Clinical impact of baseline and peri-treatment concomitant medication exposure and polypharmacy on outcomes of immune checkpoint inhibitor therapy: A real-world pan-tumor analysis.

11011 Background: Immune checkpoint inhibitors (ICIs) have transformed cancer therapy, yet real-world patients frequently receive multiple concomitant medications that may influence treatment outcomes. These medications may alter the gut microbiome and modulate host immune function, impacting ICI efficacy and survival. The clinical effects of baseline and peri-treatment medication exposure on ICI outcomes remain incompletely characterized. Methods: We conducted a retrospective study of ICI-treated solid tumors at a tertiary academic center. Concomitant medications were captured at ICI initiation (baseline chronic exposure) and during a peri-treatment window (acute exposure, 30 days before or after ICI initiation). Drug classes included antibiotics, proton pump inhibitors, corticosteroids, NSAIDs, opioids, anticoagulants, antiplatelets, statins, cardio-metabolic and psychotropic agents, and supplements. Polypharmacy was defined as ≥5 baseline medications. Outcomes included overall survival (OS), progression-free survival (PFS), immune-related adverse events (irAEs), and objective response using RECIST 1.1. Multivariable Cox proportional hazards models were used to adjust for confounding. Results: The cohort included 772 patients (60.1% male) with a median BMI of 25.8 kg/m² (IQR 23.0–29.1), and 66.2% had stage IV disease. On multivariable analysis for objective response (RECIST), baseline polypharmacy (≥5 medications) (OR 0.65, 95% CI 0.43–0.96; p=0.033), acute antibiotic exposure within 30 days of ICI initiation (OR 0.63, 95% CI 0.39–0.99; p=0.049), and metastatic disease (stage IV) (OR 0.51, 95% CI 0.26–0.98; p=0.045) independently predicted inferior response, while a higher number of immunotherapy cycles was associated with improved response (OR 1.06 per cycle, 95% CI 1.05–1.08; p<0.001). Acute antibiotic exposure within 30 days before ICI initiation was also independently associated with worse progression-free survival (HR 1.70, 95% CI 1.05–2.76; p=0.031). On multivariable Cox regression for overall survival, acute opioid exposure (HR 1.51, 95% CI 1.06–2.15; p=0.023), baseline polypharmacy (HR 1.78, 95% CI 1.19–2.65; p=0.005), and advanced disease (HR 2.78, 95% CI 1.73–4.47; p<0.001) were independently associated with worse survival, whereas a higher number of immunotherapy cycles (HR 0.96 per cycle, 95% CI 0.94–0.98; p<0.001) and prior surgery of the primary tumor (HR 0.51, 95% CI 0.33–0.79; p=0.002) were associated with improved survival. No baseline polypharmacy or specific medication exposure independently predicted the occurrence of irAEs. Conclusions: Concomitant medication exposure significantly impacts ICI outcomes, potentially through modulation of host immunity and the gut microbiome, supporting routine medication review at ICI initiation.