EV-302: Updated analysis from the phase 3 global study of enfortumab vedotin in combination with pembrolizumab (EV+P) vs chemotherapy (chemo) in previously untreated locally advanced or metastatic urothelial carcinoma (la/mUC).
Authors: Powles Thomas , Van Der Heijden Michiel Simon , Loriot Yohann , Bedke Jens , Valderrama Begoña P. , Iyer Gopa , Kikuchi Eiji , Hoffman-Censits Jeannie , Vulsteke Christof , Drakaki Alexandra , Rausch Steffen , Arafat Waddah , Park Se Hoon , Swami Umang , Li Jian-Ri , Gorla Seema Rao , Homet Moreno Blanca , Yu Xuesong , Lu Yi-Tsung , Gupta Shilpa 
Published: February 2025

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Background:
EV-302 /KEYNOTE-A39 (NCT04223856) demonstrated significant progression-free survival (PFS) and overall survival (OS) benefit with first-line (1L) EV+P vs chemo in patients (pts) with la/mUC. EV+P is the standard of care (SOC) in global treatment guidelines for pts with untreated la/mUC. We present 12 mo of additional follow-up for EV-302 (>2 y of median follow-up) and an exploratory analysis of pts with confirmed complete response (cCR).
Methods:
Pts with previously untreated la/mUC were randomized 1:1 to receive EV (1.25 mg/kg; Days 1 and 8; IV) and P (200 mg; Day 1; IV) or gemcitabine with cisplatin or carboplatin every 3 wks. Dual primary endpoints were PFS by blinded independent central review (BICR) and OS. Select secondary endpoints were confirmed objective response rate (cORR), duration of response (DOR), and safety. An exploratory analysis evaluated treatment outcomes and safety in pts with cCR.
Results:
886 pts were randomized to receive EV+P (n=442) or chemo (n=444). At data cutoff (Aug 8, 2024), median follow-up was 29.1 mo (95% CI, 28.5-29.9). PFS by BICR (HR, 0.48 [95% CI, 0.41-0.57]) and OS (HR, 0.51 [95% CI, 0.43-0.61]) were improved in the EV+P vs chemo arms (Table). OS benefit was seen irrespective of cisplatin eligibility or presence of liver metastases (mets). In the response-evaluable set, cORR was 67.5% for EV+P and 44.2% for chemo. Median DOR was 23.3 mo (95% CI, 17.8-not estimable [NE]) for EV+P and 7.0 mo (95% CI, 6.2-9.0) for chemo. 30.4% of pts in the EV+P arm and 14.5% in the chemo arm achieved cCR. Median duration of cCR was not reached for EV+P and 15.2 mo (95% CI, 10.3-NE) for chemo. Grade ≥3 treatment-related (TR) adverse events (AEs) in the EV+P vs chemo arms occurred in 57.3% vs 69.5% of pts in the safety analysis set (Table) and 61.7% vs 71.9% of pts in the cCR subgroup, respectively. TR deaths occurred in 1.1% vs 0.9% of pts in the safety analysis set in the EV+P vs chemo arms, respectively; none occurred in the cCR subgroup.
Conclusions:
EV+P continues to demonstrate superior efficacy vs chemo in a broad population, consistent with the primary analysis. Results confirm durable EV+P efficacy with no new safety signals, reinforcing EV+P as SOC for the 1L treatment of pts with la/mUC. Clinical trial information:
NCT04223856
.

Key efficacy and safety outcomes.

EV+P
Chemo
EV+P vs chemo

Efficacy (intent to treat set)
n
mo
n
mo
HR (95% CI)

Median PFS
442
12.5 (95% CI, 10.4-16.6)
444
6.3 (95% CI, 6.2-6.5)
0.48 (0.41-0.57)

Median OS
442
33.8 (95% CI, 26.1-39.3)
444
15.9 (95% CI, 13.6-18.3)
0.51 (0.43-0.61)

Cisplatin eligible
244
36.7
234
18.7
0.54 (0.42-0.70)

Cisplatin ineligible
198
25.6
210
12.7
0.50 (0.39-0.64)

Liver mets present
100
19.1
99
10.1
0.56 (0.40-0.78)

Liver mets absent
342
39.3
345
18.3
0.50 (0.40-0.62)

Safety (safety analysis set)

n

n

Grade ≥3 TRAE
440
252 (57.3%)
433
301 (69.5%)
–