Enfortumab Vedotin Plus Pembrolizumab Generates Survival Benefit in Previously Untreated Advanced Urothelial Cancer

Treatment with the combination of enfortumab vedotin-ejfv (Padcev) and pembrolizumab (Keytruda) led to an improvement in overall survival (OS) and progression-free survival (PFS) compared with chemotherapy in previously untreated patients with locally advanced or metastatic urothelial cancer who were eligible for cisplatin- or carboplatin-containing chemotherapy, meeting the coprimary end points of the phase 3 KEYNOTE-A39/EV-302 trial (NCT04223856).^1,2

OS crossed the prespecified efficacy boundary at interim analysis, according to an assessment by an independent data monitoring committee. Regarding safety, findings for enfortumab vedotin plus pembrolizumab were consistent with previously reported data for the combination in patients with locally advanced or metastatic urothelial cancer who were cisplatin ineligible.

Full data will be presented at an upcoming medical conference and shared with health authorities.

“The results of this pivotal phase 3 study are highly encouraging and showed a statistically significant survival benefit for the combination of [pembrolizumab] with the antibody-drug conjugate enfortumab vedotin in cisplatin-eligible or cisplatin-ineligible patients with previously untreated locally advanced or metastatic urothelial carcinoma,” Eliav Barr, MD senior vice president, head of global clinical development, and chief medical officer of Merck Research Laboratories, stated in a news release.¹

In April 2023, the FDA granted accelerated approval to enfortumab vedotin plus pembrolizumab for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy.³ That regulatory decision was based on data from the combined dose-escalation/cohort A and cohort K of the phase 1/2 EV-103/KEYNOTE-869 study (NCT03288545).

EV-302 was designed as a confirmatory trial for the combination of enfortumab vedotin and pembrolizumab.1The open-label, randomized, controlled trial enrolled patients with previously untreated locally advanced or metastatic urothelial cancer who may or may not have been eligible to receive treatment with cisplatin-based chemotherapy. Patients were required to have measurable disease per RECIST v1.1 criteria, an ECOG performance status of 0 to 2, and adequate hematologic and organ function.⁴

Prior systemic therapy for locally advanced or metastatic urothelial carcinoma was not allowed; however, patients were permitted to enroll if they received neoadjuvant chemotherapy with recurrence more than 12 months from completion of therapy or received adjuvant chemotherapy following cystectomy with recurrence more than 12 months from completion of therapy.

Key exclusion criteria included any prior treatment with enfortumab vedotin or other monomethyl auristatin E–based antibody-drug conjugates; any prior anti–PD-1/PD-L1 therapy; uncontrolled diabetes; an estimated life expectancy of less than 12 weeks; and active central nervous system metastases.

The study randomly assigned 886 patients in a 1:1 fashion to receive 200 mg of intravenous (IV) pembrolizumab on day 1 of each 3-week cycle for up to 35 cycles plus 125 mg/m2 of IV enfortumab vedotin on days 1 and 8 of each 3-week cycle until a protocol defined reason for study discontinuation occurred; or IV gemcitabine on days 1 and 8 of each 3-week cycle plus platinum-containing chemotherapy consisting of either IV carboplatin on day 1 of each 3-week cycle or IV cisplatin on day 1 of each 3-week cycle for a maximum of 6 cycles.¹

Blinded independent central review (BICR)–assessed PFS per RECIST v1.1 criteria and OS were the primary end points. Key secondary endpoints included overall response rate and duration of response per RECIST v1.1 by BICR assessment, as well as time to pain progression.

“Over 200,000 deaths from urothelial cancer are reported worldwide annually, making it a major cause of morbidity and mortality,” Thomas Powles, MRCP, MD, professor of genitourinary oncology at Queen Mary University of London, director of the Barts Cancer Center in London, and primary investigator of EV-302, said. “The topline results from EV-302 are encouraging for patients with advanced-stage urothelial cancer, which is aggressive and associated with devastating outcomes.”

References

1. Merck announces phase 3 KEYNOTE-A39/EV-302 trial met dual primary endpoints of overall survival (OS) and progression-free survival (PFS) in certain patients with previously untreated locally advanced or metastatic urothelial cancer. News release. Merck. September 22, 2023. Accessed September 22, 2023. https://www.merck.com/news/merck-announces-phase-3-keynote-a39-ev-302-trial-met-dual-primary-endpoints-of-overall-survival-os-and-progression-free-survival-pfs-in-certain-patients-with-previously-untreated-locally-advanced/
2. Padcev (enfortumab vedotin-ejfv) and Keytruda (pembrolizumab) significantly improve overall survival and progression-free survival in patients with previously untreated advanced bladder cancer in pivotal phase 3 EV-302 trial. News release. Astellas. September 22, 2023. Accessed September 22, 2023. https://www.astellas.com/en/news/28526
3. FDA grants accelerated approval to enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial carcinoma. FDA. April 3, 2023. Accessed September 22, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-enfortumab-vedotin-ejfv-pembrolizumab-locally-advanced-or-metastatic
4. Enfortumab vedotin and pembrolizumab vs. chemotherapy alone in untreated locally advanced or metastatic urothelial cancer (EV-302). ClinicalTrials.gov. Updated August 14, 2023. Accessed September 22, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT04223856