Impact of Dose-Effect in Smoking on the Effectiveness of Pembrolizumab in Patients with Metastatic Urothelial Carcinoma

Abstract

Background Subgroup analysis of KEYNOTE-045 suggested that cigarette smoking had a positive impact on the effectiveness of pembrolizumab in patients with advanced urothelial carcinoma (UC), whereas studies on other cancers treated with immune checkpoint inhibitors reported inconsistent results. Objectives This study aimed to examine the association between smoking-related factors and the effectiveness of pembrolizumab in patients with metastatic UC. Patients and methods This multicenter retrospective study was conducted using data from 95 patients with metastatic UC treated with pembrolizumab. The primary outcomes were progression and all-cause mortality. Time-to-event outcomes were compared with smoking history and lifetime smoking exposure at treatment initiation. Survival curves were compared using the log-rank test, with hazard ratios (HRs) estimated from Cox regression models. Cubic spline regression analysis was used to depict event hazards. Results We identified 32 (34.7%) patients with heavy smoking exposure (≥ 25 pack-years). Moreover, 19 (20.0%), 36 (37.9%), and 40 (42.1%) patients were current, former, and never smokers, respectively. Multivariable models showed that heavy smoking exposure was significantly associated with lower risk of progression (HR 0.58; 95% confidence interval (CI) 0.35–0.97; P = 0.047) and all-cause mortality (HR 0.30; 95% CI 0.11–0.82; P = 0.019). Cubic spline regression analyses revealed a dose-effect relationship. No significant association was observed between smoking history alone and effectiveness of pembrolizumab. Conclusions Lifetime smoking exposure plays a significant role in the effectiveness of pembrolizumab in patients with metastatic UC.