Enfortumab Vedotin/Pembrolizumab Shows Long-Term Survival Benefit in 1L Urothelial Carcinoma

Updated 3.5-year follow-up results from the phase 3 EV-302/KEYNOTE-A39 trial (NCT04223856) demonstrated that the combination of enfortumab vedotin (Padcev) plus pembrolizumab (Keytruda; EV+P) continued to show an overall survival (OS) benefit compared with platinum-based chemotherapy in the first-line treatment of patients with locally advanced or metastatic urothelial carcinoma. These results were presented at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting.¹

At a median follow-up of 42.8 months, EV+P continued to demonstrate a significant OS benefit over chemotherapy in the intention-to-treat (ITT) population. Median OS was 33.6 months (95% CI, 26.6-39.8) in the EV+P arm versus 15.9 months (95% CI, 13.6-18.3) in the chemotherapy arm, corresponding to a stratified hazard ratio (HR) of 0.53 (95% CI, 0.45-0.63). At 3.5 years, an estimated 44.0% of patients in the EV+P arm were alive compared with 24.6% in the chemotherapy arm.

EV+P demonstrated substantially higher objective response rates (ORRs) compared with chemotherapy. Among response-evaluable patients, the ORR was 67.5% (n = 295) with EV+P versus 44.2% (n = 195) with chemotherapy. The complete response (CR) rate was approximately doubled with EV+P: 30.4% (n = 133) versus 14.5% (n = 64) with chemotherapy.

Of the 133 patients in the EV+P arm who achieved a CR, 45 (10.3%) did so directly, while 88 (20.1%) converted from an initial partial response (PR) to CR. Among patients with a confirmed CR in the EV+P arm, 66.2% achieved a PR initially before converting to CR. The median time to CR across all patients achieving CR was 4.3 months (IQR, 2.2-8.4), while patients who converted from PR to CR achieved their CR after a median of 6.6 months from randomization (IQR, 4.3-12.1), having first achieved their initial PR at a median of 2.1 months (IQR, 1.9-2.2).

Cumulative CR rates in the EV+P arm continued to rise over time, reaching 100% of eventual CR patients by week 96, demonstrating that responses continued to accrue well beyond the initial assessment timepoints. Baseline characteristics among patients achieving CR—whether directly or after PR conversion—were generally consistent with the overall ITT population, suggesting no specific subgroup was uniquely driving these deep responses.

Survival Outcomes in Patients Achieving CR

Among patients who achieved a CR in the EV+P arm (n = 133), OS outcomes were particularly favorable. The median OS was not estimable (NE; 95% CI, NE) with EV+P versus 56.7 months (95% CI, 43.9-NE) with chemotherapy (HR, 0.36; 95% CI, 0.20-0.68), with 83.6% of EV+P patients alive at 3.5 years compared with 68.0% in the chemotherapy arm.

Notably, patients who converted from PR to CR (n = 88 in EV+P arm) achieved survival outcomes similar to those who achieved CR directly. At 3.5 years, 82.4% of PR-to-CR converters in the EV+P arm were alive, compared with 83.6% in the overall CR group. Median OS in this subgroup was NE with EV+P versus 59.4 months (95% CI, 39.6-NE) with chemotherapy (HR, 0.34; 95% CI, 0.15-0.77), reinforcing that the route to CR did not meaningfully affect long-term survival outcomes.

“With 3.5 years of median follow-up, EV+P continues to demonstrate superior OS benefit, reinforcing EV+P as the preferred SOC for first-line treatment of [locally advanced or metastatic urothelial carcinoma],” said presenting author Thomas Powles, MD, MBBS, MRCP, a professor of genitourinary oncology and director of Barts Cancer Centre at St Bartholomew’s Hospital, Queen Mary University of London in England.

“EV+P demonstrated ORRs exceeding those with chemotherapy, with approximately twice as many patients achieving CR. Cumulative responses deepened over time, with around two-thirds of patients with CR converting from PR to CR. This group achieved similar survival rates as patients with CR overall,” added Powles.

Subsequent Therapy

Among patients in the EV+P arm, 43.4% (n = 192) received subsequent anticancer therapies, with platinum-based chemotherapy being the most common first subsequent systemic treatment, received by 30.5% of patients (n = 135). Of these, carboplatin-based therapy was used in 16.5% and cisplatin-based therapy in 13.8%. The ORR among evaluable patients receiving subsequent platinum-based chemotherapy was 20.7% overall (28/135), with similar rates observed for cisplatin-based (19.7%; 12/61) and carboplatin-based regimens (21.9%; 16/73). Median OS from the start of platinum-based chemotherapy was 10.9 months (95% CI, 8.3-12.8), suggesting that platinum-based chemotherapy retained clinically meaningful activity following EV+P.

In the chemotherapy arm, 73.0% of patients (n = 324) received subsequent therapies, with PD-(L)1 inhibitor therapy being the most common first subsequent systemic treatment at 59.7% (n = 265), predominantly avelumab maintenance (30.4%) and other PD-(L)1 inhibitors (27.3%).

Treatment Duration and Dose Modifications

In the overall EV+P safety population, patients received treatment for a median of 9.6 months (range, 0.3-52). Median duration of treatment was 7.1 months (range, 0.3-52) for EV and 8.5 months (range, 0.3-31) for pembrolizumab overall. Among patients with duration of treatment (DOT) greater than 1 year (n = 184), median treatment durations were 14.5 months for EV and 24.3 months for pembrolizumab. Among those with DOT greater than 2 years (n = 102), median durations were 22.3 months and 26.4 months, respectively.

At 6 months, 67.5% of patients in the EV+P arm remained on treatment, declining to 41.8% at 12 months, 31.6% at 18 months, and 23.2% at 24 months. Treatment-related adverse events (TRAEs) leading to dose interruption occurred in 60.0% of the overall population, rising to 75.5% among patients with DOT greater than 1 year and 74.5% among those with DOT greater than 2 years. EV dose reductions occurred in 43.0% of the overall population, increasing to 65.8% in patients with DOT greater than 1 year and 70.6% in those with DOT greater than 2 years, reflecting the proactive use of dose modifications to maintain patients on therapy.

Long-Term Safety Profile

The safety profile of EV+P remained consistent with longer treatment duration, with no new safety signals emerging. TRAEs of any grade occurred in 97.3% of the overall population, 99.5% of patients with DOT greater than 1 year, and 100% of patients with DOT greater than 2 years. Grade 3 or higher TRAEs were observed in 57.0%, 58.7%, and 57.8% of patients in these groups, respectively, indicating no meaningful increase in high-grade toxicity with prolonged treatment.

Among EV-specific TRAEs of special interest, modest increases in several events—predominantly grade 1/2—were observed with longer DOT. The largest increase was seen in peripheral sensory neuropathy, rising by approximately 25 percentage points with longer treatment, consistent with cumulative monomethyl auristatin E (MMAE) exposure. Pembrolizumab-specific treatment-emergent AEs of special interest — including severe skin reactions, hypothyroidism, pneumonitis, hyperthyroidism, and hepatitis — also showed no new signals with longer treatment, with rates remaining generally consistent across the overall population and the longer DOT subgroups.

Study Design

EV-302/KEYNOTE-A39 was a randomized, open-label, phase 3 trial that enrolled 886 patients with previously untreated locally advanced or metastatic urothelial carcinoma who were eligible for EV, pembrolizumab, and platinum-based chemotherapy, were PD-(L)1 inhibitor-naive, had a glomerular filtration rate of 30 mL/min or greater, and had an ECOG performance status of 2 or less. Patients were randomized 1:1 to receive EV plus pembrolizumab (EV+P) until progression or platinum-based chemotherapy (gemcitabine plus cisplatin or carboplatin) for a maximum of 6 cycles.

“Enfortumab vedotin plus pembrolizumab is associated with durable and clinically meaningful outcomes in metastatic urothelial carcinoma,” Powles said in his concluding remarks.

Reference

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. Presented at: 2026 American Society of Clinical Oncology Annual Meeting; May 29-June 2, 2026; Chicago, IL. Abstract 4507.