received anti-PD-1 therapy or a combination therapy and experienced grade III-IV irAEs were selected and analyzed at 7 months, one year and two years after treatment was initiated. Results: Superficial spreading melanoma (SSM) and previous oncological drug administration before immunotherapy are significant risk factors for late-onset irAEs over 2 years after beginning immunotherapy in the univariate and multivariate analysis. The other parameters—sex, mutational status, association of immunotherapy (PD-1i and CTLA-4i) and overall response—were not significantly associated with late-onset irAEs. In our real-life data study, the median onset time of grade III-IV irAES was 128 days after the initiation of immune checkpoint inhibitors (ICI) therapy. Conclusions: Our study, using real-life data, suggests that patients with SSM and those who have received previous oncological treatments are more likely to experience late-onset grade III-IV irAES. Further multicentric studies with wider recruitment of patients should be performed to confirm our findings, potentially leading to changes in the recommended treatment for carefully monitored at-risk patients.