Abstract Background Medications such as proton pump inhibitors (PPIs), antihistamines, and nonsteroidal anti‐inflammatory drugs have been linked to immune checkpoint inhibitor (ICI) efficacy in patients with non–small cell lung cancer (NSCLC), but these associations may reflect unmeasured confounding rather than true pharmacologic effects. This study evaluated whether commonly prescribed medications influence ICI outcomes, using a national patient sample and a negative control cohort. Methods The authors identified Veterans Health Administration (VHA) patients with stage IV NSCLC treated with first‐ or second‐line ICI therapy ( n = 3739) or chemotherapy ( n = 6585) from 2005 to 2023. Baseline use of 20 common medication classes and an immunomodulatory drug score were assessed. Propensity‐weighted Cox regression evaluated associations between each medication class and overall survival (OS) or time‐to‐next treatment (TTNT) in the ICI group. For any medication with a nominally significant association ( p < .05), the same analysis was repeated in the chemotherapy group to test for nonspecific effects. Results After propensity weighting, 14 of 20 medication classes showed no association with OS or TTNT in the ICI cohort. Loop diuretics, anticoagulants, opioids, penicillin antibiotics, and fluoroquinolone antibiotics were associated with worse outcomes, but similar effects were seen in the chemotherapy group. A higher immunomodulatory drug score was also associated with inferior outcomes among ICI patients, but this association was likewise present in the chemotherapy cohort. Conclusion In this study, commonly prescribed medications did not appear to alter ICI efficacy in stage IV NSCLC. Prior associations reported in the literature may be attributable to unmeasured confounding rather than true drug–immunotherapy interactions.
Brinzevich et al. (2025) studied this question.