Game-Changer in Bladder Cancer: EV Plus Pembro Doubles Survival in Groundbreaking Study

The EV-302 trial confirms that the combination of enfortumab vedotin (EV) and pembrolizumab is a transformative treatment for advanced urothelial carcinoma (aUC), more than doubling median overall survival to 34 months compared to 15.9 months with chemotherapy. The study showed a 74% likelihood of maintaining a complete response at two years, leading to FDA accelerated approvals in 2023 for all newly diagnosed patients. Median progression-free survival improved significantly to 12.5 months versus 6.3 months with chemotherapy.

Notably, non-White patients in the combination arm had a higher median survival (36.3 months) than White patients (26.1 months). The treatment’s adverse events were manageable, with diarrhea and rash being the most common grade 3 or higher events. Researchers are now investigating the optimal duration of treatment to balance long-term efficacy with patient quality of life. With its durable and life-extending benefits, the EV-pembro combination is redefining the standard of care for aUC.

Game-Changer in Bladder Cancer: EV Plus Pembro Doubles Survival in Groundbreaking Study

The combination of enfortumab vedotin (EV) and pembrolizumab (pembro) is demonstrating groundbreaking benefits in treating advanced urothelial carcinoma (aUC), according to findings from the EV-302 trial. Thomas Powles, MD, PhD, of Barts Cancer Center, presented long-term data at the American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU) on February 13-15, 2025, in San Francisco. He emphasized that the EV-pembro regimen has significantly improved survival rates compared to chemotherapy, marking a transformation in the treatment of this aggressive cancer.

Previously, a 12- to 14-month survival was considered an achievement for aUC patients, but the EV-302 trial results indicate that median overall survival with the combination therapy has now reached 34 months. This development represents a substantial improvement over chemotherapy, which had been the standard of care. Notably, data showed a 74% likelihood of maintaining a complete response at two years and a 49% reduction in the risk of death compared to chemotherapy.

The EV-302 trial (NCT04223856) initially led to accelerated FDA approvals in 2023: first in April for patients ineligible for cisplatin, followed by a broader approval in December for all newly diagnosed patients, regardless of cisplatin eligibility. Enfortumab vedotin is marketed as Padcev (Astellas), and pembrolizumab as Keytruda (Merck).

Long-term findings presented at ASCO GU included an additional year of data, bringing the median follow-up to 2.5 years. The updated results reinforced the strong efficacy of the EV-pembro regimen:

• Progression-Free Survival (PFS): Median PFS was 12.5 months in the combination arm compared to 6.3 months with chemotherapy (P < .00001).
• Overall Survival (OS): Median OS was 33.8 months with EV-pembro versus 15.9 months with chemotherapy.
• Patient Response: 74.3% of patients maintained a response at the two-year mark, with 30% achieving a complete response, an unprecedented outcome in this setting.

Powles noted that the survival curves for EV-pembro and chemotherapy “go apart and stay apart,” reflecting a durable benefit from the combination treatment. He also highlighted subgroup findings, showing that non-White patients in the combination arm had a higher median OS (36.3 months) than White patients (26.1 months). Patients from Europe and North America comprised 62.2% of the combination arm’s population.

Regarding safety, no new concerns emerged, with 57% of patients experiencing grade 3 or higher adverse events (AEs), primarily diarrhea or rash. Managing AEs remains a key focus in ongoing research.

A significant question that emerged from the data was whether an optimal duration of treatment could be determined. Given the durability of responses, some experts are considering when to discontinue therapy. Powles acknowledged the importance of this question but noted that it remains difficult to answer. He suggested that while five years may be too long, six months to a year could be too short. Future discussions will be necessary to address this issue.

In conclusion, the EV-302 trial continues to provide compelling evidence that the EV-pembro combination offers transformative benefits in aUC treatment. With substantially extended survival rates, durable responses, and a manageable safety profile, this regimen is reshaping the standard of care for patients with advanced bladder cancer. Further research will focus on optimizing treatment duration and refining patient management strategies.