Effects of smoking status on incidence and severity of immunerelated adverse events among patients with melanoma receiving immune checkpoint inhibitors

Background: Treatment of melanoma with immune-checkpoint inhibitors (ICIs) is often complicated by immune-related adverse events (irAEs).(1) While studies have examined smoking history as a prognosticator for melanoma, evaluation of its association with irAEs remains limited.(2,3) We retrospectively reviewed patients with histopathologically-confirmed melanoma between 01/2010- 12/2021 treated with nivolumab, pembrolizumab, and/or ipilimumab. IrAEs were documented using CTCAE (v5.0). Mann-Whitney U, Chi-squared tests, and multivariable logistic regression analyses were performed with adjustment for age, sex, ECOG, prior therapy, ICI regimen, lactate dehydrogenase, and presence of distant metastasis at time of ICI initiation. P-values were 2- tailed. P< 0.05 determined statistical significance. 672 patients were included with 54.9% being never smokers, 39.6% being former smokers, and 5.5% being current smokers. Former and current smokers were combined to assess impact of any tobacco exposure and due to limited sample size of the latter cohort. There were no significant differences in the development of any (P=0.595) and high-grade irAEs (P=0.613) between never smokers and current/former smokers. However, current/former smokers had significantly higher odds of developing high-grade endocrine toxicity (adjusted odds ratio [aOR] 6.3, 95% confidence interval [CI] 1.2- 51, P=0.050) and requiring systemic treatment initiation for irAEs, especially for gastrointestinal toxicity (aOR 2.7, 95% CI 1.1-6.9, P=0.033). Current/former smokers also had 120% greater odds of requiring ICI discontinuation due to irAEs compared to never smokers (P=0.012). In summary, our study found that while smoking exposure does not increase incidence of irAEs, it may be associated with increased severity of toxicity requiring systemic treatment initiation and ICI regimen cessation.