Clinical impact of baseline serotonergic antidepressant use on survival and immune-related adverse events in lung cancer patients treated with immune checkpoint inhibitors: A large multicenter matched cohort study.

e20618 Background: Preclinical and mechanistic studies suggest that serotonergic antidepressants, including selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs), may exert antitumor and immunomodulatory effects through modulation of serotonin signaling, T-cell function, cytokine production, and the tumor microenvironment. However, whether these proposed effects translate into clinically meaningful outcomes or altered toxicity profiles in patients treated with immune checkpoint inhibitors (ICIs) remains uncertain. Methods: We conducted a retrospective cohort study using the TriNetX Global Collaborative Network, including adult lung cancer patients treated with ICIs between January 2015 and January 2026. Baseline SSRI/SNRI exposure was defined as use within 3 months prior to ICI initiation. Among 78,852 eligible patients (12,508 exposed; 66,344 unexposed), 1:1 propensity score matching yielded 22,940 matched patients (11,470 per group). Matching variables included age, sex, comorbidities (COPD, chronic kidney disease, diabetes, liver disease), metastatic disease, brain metastases, and prior chemotherapy. The primary endpoint was overall survival over 5 years. Secondary endpoints included pneumonitis and endocrine immune-related adverse events evaluated within 90 days. Survival analyses used Kaplan–Meier methods and Cox proportional hazards models. Results: After propensity score matching, baseline demographic and clinical characteristics were well balanced between cohorts. Overall survival did not differ between patients receiving baseline SSRIs/SNRIs and those without serotonergic antidepressant exposure (median OS 671 vs 665 days; HR 1.01, 95% CI 0.97–1.04; p = 0.75). Rates of immune-related adverse events were comparable between groups, with no statistically significant differences in pneumonitis (HR 1.24, 95% CI 0.90–1.71; p = 0.29), hypothyroidism (HR 1.01, 95% CI 0.81–1.24; p = 0.24), or adrenal insufficiency (HR 1.21, 95% CI 0.87–1.66; p = 0.63). No clinically meaningful differences in immune-related toxicity risk were identified. Conclusions: In this large, propensity-matched real-world cohort of lung cancer patients treated with ICIs between 2015 and 2026, baseline SSRI/SNRI use was not associated with differences in 5-year overall survival or immune-related adverse event risk. Despite biologic plausibility and preclinical evidence suggesting potential antitumor or immunomodulatory effects of serotonergic antidepressants, these findings indicate that such effects may not translate into clinically significant survival benefit or altered immunotherapy toxicity in routine clinical practice. These results support the continued use of SSRIs/SNRIs when clinically indicated.