Relationship of adverse events after combined immunotherapy and treatment outcomes in patients with advanced melanoma: A multicenter experience in Poland.
Authors: Pacholczak-Madej Renata , Grela-Wojewoda Aleksandra , Puskulluoglu Miroslawa , Lompart Joanna , Las-Jankowska Manuela , Krawczak Katarzyna , Olejniczak Monika , Wrona Ewa , Źrebiec-Figura Monika , Żubrowska Justyna , Zemelka Tomasz , Ziobro Marek 
Published: June 2023

e21511

Background: The combination of nivolumab and ipilimumab has become the standard of care for the first-line treatment of advanced melanoma. In this study, our objective was to evaluate the frequency of immune-related adverse events (irAEs) and to establish their relationship with treatment outcomes. Methods: We evaluated the medical records of 99 patients with advanced melanoma treated with combined immunotherapy in 7 oncology units in Poland in the period between October 2020 (the beginning of the reimbursement policy) and October 2022. We recorded therapy efficacy and irAEs at a follow-up period of 3, 12 and 18 months. Responders were defined as the patients with at least stable disease in a first follow-up, and non-responders as those with progressive disease (PD). The associations between the occurrence of irAEs and the treatment results (overall survival [OS] and progression-free survival [PFS]) were calculated using the Cox proportional hazards model. The log-rank test was applied to compare the survival distribution between the chosen factors. Results: The median duration of treatment was 2 months (interquartile ranges [IQR]: 2-6) and during the analysis, the patients were observed for a median follow-up of 6 months (IQR:3-13). After 3 months, the respondents constituted 54.5% (n = 54). At the last follow-up, 33.3% (n = 33) of the patients continued treatment and immunotherapy was stopped in the remaining patients due to PD (n = 33, 33.3%), toxicity (n = 24, 24.2%) or death (n = 8, 8.1%). In the entire group, the median OS was not reached (NR), (IQR: 8.7 months -NR) whereas PFS was 7 months (IQR:2-NR). Any grade (G) of irAEs was reported in 65 individuals (65.7%) with G3/G4 in 28 of them (43%). Thirty-one patients developed more than one episode of irAEs (2 episodes in 17.2%, n = 17; 3 episodes in 10.1%, n = 10; 4 episodes in 4%, n = 4; p = 0.006). The frequency of irAEs was 83.3% (n = 45) and 44.7% (n = 17) in responders and non-responders respectively, p = 0.0001. The OS and PFS values for patients who experienced irAEs did not reach medians and upper quartiles, but those without any irAEs had significantly worst outcome (10.5 months [IQR: 3-NR] for OS, p = 0.002; 2 months [IQR: 2-5.2] for PFS, p = 0.01). The patients with irAEs had a 30% lower risk of death (hazard ratio [HR] 0.7, 95% confidence interval [CI 0.56-0.86]) and a 40% lower risk of PD (HR 0.6, 95%CI [0.48- 0.74]). The most common irAEs were endocrine (n = 25), hepatic (n = 22) and cutaneous (n = 17). In a pairwise comparison the patients with endocrine irAEs (p = 0.01), receiving immunosuppressants for irAEs treatment (p = 0.01), and without brain metastases (p = 0.02) had a better survival rate. Conclusions: Patients with advanced melanoma treated with combined immunotherapy who experienced irAEs have a more favorable outcome, which is even better in those with more episodes of toxicity. The type of irAEs may also have predictive value.