EV-302 data on EV/pembro in urothelial carcinoma published in NEJM

Data from the phase 3 EV-302 trial (NCT04223856) have been published in the New England Journal of Medicine, showing that the combination of enfortumab vedotin-ejfv (Padcev, EV) and pembrolizumab (Keytruda) extended overall survival (OS) and progression-free survival (PFS) vs platinum-based chemotherapy in patients with previously untreated locally advanced or metastatic urothelial carcinoma.¹

The FDA approved EV plus pembrolizumab for the treatment of patients with locally advanced or metastatic urothelial carcinoma in December 2023 based on findings from the EV-302 trial.

These results represent the first time that a treatment regimen has demonstrated superiority in OS to chemotherapy in this patient population.

“I’m proud to share that NEJM Group has published the primary results from the phase 3 EV-302 trial. The results of this historic clinical trial have the potential to transform cancer care, showing that a combination treatment, including our ADC therapy, extended the lives of people diagnosed with advanced bladder cancer,” said Chris Boshoff, Chief Oncology Officer and Executive Vice President for Pfizer, in correspondence with Urology Times®. “For nearly a decade, we’ve worked with Astellas Pharma US to accelerate breakthrough medicines to bring new hope to people living with genitourinary cancer, including prostate cancer. With these groundbreaking data, this ADC combination treatment for urothelial cancer offers a potential alternative to chemotherapy treatment, which has been the standard of care for 45 years.”

Data from the EV-302 study were initially presented at the 2023 European Society for Medical Oncology (ESMO) Congress in Madrid, Spain.2 Overall, the EV-302 trial met its dual primary end points of OS and PFS.

At a median follow-up of 17.2 months, treatment with EV plus pembrolizumab reduced the rate of death by 53% vs chemotherapy. Patients in the combination arm demonstrated a median OS of 31.5 months compared with 16.1 months among patients treated with chemotherapy (HR, 0.47; 95% CI, 0.38 to 0.58; P < .001).

Additionally, the median PFS with EV/pembrolizumab was 12.5 months vs 6.3 months with chemotherapy, translating to a 55% reduction in the rate of disease progression or death (HR, 0.45; 95% CI, 0.38 to 0.54; P < .001).

Regarding the trial’s key secondary end points, the confirmed overall response rate (ORR) was 67.7% (95% CI, 63.1-72.1) in the EV/pembro arm, compared with 44.4% (95% CI, 39.7%-49.2%) in the chemotherapy arm (P < .001). The ORR in the EV/pembro cohort consisted of a complete response rate of 29.1%, vs a CR rate of 12.5% in the chemotherapy cohort.

The median duration of response was not reached in the combination arm and was 7.0 months in the chemotherapy arm. The median time to pain progression was 14.2 months among patients receiving EV/pembro vs 10.0 months among patients receiving chemotherapy, although the difference did not reach statistical significance (HR, 0.92; 95% CI, 0.72 to 1.17; P = .48).

Regarding safety, 55.9% of patients in the combination arm experienced treatment-related adverse events (TRAEs) of grade 3 or higher, vs 69.5% of patients in the chemotherapy group. The most common TRAEs in the EV/pembro arm were maculopapular rash (7.7%), hyperglycemia (5.0%), and neutropenia (4.8%). The most common TRAEs in the chemotherapy cohort were anemia (31.4%), neutropenia (30.0%), and thrombocytopenia (19.4%). TRAEs that led to a discontinuation of treatment occurred among 35% of patients receiving EV/pembro and 18.5% of patients receiving chemotherapy.

“This is revolutionary for patients. It’s a practice-changing study, where we’re nearly doubling the overall survival for patients with locally advanced and metastatic urothelial cancer. We’re also expanding the patient population who can get treated with this very active therapy because many are not candidates for or could not tolerate the prior standard chemotherapy, which can be incredibly toxic," said co-author Jean Hoffman-Censits, MD, in a news release on the study.³ Hoffman-Censits is the co-director of the Upper Tract Urothelial Cancer Multidisciplinary Clinic at the Johns Hopkins Greenberg Bladder Cancer Institute and an associate professor of oncology and urology at the Johns Hopkins Kimmel Cancer Center.

In total, the global, open-label, randomized EV-302 trial included 886 patients with previously untreated locally advanced or metastatic urothelial carcinoma. Patients were randomly assigned 1:1 to receive EV/pembro (n = 442) or chemotherapy (n = 444). Patients in the EV/pembro cohort received a median of 12 cycles (range, 1-46) of treatment vs 6 (range, 1-6) cycles in the chemotherapy cohort.

The primary end points for the trial were PFS, per blinded independent central review, and OS. Secondary outcome measures included ORR, duration of response, time to pain progression, and the incidence of adverse events.

EV plus pembrolizumab received FDA approval for the treatment of patients with locally advanced or metastatic urothelial carcinoma in December 2023 based on findings from the EV-302 trial.⁴ The combination is also currently under review for this patient population in Japan and the European Union.^5,6

References

1. Powles T, Valderrama BP, Gupta S, et al. Enfortumab vedotin and pembrolizumab in untreated advanced urothelial carcinoma. N Engl J Med. 2024;390(10):875-888. doi:10.1056/NEJMoa2312117

2. Powles TB, Perez Valderrama B, Gupta S, et al. EV-302/KEYNOTE-A39: Open-label, randomized phase III study of enfortumab vedotin in combination with pembrolizumab (EV+P) vs chemotherapy (chemo) in previously untreated locally advanced metastatic urothelial carcinoma (la/mUC). Presented at: ESMO Congress 2023; October 20-24, 2023; Madrid, Spain. Abstract LBA6

3. Combination urothelial cancer treatment nearly doubles patient survival in international trial. News release. Johns Hopkins Medicine. Published online and accessed March 7, 2024. https://www.newswise.com/articles/combination-urothelial-cancer-treatment-nearly-doubles-patient-survival-in-international-trial

4. FDA approves enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial cancer. News release. US Food and Drug Administration. Published online December 15, 2023. Accessed March 7, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enfortumab-vedotin-ejfv-pembrolizumab-locally-advanced-or-metastatic-urothelial-cancer

5. Astellas submits Supplemental New Drug Application in Japan for PADCEV (enfortumab vedotin (genetical recombination)) with KEYTRUDA (pembrolizumab (genetical recombination)) for first-line treatment of advanced bladder cancer. Published online January 30, 2024. Accessed March 7, 2024. https://www.prnewswire.com/news-releases/astellas-submits-supplemental-new-drug-application-in-japan-for-padcev-enfortumab-vedotin-genetical-recombination-with-keytruda-pembrolizumab-genetical-recombination-for-first-line-treatment-of-advanced-bladder-cancer-302048608.html

6. European Medicines Agency validates type II variation application for PADCEV (enfortumab vedotin) with KEYTRUDA (pembrolizumab) for first-line treatment of advanced bladder cancer. Published online January 26, 2024. Accessed March 7, 2024. https://www.astellas.com/en/news/28801