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

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.