Longest Follow-Up of Enfortumab Vedotin Plus Pembrolizumab Confirms Durable Benefit in Advanced Urothelial Cancer

Clinical Summary:

• Design/Population: EV-103/KEYNOTE-869 dose escalation/cohort A evaluated first-line enfortumab vedotin plus pembrolizumab in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer after 5 years of follow-up.
• Key Outcomes: The combination demonstrated durable antitumor activity, with a confirmed objective response rate of 73.3%, median duration of response of 22.1 months, median progression-free survival of 12.7 months, and median overall survival of 26.1 months. The 5-year overall survival rate was 41.5%, and no new treatment-related deaths were reported. 
• Clinical Relevance: Representing the longest follow-up reported for enfortumab vedotin plus pembrolizumab, these findings reinforce the regimen's durable clinical benefit and support its role as the standard first-line treatment for locally advanced or metastatic urothelial carcinoma.

The longest reported follow-up of enfortumab vedotin plus pembrolizumab demonstrated durable long-term survival and sustained clinical benefit in cisplatin-ineligible patients with previously untreated locally advanced or metastatic urothelial cancer, further supporting the combination as the standard first-line treatment. 

“First-line treatment for locally advanced [or] metastatic urothelial cancer has traditionally been dependent on cisplatin eligibility, with approximately half of patients being cisplatin ineligible due to impaired renal function, poor performance status, and other comorbidities limiting treatment options,” stated Jonathan Rosenberg, MD, Memorial Sloan Kettering Cancer Center, New York, New York, and coauthors. “With [enfortumab vedotin plus pembrolizumab] now considered [the standard of care], understanding long-term outcomes of [enfortumab vedotin plus pembrolizumab] treatment remains essential.”

In this study, 45 cisplatin-ineligible patients with histologically confirmed locally advanced or metastatic urothelial cancer received 1.25 mg/kg of enfortumab vedotin on days 1 and 8 plus 200 mg of pembrolizumab on day 1 of each 3-week cycle. The primary end point was safety. Key secondary end points included confirmed objective response rate (ORR), duration of response, disease control rate, progression-free survival (PFS), and overall survival (OS).

At a median follow-up of 62.1 months, the confirmed ORR was 73.3%, including complete responses observed in 15.6% of patients and partial responses in 57.8% of patients. The disease control rate was 84.4%, and the median duration of response was 22.1 months. 

Median PFS was 12.7 months, with an estimated 5-year PFS rate of 38.2%. Median OS was 26.1 months, with an estimated 5-year OS rate of 41.5%.

Importantly, among patients who remained in response at 2 years, no disease progression was observed during subsequent follow-up, highlighting the durability of long-term responses.

No new safety signals emerged during extended follow-up, and the safety profile remained consistent with prior findings. The most frequently reported treatment-related adverse events of any grade included peripheral sensory neuropathy, fatigue, and alopecia. The most frequently reported grade ≥3 treatment-related adverse events included increased lipase, fatigue, and maculopapular rash. Serious treatment-related adverse events occurred in 15.6% of patients. Treatment-related adverse events led to dose reductions in 33.3% of patients and treatment discontinuations in 44.4% of patients. One treatment-related death due to multiple organ dysfunction syndrome with concurrent bullous dermatitis had been previously reported, and no new treatment-related deaths occurred with extended follow-up.

“These encouraging findings are corroborated by EV-302, which established [enfortumab vedotin plus pembrolizumab] as the first line [standard of care] for patients with [locally advanced or metastatic urothelial cancer], irrespective of cisplatin eligibility,” concluded Dr Rosenberg et al. 

Source:

Rosenberg JE, O’Donnell PH, Petrylak DP, et al. EV-103 dose escalation/cohort A: 5-year follow-up of enfortumab vedotin plus pembrolizumab in previously untreated locally advanced/metastatic urothelial carcinoma. ESMO Open. Published online: May 19, 2026. doi: 10.1016/j.esmoop.2026.107700