Association between selective serotonin reuptake inhibitor use and outcomes in metastatic melanoma treated with immune checkpoint inhibitors: A real-world cohort study.

11188 Background: Immune checkpoint inhibitors (ICIs) have transformed outcomes for metastatic melanoma, yet substantial variability in response remains. Evidence suggests that concomitant medications may modulate antitumor immunity and influence ICI effectiveness. For example, recent mechanistic and translational studies indicate that selective serotonin reuptake inhibitors (SSRIs) enhance T-cell–mediated antitumor immunity and may synergize with PD-1 blockade, with preliminary clinical signals of improved survival. However, real-world evidence in melanoma is limited. We conducted a real-world cohort study to assess the association between baseline SSRI use and outcomes among metastatic melanoma patients treated with ICIs. Methods: We performed a retrospective cohort study using a nationally representative real-world dataset from the Atropos Evidence Network integrating open claims and EHR data mapped to OMOP CDM v5.3. Adults with metastatic melanoma treated with first-line pembrolizumab, nivolumab, or ipilimumab were identified using ICD and RxNorm codes. The index date was ICI initiation. The SSRI cohort required ≥30 days of use prior to index; comparators had no prior SSRI exposure. Patients were matched 1:1 using high-dimensional propensity scores (hdPS) derived from ICD, CPT, and RxNorm features and fitted with LASSO-regularized logistic regression. Outcomes included 1-year overall survival (OS), time to ICI discontinuation, ICI duration, and post-index steroid use. Results: Among 3,597 metastatic melanoma patients initiating ICIs, 307 had baseline SSRI exposure and 3,290 had no prior SSRI use. After 1:1 hdPS matching, 304 well-balanced pairs were identified. Baseline SSRI use was associated with a numerically lower but not statistically significant risk of death at 1 year (HR 0.70; 95% CI 0.46–1.06; p = 0.092). No significant difference in ICI discontinuation was observed between cohorts (HR 1.07; 95% CI 0.87–1.31; p = 0.53). Mean duration of ICI was similar in the propensity-matched analysis (158.7 days in no-SSRI vs 142.4 days in SSRI; mean difference −16 days; 95% CI −40 to 7.3; p = 0.175). Post-index steroid use also did not differ between groups (IRR 1.02; 95% CI 0.60–1.73; p = 0.94). Across all endpoints, effect estimates were consistent with no clinically meaningful association between baseline SSRI exposure and immunotherapy outcomes. Conclusions: In this large real-world analysis, baseline SSRI use was not associated with improved OS, reduced discontinuation, or increased steroid use among metastatic melanoma patients treated with ICIs. Despite strong mechanistic rationale suggesting potential synergy, these findings highlight a disconnect between preclinical observations and real-world outcomes. Prospective studies are needed to identify subpopulations that may benefit.