Introduction: Although neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy and pelvic lymph node dissection (RC+PLND) is standard of care for patients with MIBC, patients experience disease recurrence or progression. The PD-1 inhibitor pembrolizumab has been effective for cisplatin-ineligible and platinum-resistant/refractory metastatic urothelial carcinoma (mUC) and Bacillus Calmette-Guerin–unresponsive high-risk non–muscle-invasive bladder cancer. 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, which has been effective in patients with mUC who previously received a PD-1/PD-L1 inhibitor. Results of KEYNOTE-869/EV-103, a phase 1/2 study (NCT03288545), showed that EV + pembrolizumab had encouraging antitumor activity and acceptable safety as first-line treatment for cisplatin-ineligible patients with metastatic urothelial cancer, suggesting that combination therapy might be promising (Rosenberg JE et al. J Clin Oncol. 2020;38[15 suppl]:5044).
Methods: KEYNOTE-B15/EV-304 (NCT04700124) is 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. Approximately 784 patients will be randomly assigned 1:1 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. Neoadjuvant and adjuvant pembrolizumab 200 mg + EV 1.25 mg/kg will be administered intravenously every 3 weeks (Q3W), and neoadjuvant chemotherapy will consist of gemcitabine 1000 mg/m2+ cisplatin 70 mg/m2 Q3W. Randomization will be stratified by centrally determined (pathology or imaging) initial T and N stage (T2N0 or T3/T4aN0 or T1-T4aN1), PD-L1 combined positive score (CPS ≥10 or CPS <10), and geographic region (United States or Europe or most of world). Patients must have histologically confirmed urothelial cancer/MIBC (clinical stage T2-T4aN0M0 or T1-T4aN1M0) with predominant (≥50%) urothelial histology, have nonmetastatic disease (≥N2 disease and/or M1 excluded) confirmed by blinded independent central review (BICR), have ECOG PS 0 or 1, and not have previously received systemic therapy for MIBC. Imaging (CT or MRI) will be performed ≤6 weeks before cystectomy and 6 weeks after cystectomy. After postcystectomy imaging, additional imaging will be performed Q12W up to the end of year 2 (week 96) and at discontinuation. In year 3 and beyond, imaging will be performed Q24W. Primary end points are pathologic complete response and event-free survival by BICR. Secondary end points are overall survival, disease-free survival, pathologic downstaging, and safety and tolerability.
Results: The KEYNOTE-B15/EV-304 study is enrolling in Africa, Asia, Australia, Europe, and North America.
Conclusions: Results of KEYNOTE-B15/EV-304 will provide further clarity on the efficacy of perioperative EV + pembrolizumab in cisplatin-eligible patients with MIBC.

Perioperative Enfortumab Vedotin Plus Pembrolizumab Versus Chemotherapy in Cisplatin-Eligible Patients With Muscle-Invasive Bladder Cancer (MIBC): Randomized Phase 3 KEYNOTE-B15/EV-304 Study

For 2021, our focus remains: turning new data into your daily practice. The programme will consist of state-of-the-art lectures, case discussions and panel debates. Our faculty is a group of international & multidisciplinary experts.

We will take you on our journey to Ghent and beyond. Prior the congress, we send out case challenges, where you can compare your opinion with peers & experts. These cases will be part of the Global Congresses on Prostate & Bladder Cancer programme during the congress days (12 & 13 October for PROSCA and 14 & 15 October for BLADDR). After these days, you will be updated on prostate & bladder cancer management.