ASCO 2021: KEYNOTE-B15/EV-304: Randomized Phase 3 Study of Perioperative Enfortumab Vedotin Plus Pembrolizumab vs Chemotherapy in Cisplatin-Eligible Patients with Muscle-Invasive Bladder Cancer

( The standard of care for patients with muscle-invasive bladder cancer remains neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy and pelvic lymph node dissection (RC+PLND). However, many patients will experience disease recurrence, progression, and bladder cancer-related death following neoadjuvant chemotherapy and RC+PLND. This has led to interest in both adjuvant therapy and improved neoadjuvant therapies.

Immunotherapy, using anti-PD-1 and anti-PD-L1 agents, has become the standard of care for patients with advanced bladder cancer who have progressed following chemotherapy or are ineligible for chemotherapy. Additionally, recent work has focused on developing new small molecular targeted therapies for treatment of patients with advanced bladder cancer. One such agent is enfortumab vedotin (EV) is a Nectin-4–directed antibody–drug conjugate comprising a fully human, monoclonal antibody and the microtubule-disrupting agent monomethyl auristatin E. A phase 1/2 study of pembrolizumab with EV (KEYNOTE-869/EV-103; NCT03288545) demonstrated promising anti-tumor activity and acceptable safety as first-line treatment for patients with metastatic urothelial cancer who were ineligible for cisplatin. These data formed the basis of the use of this combination earlier in the disease process.

In the Kidney and Bladder Poster session at the 2021 American Society of Clinical Oncology 2021 Annual Meeting held on Friday June 4th, 2021, Dr. Hoimes presented the design of the KEYNOTE-B15/EV-304 (NCT04700124), a randomized, open-label, phase 3 study to evaluate the efficacy and safety of perioperative EV + pembrolizumab versus neoadjuvant chemotherapy using gemcitabine/cisplatin in cisplatin-eligible patients with MIBC.

In KEYNOTE-B15/EV-304, the authors aim to accrue 784 patients with histologically confirmed urothelial cancer/MIBC (clinical stage T2-T4aN0M0 or T1-T4aN1M0) with predominant (≥50%) urothelial histology who have nonmetastatic disease (≥N2 disease and/or M1 excluded) confirmed by blinded independent central review (BICR). Additionally, patients must have ECOG PS 0 or 1 and not have previously received systemic therapy for MIBC.

Following enrollment, patients will be randomly assigned in a 1:1 fashion to receive either 4 cycles of neoadjuvant EV + pembrolizumab followed by 5 cycles of adjuvant EV + 13 cycles of adjuvant pembrolizumab after RC+PLND or 4 cycles of neoadjuvant cisplatin-based chemotherapy followed by observation after RC+PLND (the current standard of care). Randomization will be stratified by initial T and N stage (T2N0 or T3/T4aN0 or T1-T4aN1; based on centrally determined pathology or imaging review), PD-L1 combined positive score (CPS ≥10 or CPS < 10), and geographic region (United States or Europe or most of world).


Neoadjuvant and adjuvant pembrolizumab 200 mg + EV 1.25 mg/kg will be administered intravenously every 3 weeks, and neoadjuvant chemotherapy will consist of gemcitabine 1000 mg/m2 + cisplatin 70 mg/m2 every 3 weeks.

Patients will undergo baseline imaging (CT or MRI) ≤6 weeks before cystectomy and 6 weeks after cystectomy. Following the immediate post-cystectomy imaging, further imaging will be performed every 12 weeks up to the end of year 2 (week 96) and then again at discontinuation. In year 3 and beyond, imaging will be performed every 24 weeks.

The primary study endpoints are pathological complete response (pCR) and event-free survival by BICR. Additional secondary end points include overall survival, disease-free survival, pathological downstaging, patient-reported outcomes, and safety and tolerability.

Presented by: Christopher Hoimes, DO, Ph.D., Associate Professor of Medicine, Duke Cancer Institute 

Written by: Christopher J.D. Wallis, Urologic Oncology Fellow, Vanderbilt University Medical Center, Contact: @WallisCJD on Twitter at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, Virtual Annual Meeting #ASCO21, June, 4-8, 2021