KEYMAKER-U04 substudy 04B: First-line (1L) enfortumab vedotin (EV) plus pembrolizumab (pembro)-based immune checkpoint inhibitor (ICI) combinations for advanced urothelial cancer (UC).

Abstract

EV + pembro is the preferred standard 1L therapy for patients with locally advanced or metastatic UC (la/mUC). The randomized, open-label phase 1/2 substudy 04B in the KEYMAKER-U04 umbrella study (NCT05845814) aimed to build on the efficacy of this combination and evaluated EV + pembro-containing ICI coformulations and EV + pembro as 1L treatment in participants (pts) with la/mUC. Method(s): Adult pts without prior systemic therapy for la/mUC and an ECOG PS of 0-1 were randomized 1:1:1 to EV + coformulated favezelimab (fave; anti-LAG3)/pembro 800 mg/200 mg (arm A), EV + coformulated vibostolimab (vibo; anti-TIGIT)/pembro 200 mg/200 mg (arm B), and EV + pembro 200 mg (arm C). Pts received EV 1.25 mg/kg IV on d1 and d8 Q3W until disease progression, intolerable toxicity, or study withdrawal, and pembro or pembro-containing coformulations IV on d1 Q3W for <=2 years. A safety lead-in was performed for the first 10 pts in each of EV + fave/pembro and EV + vibo/pembro arms per modified toxicity probability interval with dose-limiting toxicity (DLT) monitoring in cycle 1. Primary end points: ORR per RECIST v1.1 by blinded independent central review (BICR) and safety. Secondary end points: PFS and DOR per RECIST v1.1 by BICR. Result(s): 124 pts received treatment (arm A: n = 41; arm B: n = 41; arm C: n = 42). Median follow-up (time from randomization to data cutoff [Dec 16, 2024]) (range) was 11.9 mo (9.7-17.0), 11.7 mo (9.7-16.3), and 11.8 mo (9.8-16.8), respectively. Most pts were male (74%); median age was 69 yrs. DLT was reported for 1/10 pts on EV + fave/pembro and no pts on EV + vibo/pembro. Efficacy results are in the table. Any-grade TRAEs were similar across all arms (arm A: 100%; arm B: 100%; arm C: 97.6%); grade >=3 TRAEs were reported for 56.1%, 73.2%, and 61.9% of pts, respectively. Immune-mediated AEs and infusion reactions were reported for 65.9% pts in arm A, 53.7% in arm B, and 42.9% in arm C; immune-mediated AEs with > 10% higher incidence in any EV + pembro-containing ICI coformulation were hypothyroidism (31.7%, 14.6%, and 2.4%, respectively), severe skin reactions (24.4%, 29.3%, and 14.3%, respectively), hyperthyroidism (22.0%, 4.9%, and 4.8%, respectively), and infusion reactions (17.1%, 2.4%, and 0%, respectively). Conclusion(s): In pts with la/mUC, the addition of LAG3- or TIGIT-targeted ICIs to EV + pembro did not have a clinically significant impact on efficacy. No new safety signals were identified. Incidence of certain immune-mediated AEs was higher with pembro-containing coformulations compared to EV + pembro. Clinical trial information: NCT05845814. [Table presented] Copyright © 2026 by American Society of Clinical Oncology