Real-world safety of first-line (1L) therapies for locally advanced or metastatic urothelial cancer (la/mUC) in the US.
Authors: Amanda Nizam, Mairead Kearney, Valerie A. Morris, Seyed Hamidreza Mahmoudpour, Carroline Lobo, Jason Hoffman, Ilian Iliev, Prakirthi Yerram, Mark Guinter
Journal: Journal of Clinical Oncology (2025)

759 Background: The 1L treatment landscape in la/mUC has evolved rapidly, encompassing platinum-based chemotherapy, immune checkpoint inhibitors (ICIs), and antibody-drug conjugates, and including monotherapy and combination regimens. Real-world data on adverse events (AEs) with novel 1L therapies are limited. This study aims to fill this evidence gap by comprehensively characterizing the incidence of real-world treatment-emergent AEs (rwTEAEs) with 1L regimens for la/mUC. Methods: This is a retrospective observational cohort study of patients (pts) in the nationwide Flatiron Health electronic health record–derived deidentified database. The study population included adults diagnosed with la/mUC who initiated 1L treatment with a regimen of interest (Table) since January 1, 2016. Machine learning was used to extract clinician documentation of a prespecified list of 30 rwTEAEs from 1L treatment initiation to the earliest of 90 days after last 1L dose, start of subsequent treatment, or death. Occurrence of rwTEAEs (overall incidence and exposure-adjusted rate based on treatment-months) was described across groups. Results: Of 5,235 pts who met study criteria, 73% were male, median age was 74 years (IQR, 66-80), 70% were White, 66% had ECOG PS of 0-1, and practice setting was community/academic/both in 79%/14%/7%. The most common rwTEAEs in the overall cohort were fatigue (64%), anemia (43%), loss of appetite (43%), and nausea (42%). When adjusted for time on treatment, relative rates of some rwTEAEs differed greatly from incidences (Table). Conclusions: These data aid in understanding the real-world safety of 1L treatment options for la/mUC and help inform the development of patient supportive care plans by population-based healthcare decision-makers. Time on treatment should be considered when interpreting the incidence of safety events. Incidence of rwTEAEs, % (rate per 1,000 person-months on treatment) Overall N=5,235 Enfortumab vedotin + pembrolizumabn=198 ICI monotherapy n=2,146 Cisplatin-based chemo without avelumab 1LMn=1,372 Carboplatin-based chemo without avelumab 1LMn=1,140 Cisplatin-based chemo with avelumab 1LMn=197 Carboplatin-based chemo with avelumab 1LMn=182 Fatigue 63.7 (266.6) 68.7 (234.3) 62.2 (172.0) 75.7 (406.9) 72.5 (380.4) 95.4 (371.3) 96.7 (375.5) Weight loss 31.0 (66.6) 47.0 (102.2) 32.9 (53.2) 33.0 (84.1) 32.5 (84.9) 51.8 (35.1) 48.4 (34.6) Diarrhea 27.8 (58.2) 45.0 (98.4) 30.2 (49.5) 27.8 (66.9) 29.5 (74.9) 40.6 (24.9) 40.7 (29.1) Rash 17.9 (35.6) 47.0 (108.7) 21.9 (33.5) 14.7 (32.5) 15.3 (34.4) 34.0 (20.1) 31.9 (20.8) Pruritus 12.8 (24.3) 36.9 (72.5) 19.9 (30.7) 6.1 (12.4) 7.8 (16.4) 23.4 (13.0) 21.4 (13.4) Peripheral neuropathy 4.4 (7.6) 17.7 (29.0) 3.6 (4.4) 5.3 (10.9) 3.8 (7.6) 16.8 (8.4) 6.6 (2.8) Hyperglycemia 3.3 (5.6) 8.6 (12.7) 3.4 (4.1) 3.9 (7.9) 2.7 (5.4) 9.1 (4.0) 5.5 (2.6) 1LM, 1L maintenance; chemo, chemotherapy.