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

e16600 Background: Enfortumab vedotin plus pembrolizumab (EV+P) is first line standard of care for locally advanced or metastatic urothelial carcinoma (LA/mUC). Both agents carry pneumonitis risk, yet real-world incidence and predictors of pneumonitis with this combination remain poorly characterized. Methods: We conducted a retrospective cohort study of patients receiving EV+P for LA/mUC at MD Anderson Cancer Center. Pneumonitis was adjudicated by a pulmonologist and graded per CTCAE v5.0. Given the high risk for mortality from other causes, cumulative incidence was estimated using Fine-Gray competing risk analysis with death as competing event. Risk factors were evaluated using univariable subdistribution hazard regression. Results: Among 264 patients (median age 72 years; 76% male; 67% metastatic; median follow-up 10.3 months), pneumonitis developed in 17 (6.4%; 95% CI, 4.1-10.1%): Grade 1-2, 9 (53%); Grade ≥3, 8 (47%). Median time to onset was 69 days (IQR, 48-82), with 82% of events occurring within 90 days. During follow-up, 70 deaths occurred; the 90-day cumulative incidence was 5.4% (95% CI, 2.5-8.3%). One patient (6%) required ICU admission; none required mechanical ventilation. Corticosteroids were administered in 7 (41%). In competing risk regression, baseline interstitial lung abnormalities (ILA; sHR 2.99; 95% CI, 0.84-10.66; P = 0.09), prior ICI therapy (sHR 2.46; 95% CI, 0.81-7.44; P = 0.11), and COPD (sHR 2.36; 95% CI, 0.80-6.96; P = 0.12) showed the strongest signals, though statistical significance was not reached (Table). Pneumonitis incidence was higher in patients with ILA (17.6% vs 5.7% without), and 12.9% with prior ICI vs 5.6% without. In time-dependent Cox analysis, pneumonitis was associated with a trend toward increased mortality (HR 1.67; 95% CI, 0.76–3.69; P = 0.20), though this did not reach statistical significance. Conclusions: Pneumonitis occurred in 6.4% of patients receiving EV+P; however, 47% of events were Grade ≥3 and most occurred within 90 days. Baseline ILA, prior ICI therapy, and COPD showed higher incidence, representing hypothesis-generating signals for risk stratification. Close pulmonary monitoring during early treatment cycles may be warranted in patients with these features. Risk factors for pneumonitis (fine-gray subdistribution hazard model). Variable sHR (95% CI) P-value Age (per 10 years) 0.88 (0.66-1.17) 0.39 Male sex 0.57 (0.21-1.55) 0.27 Ever smoker 1.18 (0.44-3.17) 0.75 Interstitial lung abnormalities 2.99 (0.84-10.66) 0.09 Prior ICI therapy 2.46 (0.81-7.44) 0.11 COPD 2.36 (0.80-6.96) 0.12 Prior therapy lines (per line) 1.16 (0.99-1.35) 0.07 ECOG ≥2 0.63 (0.15-2.73) 0.54 Abbreviations: CI, confidence interval; COPD, chronic obstructive pulmonary disease; ECOG, Eastern Cooperative Oncology Group; ICI, immune checkpoint inhibitor; sHR, subdistribution hazard ratio.