Enfortumab vedotin (EV) with or without pembrolizumab (P) in patients (pts) who are cisplatin-ineligible with previously untreated locally advanced or metastatic urothelial cancer (la/mUC): Additional 3-month follow-up on cohort K data.
Authors: Friedlander Terence W. , Milowsky Matthew I. , O'Donnell Peter H. , Petrylak Daniel P. , Hoimes Christopher J. , Flaig Thomas W. , Mar Nataliya , Moon Helen H , McKay Rana R. , Bilen Mehmet Asim , Borchiellini Delphine , Iafolla Marco , Carret Anne-Sophie , Yu Yao , Guseva Maria , Kataria Ritesh S. , Rosenberg Jonathan E. 
Published: June 2023

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Background: There is a high unmet need for effective and durable first-line (1L) treatment options in cisplatin-ineligible la/mUC. EV and P have shown survival benefit as monotherapies in 2L+ la/mUC, and preclinical studies demonstrate that EV induces hallmarks of immunogenic cell death, which may be further augmented by PD-1 inhibitors (e.g., P). Promising results from EV-103 dose escalation/Cohort A (DE/A) provided rationale for this randomized Cohort K for which we are disclosing additional follow-up to previous reports (Rosenberg, ESMO 2022) on efficacy and safety. Methods: Untreated cisplatin-ineligible pts with la/mUC were randomized 1:1 to EV (1.25 mg/kg, day 1, day 8) as monotherapy (EV mono) or in combination with P (200 mg, day 1) using 3-week cycles. The primary endpoint was confirmed objective response rate (cORR) per RECIST v1.1 by blinded independent central review (BICR). Secondary endpoints included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. No formal statistical comparisons were planned between treatment arms. Results: 149 pts were treated; EV+P, n=76; EV, n=73. Median follow-up (95% CI) for EV+P, 17.6 (16.03, 20.37) months; EV+P cORR (95% CI), 64.5% (52.7, 75.1); median DOR not reached; DCR, 86.6% (77.1, 93.5); median PFS, and OS not reached. PFS rate at 6 and 12 months (95% CI), 73.8% (62.01, 82.42) and 54.5% (41.74, 65.61); OS rate at 6 and 12 months (95% CI), 88.2% (78.48, 93.65) and 81.5% (70.78, 88.61). Median follow-up (95% CI) for EV mono, 18.2 (15.90, 20.07) months; cORR (95% CI), 45.2% (33.5, 57.3); median DOR, 13.2 months (6.14, -); DCR, 79.5% (68.4, 88.0); median PFS and OS, 8.2 (6.05, 15.28) and 21.7 (15.47, -) months; PFS rate at 6 and 12 months, 64.2% (51.09, 74.69) and 40.3% (26.62, 53.60); OS rate at 6 and 12 months, 83.6% (72.87, 90.31) and 69.7% (57.68, 78.87). EV treatment-related adverse events of special interest (AESIs) include skin reactions (EV+P, 67.1%; EV mono, 45.2%), peripheral neuropathy (EV+P, 63.2%; EV mono, 54.8%), and hyperglycemia (EV+P, 14.5%; EV mono, 11.0%). In EV+P, the most frequent (any grade) P treatment-emergent adverse events of special interest were severe skin reactions (27.6%), hypothyroidism (13.2%), and pneumonitis (9.2%). Conclusions: With an additional 3 months of follow-up, EV+P continues to show a high cORR with rapid and durable responses as 1L treatment in cisplatin-ineligible pts with la/mUC, including a manageable safety profile with no new safety concerns after extended treatment exposure. DOR, PFS and OS will evolve with further follow-up and continue to trend similarly to those of DE/A; EV monotherapy was consistent with prior results. Clinical trial information: NCT03288545 .