Association Between Early on-Treatment Weight Loss With Enfortumab Vedotin Plus Pembrolizumab and Survival in Advanced Urothelial Carcinoma.

[BACKGROUND] Combination therapy with enfortumab vedotin plus pembrolizumab (EV+P) is now the preferred first-line (1L) therapy for advanced urothelial carcinoma (aUC), but prognostic indicators for patients on 1L EV+P have not yet been described.

[PATIENTS AND METHODS] We conducted a retrospective cohort study of patients receiving 1L EV+P for aUC. We analyzed deidentified electronic health record data from the Flatiron Health database to identify adults with aUC who initiated EV+P between April 3, 2023 and December 31, 2024. Inclusion required absence of death, disease progression, or second line therapy start within 30 days of EV+P initiation, as well as documented weight measurements at the time of EV+P initiation (i.e., day 0) and day 28. We used Cox proportional hazards modeling with stabilized inverse probability treatment weighting (IPTW) to evaluate the association of early on-treatment weight loss with overall survival (OS), progression-free survival (PFS), and time to EV discontinuation.

[RESULTS] A total of 401 patients met study criteria. Of these, 78 patients (19.5%) experienced ≥ 5% weight loss by day 28 following EV+P initiation. Early on-treatment weight loss was associated with inferior OS (median 12.8 vs. 20.4 months; IPTW-adjusted HR [aHR] = 2.04 [1.41-2.95], P = 1.9 × 10), but not with PFS (aHR = 1.22 [0.89-1.65], P = .22) or time to EV discontinuation (aHR = 1.30 [0.96-1.77], P = .090). The association of early on-treatment weight loss with OS was conserved in subgroup analyses stratifying patients by baseline albumin or BMI.

[CONCLUSION] Early weight loss ≥5% occurred in one fifth of patients receiving 1L EV+P treatment and was associated with inferior overall survival.