Editor’s Note: During a recent clinical oncology symposium, Professor Matthew D. Galsky from the Icahn School of Medicine at Mount Sinai presented the primary results of the Phase 3 KEYNOTE-B15 study (also known as EV-304). This trial evaluated the efficacy and safety of perioperative enfortumab vedotin (EV) in combination with pembrolizumab for patients with cisplatin-eligible muscle-invasive bladder cancer (MIBC).01 Research Background:
Challenging the 25-Year Dominance of Cisplatin While radical cystectomy (RC) remains the standard of care for MIBC, a substantial proportion of patients experience metastatic recurrence following surgery alone. For nearly 25 years, cisplatin-based neoadjuvant chemotherapy (NAC) has been the established standard for cisplatin-eligible patients. Although EV plus pembrolizumab has redefined the first-line treatment for metastatic urothelial carcinoma, there has been an urgent clinical need to determine if this non-platinum-based regimen can surpass the efficacy of traditional chemotherapy in the perioperative MIBC setting.
02 Study Design:
Comprehensive Perioperative Management KEYNOTE-B15 is a randomized, open-label, global Phase 3 trial. A total of 808 cisplatin-eligible, surgery-ready MIBC patients were randomized 1:1 into two arms:
- EV + Pembro Arm: Patients received 4 cycles of neoadjuvant EV plus pembrolizumab, followed by RC, and then 13 cycles of adjuvant pembrolizumab (with the first 5 cycles administered concurrently with EV).
- GemCis Arm: Patients received 4 cycles of neoadjuvant gemcitabine plus cisplatin (GemCis), followed by RC, and then observation (adjuvant nivolumab was permitted if clinically indicated).
The primary endpoint was event-free survival (EFS) per blinded independent central review (BICR). Key secondary endpoints included overall survival (OS), pathologic complete response (pCR) rate, and safety.
03 EFS Results:
47% Risk Reduction and Consistent Subgroup Benefit The median follow-up data demonstrated that the EV + Pembro regimen was significantly superior to the GemCis chemotherapy arm in terms of EFS:
- Hazard Ratio (HR): 0.53 (95% CI: 0.40–0.70), representing a 47% reduction in the risk of disease progression precluding cystectomy, recurrence, or death.
- Survival Rates: The 24-month EFS rate was 79.4% in the EV + Pembro arm compared to 60.1% in the GemCis arm.
- Subgroup Analysis: The EFS benefit was generally consistent across all key subgroups, regardless of PD-L1 expression, clinical stage, or geographic region.
04 OS and pCR:
Dual Breakthrough in Survival and Pathologic Response Secondary endpoints further reinforced the superiority of the EV plus pembrolizumab combination:
- Overall Survival (OS): Although the data are still maturing, the EV + Pembro arm showed a significant survival advantage. The 24-month OS rate was 86.9% for the trial group versus 79.1% for the chemotherapy group, with an HR of 0.65.
- Pathologic Complete Response (pCR): In the intention-to-treat (ITT) population, the pCR rate was 55.8% in the EV + Pembro arm versus 32.5% in the GemCis arm (an estimated difference of 23.3%). Notably, among patients who successfully underwent cystectomy, the pCR rate in the EV + Pembro arm reached a remarkable 64.4%.
05 Safety Profile:
Distinct Toxicity Patterns and High Surgical Compliance Surgical completion rates were comparable between the two arms (87% in EV + Pembro vs. 90% in GemCis), indicating that the neoadjuvant ADC + IO regimen does not compromise surgical feasibility:
- Adverse Events (AEs): Grade ≥3 treatment-emergent AEs occurred in 75.7% of patients in the EV + Pembro arm and 66.2% in the GemCis arm.
- Toxicity Characteristics: The safety profile of EV + Pembro was consistent with prior observations in metastatic settings. The most common AEs in the trial arm included pruritus, diarrhea, alopecia, and rash, whereas the GemCis arm was characterized by higher rates of hematologic toxicities such as neutropenia, thrombocytopenia, and anemia.
06 Conclusion and Outlook:
A Paradigm Shift in MIBC Perioperative Care Professor Matthew D. Galsky concluded that the KEYNOTE-B15 results represent a pivotal moment in oncology. For the first time in a quarter-century, a non-platinum-based neoadjuvant regimen has demonstrated superiority over the cisplatin-based standard of care. Coupled with the results of the KEYNOTE-905 study in cisplatin-ineligible patients, perioperative EV plus pembrolizumab is poised to become a novel standard treatment option for MIBC patients, regardless of their cisplatin eligibility.
