Updated EV-302 Data Reinforce Enfortumab Vedotin Combo’s Durability in Urothelial Carcinoma at ASCO 2026

At the 2026 ASCO Annual Meeting, 3.5-year follow-up findings from the phase 3 EV-302/KEYNOTE-A39 study (NCT04223856) have been presented.¹

At a median follow-up of 42.8 months, enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda; n = 442) led to a median overall survival (OS) of 33.6 months (95% CI, 26.6-39.8) vs 15.9 months (95% CI, 13.6-18.3) with chemotherapy (n = 444) in patients with previously untreated locally advanced or metastatic urothelial carcinoma (HR, 0.53; 95% CI, 0.45-0.63). The 42-month OS rates in the respective arms were 44.0% and 24.6%, respectively.

In the enfortumab vedotin arm, the overall response rate (ORR) was 67.5%, including complete response (CR) and partial response (PR) rates of 30.4% and 37.1%, respectively. In the chemotherapy arm, these respective rates were 44.2%, 14.5%, and 29.7%. In the enfortumab vedotin arm, 10.3% of patients achieved a CR directly, and 20.1% of patients achieved a CR after a PR. These rates were 5.9% and 8.6%, respectively, in the chemotherapy arm.

In those who received the enfortumab vedotin regimen and achieved a CR (n = 133), the median OS was not evaluable (NE), and the 42-month OS rate was 83.6%. The median time to CR was 4.3 months (IQR, 2.2-8.4). Conversely, among patients in this population in the chemotherapy arm, the median OS was 56.7 months (95% CI, 43.9-NE), and the 42-month OS rate was 68.0% (HR, 0.36; 95% CI, 0.20-0.68).

In patients who received the enfortumab vedotin combination and achieved a CR after a PR (n = 88), the median OS was also NE, and the 42-month OS rate was 82.4%. The median time to CR in this group was 6.6 months (IQR, 4.3-12.1), and the median time to initial PR was 2.1 months (IQR, 1.9-2.2). Among patients with this response pattern in the chemotherapy arm, the median OS was 59.4 months (95% CI, 39.6-NE), and the 42-month OS rate was 67.1% (HR, 0.34; 95% CI, 0.15-0.77).

In total, 43.4% of patients in the enfortumab vedotin arm received subsequent anticancer therapies, including 39.1% of patients who received subsequent systemic therapy. Among first subsequent systemic therapies were platinum-containing chemotherapy (30.5%), PD-(L)1 inhibition (3.8%), and other therapies (4.8%). Among patients who received subsequent platinum-containing chemotherapy, the ORR was 20.7%, and the median OS from the start of platinum-based chemotherapy was 10.9 months (95% CI, 8.3-12.8).

Regarding safety, in the enfortumab vedotin arm, 67.5%, 41.8%, 31.6%, and 23.2% of patients remained on treatment at 6, 12, 18, and 24 months, respectively. Treatment-related adverse effects (TRAEs) leading to dose interruptions of enfortumab vedotin in patients with a duration of treatment (DOT) longer than 1 year occurred in 75.5% of patients; TRAEs leading to dose interruptions of this agent in patients with a DOT longer than 2 years occurred in 74.5% of patients. TRAEs leading to dose interruptions of pembrolizumab in patients with a DOT longer than 1 year occurred in 65.2% of patients; TRAEs leading to dose interruptions of this agent in patients with a DOT longer than 2 years occurred in 64.7% of patients. TRAEs leading to enfortumab vedotin dose reductions at less than 1 year and less than 2 years occurred in 65.8% and 70.6% of patients, respectively.

In the overall enfortumab vedotin arm, the median duration of enfortumab vedotin treatment was 7.1 months (95% CI, 0.3-52), and the median duration of pembrolizumab treatment was 8.5 months (95% CI, 0.3-31). The safety profile of the combination in patients who were able to stay on treatment with a duration of treatment of greater than 1 or 2 years was similar to that in the overall population, despite the longer treatment intervals. In the overall population, any-grade TRAEs were observed in 97.3% of patients, and grade 3 or higher TRAEs were seen in 57.0% of patients. No new safety signals were seen.

What are the design and key objectives of EV-302?

The trial included patients with previously untreated locally advanced or metastatic urothelial carcinoma who were eligible to receive platinum chemotherapy, enfortumab vedotin, and pembrolizumab.² Patients could not have had exposure to a PD-1 or PD-L1 inhibitor but must have had a glomerular filtration rate of at least 30 mL/min and an ECOG performance status of 0 to 2.

Patients 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 progression-free survival (PFS) by blinded independent central review 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.

What previous results have been reported with enfortumab vedotin in EV-302?

At a median follow-up of 17.2 months, the median PFS was 12.5 months (95% CI, 10.4-16.6) with the enfortumab vedotin regimen vs 6.3 months (95% CI, 6.2-6.5) with chemotherapy (HR, 0.45; 95% CI, 0.38-0.54; P < .001).³ The median OS values at this time point were 31.5 months (95% CI, 25.4-not reached) and 16.1 months (95% CI, 13.9-18.3), respectively (HR, 0.47; 95% CI, 0.38-0.58; P < .001).

These findings supported the December 2023 FDA approval of enfortumab vedotin plus pembrolizumab in patients with locally advanced or metastatic urothelial carcinoma.⁴ “This study represents a significant advancement in the management of urothelial cancer,” Joaquim Bellmunt, MD, PhD, of Dana-Farber Cancer Institute, told OncLive.⁵ “In fact, it is a paradigm shift. Now [the combination is] becoming the new standard of care for patients with locally advanced or metastatic bladder cancer, including patients who are fit or unfit for cisplatin.”

John K. Lee, MD, PhD, of David Geffen School of Medicine, UCLA Heath, further discussed the significance of the phase 3 EV-302 study:⁶

In a past episode of Oncology Unplugged, host Chandler Park, MD, MSc, FACP, of Norton Cancer Institute in Louisville, Kentucky, sat down with Guru P. Sonpavde, MD, of AdventHealth Cancer Institute in Orlando, Florida, to further discuss the topline data from the EV-302 trial, considerations for community oncologists when deciding whether to prescribe enfortumab vedotin plus pembrolizumab to patients with urothelial carcinoma, their advice for monitoring and managing treatment-related toxicities with this combination, and more.⁷

Updated OS data shared during the 2025 Genitourinary Cancers Symposium (ASCO GU) 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 enfortumab vedotin plus pembrolizumab vs 15.9 months (95% CI, 13.6-18.3) with chemotherapy (HR, 0.51; 95% CI, 0.43-0.61).⁸

In a previous interview with OncLive, Shilpa Gupta, MD, of the Cleveland Clinic in Ohio, discussed the implications of the ASCO GU data readout.⁹ “It is very reassuring to see long-term follow-up data,” she said. “This is the first time that we have presented the long-term follow-up, and I am sure that there is more to come in the coming years.”

What is the significance of the EV-302 data for the urothelial cancer treatment paradigm?

“[The phase 3] EV-302 trial established enfortumab vedotin plus pembrolizumab as a standard first-line treatment for locally advanced/metastatic urothelial cancer,” Park said in an exclusive ASCO 2026 preview.¹⁰ This update will tell us whether the OS and PFS benefits are durable at extended follow-up and whether any new or emerging safety signals have developed with longer treatment exposure.”

When asked about the abstracts he was most anticipating learning about at the meeting, Sonpavde agreed that EV-302 is on his list, saying, “This is a long-term update of the EV-302 trial that established enfortumab vedotin plus pembrolizumab as the preferred first-line therapy for advanced urothelial carcinoma.”

References

1. Powles T, Van Der Heijden MS, Bedke J, et al. Enfortumab vedotin plus pembrolizumab (EV+P) vs chemotherapy for previously untreated locally advanced or metastatic urothelial carcinoma (la/mUC): 3.5-year follow-up and response analyses from the phase 3 EV-302 study. J Clin Oncol. 2026;44(suppl 16):4507. doi:10.1200/JCO.2026.44.16_suppl.4507
2. 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
3. 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
4. FDA approves enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial cancer. FDA. December 15, 2023. Accessed May 21, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enfortumab-vedotin-ejfv-pembrolizumab-locally-advanced-or-metastatic-urothelial-cancer
5. Flaherty C. EV-302 trial ushers in era of novel combos in first-line metastatic urothelial cancer: Q&A with Joaquim Bellmunt, MD, PhD. OncLive.com. May 10, 2024. Accessed May 21, 2026. https://www.onclive.com/view/ev-302-trial-ushers-in-era-of-novel-combos-in-first-line-metastatic-urothelial-cancer
6. Lee JK. Dr Lee on the efficacy of enfortumab vedotin plus pembrolizumab in urothelial cancer. OncLive.com. January 15, 2025. Accessed May 21, 2026. https://www.onclive.com/view/dr-lee-on-the-efficacy-of-enfortumab-vedotin-plus-pembrolizumab-in-urothelial-cancer
7. Park C, Sonpavde G. Park and Sonpavde on considerations for enfortumab vedotin plus pembrolizumab in bladder cancer. OncLive.com. May 30, 2024. Accessed May 21, 2026. https://www.onclive.com/view/park-and-sonpavde-on-considerations-for-enfortumab-vedotin-plus-pembrolizumab-in-bladder-cancer
8. 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
9. Gupta S. Dr Gupta on the efficacy of enfortumab vedotin plus pembrolizumab in urothelial carcinoma. OncLive.com. October 15, 2025. Accessed May 21, 2026. https://www.onclive.com/view/dr-gupta-on-the-efficacy-of-enfortumab-vedotin-plus-pembrolizumab-in-urothelial-carcinoma
10. Doherty K. GU cancer experts highlight top abstracts to watch during ASCO 2026. OncLive.com. May 12, 2026. Accessed May 21, 2026. https://www.onclive.com/view/gu-cancer-experts-highlight-top-abstracts-to-watch-during-asco-2026