Enfortumab Vedotin/Pembrolizumab Maintains OS Benefit in Urothelial Carcinoma

Enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda) had superior overall survival (OS) vs platinum-based chemotherapy in patients with previously untreated locally advanced or metastatic urothelial carcinoma (la/mUC), according to the phase 3 EV-302/KEYNOTE-A39 trial (NCT04223856) presented at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting by Thomas B. Powles, MD, of Barts Cancer Centre, Queen Mary University of London.¹

In the intention-to-treat (ITT) population, the 3.5-year update confirmed and extended the OS benefit previously observed with enfortumab vedotin plus pembrolizumab (EV+P). Patients in the EV+P arm achieved a median OS of 33.6 months (95% CI, 26.6–39.8) vs 15.9 months (95% CI, 13.6–18.3) in the chemotherapy arm, corresponding to a stratified HR of 0.53 (95% CI, 0.45–0.63). At 3.5 years, an estimated 44.0% of patients receiving EV+P remained alive compared with 24.6% in the chemotherapy arm.

EV+P also demonstrated substantially higher response rates. The objective response rate (ORR) was 67.5% (n = 295) with EV+P vs 44.2% (n = 195) with chemotherapy. The complete response (CR) rate was approximately doubled in the EV+P arm— 30.4% (n = 133) vs 14.5% (n = 64)—among response-evaluable patients. Exploratory analyses characterizing CR evolution revealed that 66.2% of patients who achieved a CR with EV+P (n = 88/133) initially reached a partial response (PR) and subsequently deepened to CR. The median time from randomization to CR was 4.3 months (interquartile range [IQR], 2.2–8.4) across all patients with CR, while those who converted from PR to CR achieved their initial PR at a median of 2.1 months and their subsequent CR at a median of 6.6 months from randomization (IQR, 4.3–12.1).

Cumulative CR rates in the EV+P arm continued to accrue through week 96, and established CRs demonstrated sustained durability. Among EV+P-treated patients who achieved a CR (n = 133), the median OS was not estimable compared with 56.7 months in the chemotherapy CR subgroup (stratified HR, 0.36; 95% CI, 0.20–0.68), with an estimated 83.6% alive at 3.5 years. The PR-to-CR subgroup (n = 88) showed similarly favorable long-term outcomes, with an estimated 82.4% alive at 3.5 years and a median OS that was also not estimable (stratified HR, 0.34; 95% CI, 0.15–0.77), confirming that response deepening translates to meaningful and durable survival benefit.

The randomized, open-label trial enrolled 886 patients with untreated la/mUC who were eligible for enfortumab vedotin, pembrolizumab, and platinum chemotherapy, were PD-(L)1 inhibitor–naive, had a glomerular filtration rate of at least 30 mL/min, and had an ECOG performance status of 0 to 2. Patients were stratified by cisplatin eligibility, PD-L1 expression (combined positive score ≥10 vs <10), and presence of liver metastases, then randomly assigned 1:1 to receive either EV+P until disease progression or a maximum of 35 cycles, or gemcitabine plus cisplatin or carboplatin for up to 6 cycles. Dual primary end points were progression-free survival (PFS) by blinded independent central review and OS. At the data cutoff of October 6, 2025, median follow-up in the ITT population was 42.8 months.

Of the 442 patients treated in the EV+P arm, 192 (43.4%) received subsequent anticancer therapy. Platinum-based chemotherapy was the most common first subsequent systemic treatment, administered to 135 patients (30.5%). Among evaluable patients receiving subsequent platinum-based regimens, the ORR was 20.7% for the carboplatin-based regimen and 21.9% for the and cisplatin-based regimen, with a median OS from the start of subsequent platinum chemotherapy of 10.9 months (95% CI, 8.3–12.8). These findings indicate that patients progressing on EV+P retain meaningful sensitivity to platinum-based salvage, consistent with enfortumab vedotin’s non-platinum mechanism of action. Enfortumab vedotin’s continued development across bladder cancer settings was also recently highlighted when the perioperative EV plus pembrolizumab combination earned FDA Priority Review for muscle-invasive bladder cancer based on data from the phase 3 EV-304 trial.²

The updated safety profile remained consistent with prior analyses, and no new safety signals emerged with extended treatment. In the overall EV+P safety population, patients received treatment for a median of 9.6 months (range, 0.3–52 months). At longer durations of treatment, modest increases in treatment-related adverse events (TRAEs) of special interest were observed, predominantly grade 1 or 2. The most notable increase—approximately 25%—occurred in peripheral sensory neuropathy among patients with a duration of treatment greater than 2 years, consistent with cumulative exposure to MMAE, the cytotoxic payload of enfortumab vedotin. Dose interruptions and reductions for EV were reported in 60.0% and 43.0% of the overall safety population, respectively, and were identified as important management strategies to allow patients to remain on therapy.

Powles concluded that with approximately 3.5 years of median follow-up, EV+P continued to demonstrate superior and durable OS benefit over platinum-based chemotherapy, reinforcing the combination as the preferred standard of care for first-line treatment of la/mUC. The data further establish that the deepening of responses from PR to CR is a clinically meaningful and durable phenomenon, with survival outcomes in this group comparable to those seen in patients achieving direct CR. The consistent safety profile across extended treatment durations supports the use of dose modifications as a practical strategy to optimize long-term outcomes in this population.

References

1. Powles TB, van der Heijden MS, Bedke J, et al. Enfortumab vedotin plus pembrolizumab vs chemotherapy for previously untreated locally advanced or metastatic urothelial carcinoma: 3.5-year follow-up and response analyses from the phase 3 EV-302 study. J Clin Oncol. 2026;44(suppl 16):4503. doi:10.1200/JCO.2026.44.16_suppl.4503
2. Perioperative Enfortumab Vedotin Combo Earns Priority Review for MIBC. Cancer Network. Published April 20, 2026. Accessed May 30, 2026. https://www.cancernetwork.com/view/perioperative-enfortumab-vedotin-combo-earns-priority-review-for-mibc