EV-302 Regimen Shows Sustained Efficacy Vs Chemo Across Key Subgroups of Urothelial Cancer

Urothelial Carcinoma |
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The frontline combination of enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda; EV+P) continued to demonstrate better efficacy outcomes than chemotherapy across prespecified subgroups of patients with previously untreated locally advanced or metastatic urothelial carcinoma, according to long-term subgroup analysis findings from the phase 3 EV-302/KEYNOTE-A39 study (NCT04223856).1

The data cutoff date for the analysis was August 8, 2024, and the median follow-up was 29.1 months (95% CI, 28.5-29.9). In patients with primary disease site of origin in the upper tract, EV+P (n = 135) led to a median progression-free survival (PFS) of 12.3 months (95% CI, 7.6-16.4) by blinded independent central review (BICR) vs 6.2 months (95% CI, 6.1-6.9) with chemotherapy (n = 104; HR, 0.542; 95% CI, 0.384-0.763). The median overall survival (OS) in the respective arms was 36.5 months (95% CI, 23.8-not evaluable [NE]) and 18.3 months (95% CI, 12.5-23.8; HR, 0.538; 95% CI, 0.371-0.781).

In those with lymph node–only metastases, the median PFS with the enfortumab vedotin combination (n = 103) or chemotherapy (n = 104) was 22.1 months (95% CI, 15.3-NE) and 8.3 months (95% CI, 6.2-13.1), respectively (HR, 0.473; 95% CI, 0.317-0.704). The median OS in the respective arms was NE (95% CI, 39.3-NE) and 24.4 months (95% CI, 18.3-NE; HR, 0.512; 95% CI, 0.332-0.789). Additionally, in those with visceral metastases who received EV+P (n = 318), the median PFS was 10.4 months (95% CI, 8.3-12.7); those who received chemotherapy (n = 318) had a median PFS of 6.2 months (95% CI, 6.0-6.3; HR, 0.477; 95% CI, 0.393-0.579). The median OS in the respective arms was 25.7 months (95% CI, 23.8-33.8) and 13.5 months (95% CI, 11.8-15.6; HR, 0.505; 95% CI, 0.412-0.619).

Lastly, those with liver metastases who received EV+P (n = 100) or chemotherapy (n = 99) experienced a median PFS of 8.1 months (95% CI, 6.1-12.0) and 6.0 months (95% CI, 4.4-6.3), respectively (HR, 0.548; 95% CI, 0.392-0.766). The median OS in the respective arms was 19.1 months (95% CI, 14.5-24.3) and 10.1 months (95% CI, 7.9-11.8; HR, 0.556; 95% CI, 0.399-0.776).

“EV+P continues to demonstrate superior efficacy vs chemotherapy across prespecified subgroups after a median of [approximately] 2.5 years of follow-up, with a magnitude of benefit aligned with the overall population,” Jens Bedke, MD, of the Department of Urology and Eva Mayr-Stihl Cancer Center, Klinikum Stuttgart, in Germany, and colleagues wrote in a poster. “These data reinforce EV+P as the standard of care for the first-line treatment of patients with locally advanced or metastatic urothelial carcinoma.”

Examining EV-302: Design, Objectives, Earlier Data

The trial enrolled patients with previously untreated locally advanced or metastatic urothelial carcinoma who were candidates for platinum chemotherapy, enfortumab vedotin, and pembrolizumab. Patients could not have had exposure to a PD-1 or PD-L1 inhibitor, needed to have a glomerular filtration rate of at least 30 mL/min, and needed to have an ECOG performance status no higher than 2.

Participants were randomly assigned 1:1 to receive 3-week cycles of 1.25 mg/kg of enfortumab vedotin on days 1 and 8 plus 200 mg of pembrolizumab on day 1 or chemotherapy comprised of cisplatin or carboplatin plus gemcitabine. No maximum number of treatment cycles for enfortumab vedotin was set; the maximum number of cycles for pembrolizumab was 35; the maximum for chemotherapy was 6 cycles. Patients were stratified based on cisplatin eligibility (yes vs no), PD-L1 expression (combined positive score [CPS] ≥ 10 vs CPS < 10), and presence of liver metastases (yes vs no).

The dual primary end points were PFS by BICR and OS. Key secondary end points included objective response rate (ORR) per RECIST 1.1 criteria by investigator assessment and BICR, duration of response (DOR), and safety. For the subgroup analysis, the subgroups of clinical interest included primary disease site of origin, lymph node–only disease, visceral metastases, and liver metastases.

At a median follow-up of 17.2 months, the median PFS was 12.5 months (95% CI, 10.4-16.6) with EV+P vs 6.3 months (95% CI, 6.2-6.5) with chemotherapy (HR, 0.45; 95% CI, 0.38-0.54; P < .001).2 The median OS in the respective arms was 31.5 months (95% CI, 25.4-not reached) and 16.1 months (95% CI, 13.9-18.3; HR, 0.47; 95% CI, 0.38-0.58; P < .001). These data supported the December 2023 FDA approval of enfortumab vedotin plus pembrolizumab in patients with locally advanced or metastatic urothelial carcinoma.3 Updated OS data shared during the 2025 Genitourinary Cancers Symposium showed that at a median follow-up of 29.1 months, the median OS was 33.8 months (95% CI, 26.1-39.3) with EV+P vs 15.9 months (95% CI, 13.6-18.3) with chemotherapy (HR, 0.51; 95% CI, 0.43-0.61).4

Taking a Closer Look at the Current Analysis: Efficacy Data

At the data cutoff date, 12% of patients on the EV+P arm (n = 54/442) remained on treatment; no patients remained on chemotherapy (n = 0/444); 49% and 30% of patients, respectively, remained on study.1 Across the subgroups, the median patient age ranged from 68.0 years to 69.0 years (range, 22-91); more than half of patients were male, and most patients had an ECOG performance status of 0 or 1. Most patients had visceral metastases.

In those with upper tract disease who received EV+P (n = 133), the ORR was 67.7% and included a complete response (CR) rate of 28.6% and a partial response (PR) rate of 39.1%. The median DOR was 23.3 months (95% CI, 12.6-NE). In those with upper tract disease who received chemotherapy (n = 103), the ORR was 40.8%, which was comprised of CR and PR rates of 10.7% and 30.1%, respectively; the median DOR was 6.2 months (95% CI, 4.9-12.5). In those with lower tract disease who received EV+P (n = 302) or chemotherapy (n = 337), the respective ORRs were 67.5% (CR rate, 31.1%; PR rate, 36.4%) and 45.4% (15.7%; 29.7%), and the respective median DORs were 23.9 months (95% CI, 17.3-NE) and 7.0 months (95% CI, 6.2-10.2).

In those with lymph node–only metastases who received EV+P (n = 102) or chemotherapy (n = 103), the respective ORRs were 77.5% (CR rate, 50.0%; PR rate, 27.5%) and 53.4% (26.2%; 27.2%), and the respective median DORs were NE (95% CI, 19.9-NE) and 12.4 months (95% CI, 8.6-24.9). In those with visceral metastases who received EV+P (n = 315) or chemotherapy (n = 318), the respective ORRs were 63.8% (CR rate, 23.5%; PR rate, 40.3%) and 39.3% (10.1%; 29.2%), and the respective median DORs were 20.2 months (95% CI, 14.7-25.6) and 6.1 months (95% CI, 5.4-6.9). In those with liver metastases who received EV+P (n = 100) or chemotherapy (n = 99), the respective ORRs were 59.0% (CR rate, 20.0%; PR rate, 39.0%) and 40.4% (7.1%; 33.3%), and the median DORs were 12.9 months (95% CI, 8.4-20.2) and 5.0 months (95% CI, 4.3-6.2), respectively. Lastly, in those without liver metastases who received EV+P (n = 337) or chemotherapy (n = 342), the respective ORRs were 70.0% (CR rate, 33.5%; PR rate, 36.5%) and 45.3% (16.7%; 28.7%); the median DORs were 34.2 months (95% CI, 21.5-NE) and 8.4 months (95% CI, 6.6-10.4).

Safety Revelations

Within the population of patients who had upper tract disease, any treatment-related adverse effects (TRAEs) occurred in 98.5% of those in the EV+P arm (n = 135) vs 94.8% of those in the chemotherapy arm (n = 97); these TRAEs were grade 3 or higher for 60.7% and 71.1% of patients, respectively, and they were serious for 28.9% and 13.4% of patients, respectively. The most common TRAEs of special interest for enfortumab vedotin in the EV+P arm were rash (any grade 68.1%; grade ≥ 3, 20.0%), peripheral neuropathy (65.9%; 7.4%), and sensory events (65.2%; 5.9%). The most common treatment-emergent AEs of special interest for pembrolizumab in the EV+P arm were severe skin reactions (any grade, 16.3%; grade ≥ 3, 12.6%), hypothyroidism (12.6%; 1.5%), and pneumonitis (10.4%; 4.4%).

In those with lower tract disease, any TRAEs occurred in 96.7% of those in the EV+P arm (n = 303) and 95.8% of those in the chemotherapy arm (n = 335); these effects were grade 3 or higher for 56.1% and 69.0% of patients, respectively, and serious for 29.7% and 21.2% of respective patients. The most common TRAEs of special interest for enfortumab vedotin in the combination arm were skin reactions (any grade, 65.7%; grade ≥ 3, 13.9%), peripheral neuropathy (63.7%; 7.6%), and rash (60.1%; 13.2%). The most common treatment-emergent AEs of special interest for pembrolizumab in the combination arm were severe skin reactions (any grade, 18.5%; grade ≥ 3, 12.2%), hypothyroidism (11.9%; 0.3%), and pneumonitis (10.2%; 3.6%).

In the subgroup of those with lymph node–only metastases, any TRAEs occurred in 97.1% of those given EV+P (n = 103) vs 96.1% of those given chemotherapy (n = 102); these TRAEs were grade 3 or higher for 53.4% vs 66.7% of patients, respectively, and serious for 25.2% vs 17.6% of respective patients. In this group, the most common TRAEs of special interest for enfortumab vedotin in the combination arm were peripheral neuropathy (any grade, 69.9%; grade ≥ 3, 8.7%), rash (66.0%; 13.6%), and sensory events (65.0%; 6.8%). The most common treatment-emergent AEs for pembrolizumab in the combination arm were severe skin reactions (any grade, 18.4%; grade ≥ 3, 7.8%), hypothyroidism (16.5%; 1.0%), and pneumonitis (10.7%; 1.9%).

In the subset of patients with visceral metastases who received the enfortumab vedotin regimen (n = 316) or chemotherapy (n = 309), any TRAEs were reported in 97.2% and 95.5% of patients, respectively; grade 3 or higher TRAEs occurred in 58.5% and 70.9% of respective patients, and serious TRAEs were reported in 30.1% and 20.7% of patients, respectively. The most common TRAEs of special interest with enfortumab vedotin in the combination arm included skin reactions (any grade, 64.2%; grade ≥ 3, 17.1%), peripheral neuropathy (62.0%; 7.0%), and rash (61.1%; 16.1%). The most frequent treatment-emergent AEs of special interest for pembrolizumab in the combination arm included severe skin reactions (any grade, 18.0%; grade ≥ 3, 14.2%), pneumonitis (10.1%; 4.4%), and hypothyroidism (9.5%; 0.6%).

In those with liver metastases who received EV+P (n = 99) or chemotherapy (n = 96), any TRAEs occurred in 96.0% and 96.9% of patients, respectively; these TRAEs were grade 3 or higher for 55.6% and 74.0% of patients, respectively, and they were serious for 32.3% and 16.7% of respective patients. The most common TRAEs of special interest for enfortumab vedotin in the combination arm were skin reactions (any grade, 64.6%; grade ≥ 3, 12.1%), rash (59.6%; 11.1%), and peripheral neuropathy (53.5%; 6.1%). The most frequent treatment-emergent AEs of special interest for pembrolizumab in the combination arm were severe skin reactions (any grade, 18.2%; grade ≥ 3, 13.1%), hypothyroidism (7.1%; 0%), and hyperthyroidism (5.1%; 0%).

Lastly, in those without liver metastases who were given EV+P (n = 341) or chemotherapy (n = 337), any TRAEs were reported in 97.7% and 95.3% of patients; these TRAEs were grade 3 or higher for 57.8% and 68.2% of patients, respectively, and they were serious for 28.4% and 20.5% of respective patients. The most common TRAEs of special interest for enfortumab vedotin in the combination arm included skin reactions (any grade, 68.0%; grade ≥ 3, 17.0%), peripheral neuropathy (67.4%; 7.9%), and sensory events (63.9%; 5.0%). The most frequent treatment-emergent AEs of special interest for pembrolizumab in the combination arm included severe skin reactions (any grade, 17.6%; grade ≥ 3, 12.0%), hypothyroidism (13.5%; 0.9%), and pneumonitis (12.0%; 4.4%).

“AE frequencies across subgroups were generally consistent with those in the overall population,” the study authors wrote

Disclosures: Bedke disclosed serving in a consulting or advisory role for Apogepha, Astella Pharma, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo Europe GmbH, Eisai, Ipsen, Janssen, Merck KGaA, MSD Oncology, Pfizer, and Roche. He is on the Speakers’ Bureau for Apogepha, Astellas Pharma, Bristol Myers Squibbb, Ipsen, Merck KGaA, MSD Oncology, and Pfizer. Research funding was received Astellas Pharma (Inst), Bristol Myers Squibb (Inst), Exelixis (Inst), Ipsen (Inst), MSD Oncology (Inst), Pfizer (Inst), Roche (Inst), and SeaGen (Inst). Travel, accommodations, and expenses were provided by Ipsen (Inst) and Merck KGaA (Inst).

References

1. Bedke J, Powles TB, Valderrama BP, et al. EV-302: long-term subgroup 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). J Clin Oncol. 2025;43(suppl 16):4571. doi:10.1200/JCO.2025.43.16_suppl.4571
2. Powles T, Valderrama BP, Gupta S, et al. Enfortumab vedotin and pembrolizumab in untreated advanced urothelial cancer. N Engl J Med. 2024;390(10):875-888. doi:10.1056/NEJMoa2312117
3. FDA approves enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial cancer. FDA. December 15, 2023. Accessed June 9, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enfortumab-vedotin-ejfv-pembrolizumab-locally-advanced-or-metastatic-urothelial-cancer
4. Powles T, Van Der Heijden MS, Loriot Y, et al. 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). J Clin Oncol. 2025;43(suppl 5):664. doi:10.1200/JCO.2025.43.5_suppl.664