Outcomes with enfortumab vedotin (EV) rechallenge after disease progression in metastatic urothelial carcinoma.

4578 Background: EV, alone (mono) or with pembrolizumab (EVP), is an established therapy for metastatic urothelial carcinoma (mUC). However, the activity with EV rechallenge after prior exposure and subsequent disease progression is not well defined. Methods: A retrospective institutional database of patients (pts) treated with EV mono (n=395) or EVP (n=256) for mUC was reviewed to identify pts who received EV rechallenge after disease progression. EV-free interval (EVFI) was defined as the time from last EV1 (initial) dose to first EV2 (rechallenge) dose. Investigator-assessed objective response rate (ORR; CR/PR), progression free survival (PFS), overall survival (OS), and duration of response (DoR, from first documented response) were summarized descriptively. Results: Of 42 pts identified, EV1 regimen was mono for 62% (n=26; EV1-mono) and EVP for 38% (n=16; EVP1). Median age was 77, 76% were male, and 45% had upper tract primary. Most pts (n=35; 83%) discontinued EV1 for toxicity, predominantly peripheral neuropathy. Median follow up from EV2 initiation was 26 mo (95% CI 17-NR). At rechallenge, 10 pts (24%) switched EV regimens (EV1-mono to EVP2, n=5; EVP1 to EV2-mono, n=5). EV2 was initiated at 1.25 mg/kg in four pts (9.5%), 1.0 mg/kg in 13 pts (31%), and ≤0.75 mg/kg in 25 pts (60%). Among response-evaluable pts (n=39), ORR to EV2 was 21% (8/39; 95% CI 9%-36%), including 2 CRs (5%), both with prior CR to EV1. No responses were observed in pts with SD/PD to EV1 (0/8; 0%), or those with EV1 PFS <6 mo (0/11; 0%). Among pts with long (>12 mo) or intermediate (6-12 mo) EVFI, ORR to EV2 was 33% (4/12) and 31% (4/13), respectively. No responses were reported with short (<6 mo) EVFI (0/14; 0%). EV2 was initiated at 0.75 mg/kg in 5/8 pts with CR/PR. Median PFS and OS estimated from EV2 start were 2.8 and 18.5 mo. Among pts with CR/PR, median DoR was 7.0 mo (95% CI 3.5-NR). At last follow up, three pts remained on EV2; 39 pts discontinued EV2 due to progression (74%, n=29), toxicity (23%, n=9) or pt preference (2.6%, n=1). Conclusions: In a real-world cohort, EV rechallenge demonstrated modest activity, primarily in pts with prior benefit from EV and EVFI >6 mo. These observations underscore the need for further studies to clarify the effects of repeated EV exposure and optimize patient selection. This is particularly relevant given efforts to mitigate toxicity and the emerging issue of recurrent disease after perioperative EVP. AllN = 42 EV1-monoN = 26 EVP1N = 16 EV1 ORR (95% CI) 79% (63%–90%) 85% (65%–96%) 69% (41%–89%) Median PFS, mo (95% CI) 8.3 (7.5–9.9) 8.6 (7.7–19.1) 7.6 (5.5–11.9) Median Time on EV, mo [IQR] 4.9 [3.7–7.2] 5.1 [4.1–8.7] 4.1 [2.4–5.7] EV2 ORR (95% CI)NE 8/39; 21% (9%-36%)3 5/25; 20% (7%–41%)1 3/14; 21% (5%–51%)2 Median PFS, mo (95% CI) 2.8 (2.6–5.1) 2.7 (2.6–5.3) 4.1 (2.6–NR) Median OS, mo (95% CI) 18.5 (11.6–29.7) 18.5 (11.0–29.7) 15.2 (12.6–NR) Median Time on EV, mo [IQR] 2.8 [1.9–5.6] 2.5 [1.9–5.1] 3.4 [1.9–6.1]