Incidence and risk factors for pneumonitis in urothelial carcinoma treated with enfortumab vedotin plus pembrolizumab: retrospective study.

BACKGROUND: Enfortumab vedotin plus pembrolizumab (EVP) is first-line standard therapy for locally advanced or metastatic urothelial carcinoma (LA/mUC), but real-world pneumonitis incidence and predictors remain poorly characterized. MATERIAL AND METHODS: We conducted a retrospective cohort study of patients with LA/mUC treated with EVP at MD Anderson Cancer Center. Pneumonitis was adjudicated by pulmonology and graded using CTCAE v5.0. Prior immune checkpoint inhibitor (ICI) exposure was defined as ICI treatment before EVP initiation. Risk factors were assessed using Cox proportional hazards and Fine-Gray competing-risk regression; associations with overall survival (OS) and progression-free survival (PFS) were evaluated using extended Cox models. RESULTS: Pneumonitis occurred in 22 patients (7.0%), with median onset at 77 days; 10 events (45%) were grade ≥3, including one fatal case. Prior ICI exposure was the strongest independent predictor of pneumonitis (any-grade adjusted HR 2.68; 95% CI, 1.03-6.98; p = 0.04; grade ≥2 adjusted HR 5.91; 95% CI, 1.94-18.02; p = 0.002). No other baseline variable was significantly associated with pneumonitis. Grade ≥2 pneumonitis was associated with increased mortality (HR 2.35; 95% CI, 1.02-5.45; p = 0.04), whereas any-grade pneumonitis was not. Twelve patients underwent treatment re-exposure; all had no clinically meaningful recurrent or worsening pneumonitis during subsequent evaluable follow-up, with 8 resuming EV plus pembrolizumab and 4 EV alone. CONCLUSION: Pneumonitis occurred in 7.0% of EVP-treated patients and generally arose early. Prior ICI exposure predicted pneumonitis, particularly grade ≥2 events, which were associated with increased mortality; any-grade pneumonitis and PFS were not.