In the phase III KEYNOTE-B15 trial, EV plus pembrolizumab was superior to standard chemotherapy in MIBC with a 47% risk reduction in EFS, a 35% reduction in OS and a 55.8% pCR rate.
A 47% risk reduction in event-free survival and a 35% reduction in overall survival - is the standard of care changing?
25 June 2026 | Source: Journal of Clinical Oncology (ASCO 2026), UroToday, ASCO Post, OncLive, Targeted Oncology, Astellas Newsroom | Topic: Bladder Cancer / Uro-Oncology
KEY FINDINGS
- Trial: The phase III KEYNOTE-B15 trial was presented at ASCO 2026 (Abstract LBA630). Perioperative enfortumab vedotin (EV) plus pembrolizumab outperformed neoadjuvant gemcitabine plus cisplatin (GC) chemotherapy on multiple endpoints.
- Event-free survival (EFS): HR 0.53 (P < 0.0001) - a 47% reduction in risk.
- Overall survival (OS): HR 0.65 (P = 0.0029) - a 35% reduction in the risk of death.
- Pathological complete response (pCR): 55.8% versus 32.5% - a 23-point increase.
- FDA process: The FDA granted priority review in April 2026; PDUFA date: 17 August 2026.
Background: The Current Situation in Muscle-Invasive Bladder Cancer
Muscle-invasive bladder cancer (MIBC; ≥T2) accounts for approximately 25% of bladder cancer, and 5-year overall survival falls markedly without radical cystectomy. Neoadjuvant chemotherapy (NAC) has for many years remained the standard approach for cisplatin-eligible patients.
However, the pCR rate with the neoadjuvant cisplatin plus gemcitabine (GC) regimen remains at approximately 30-35%. This shows that a substantial proportion of patients do not derive adequate benefit from the current standard of care.
Enfortumab vedotin (EV) is an antibody-drug conjugate directed against Nectin-4. Pembrolizumab is an immune checkpoint inhibitor targeting PD-1. Observing the strong efficacy of these two agents in metastatic urothelial cancer, investigators designed the KEYNOTE-B15 trial to test whether the combination could also demonstrate superiority over chemotherapy in MIBC.
Study Design
A randomized, open-label phase III trial. Cisplatin-eligible MIBC patients were assigned 1:1 to two arms: EV plus pembrolizumab (perioperative) and neoadjuvant GC (standard arm). Median follow-up was 33.6 months (data cut-off: 27 October 2025).
| Parameter | Value |
|---|---|
| Design | Randomized, open-label, phase III |
| Arm 1 | Perioperative enfortumab vedotin (EV) plus pembrolizumab (n=405) |
| Arm 2 | Neoadjuvant gemcitabine plus cisplatin (GC), standard arm (n=403) |
| Total number of patients | 808 |
| Median follow-up | 33.6 months |
| Data cut-off | 27 October 2025 |
Key Results
| Endpoint | EV + Pembrolizumab | Gemcitabine + Cisplatin | HR / p value |
|---|---|---|---|
| Median EFS | Not reached | 48.5 months | HR 0.53; P < 0.0001 |
| 24-month EFS rate | 79.4% | 66.2% | - |
| Median OS | Not reached | Not reached | HR 0.65; P = 0.0029 |
| 24-month OS rate | 86.9% | 81.3% | - |
| Pathological complete response (pCR) | 55.8% | 32.5% | +23 point difference |
| Number of patients | 405 | 403 | - |
It is particularly notable that the overall survival endpoint reached statistical significance, given that median OS had not yet been reached in either arm at this stage. This finding shows that the EV plus pembrolizumab combination significantly reduces not only disease progression but also the risk of death.
Safety Profile
Treatment-related adverse events remained manageable in both arms. Treatment-emergent adverse events assessed including the surgical period were observed in 70.7% of the EV plus pembrolizumab arm and 65.2% of the GC arm.
The main adverse effects specific to the EV plus pembrolizumab combination include peripheral neuropathy, skin rash (particularly maculopapular), hyperglycaemia and immune-mediated adverse events. This profile requires patients to be informed in detail before combination treatment begins.
Regulatory Process and Expectations
Based on the KEYNOTE-B15 data, Merck and Astellas submitted a supplemental biologics license application to the FDA for the pembrolizumab plus enfortumab vedotin combination; the FDA granted this application priority review in April 2026.
PDUFA date: 17 August 2026 - This is the date by which the FDA is expected to announce its approval decision for perioperative EV plus pembrolizumab in cisplatin-eligible MIBC patients. If approval is granted, this combination could become the first choice before cystectomy.
In Europe, the EMA validated and accepted for review a Type II variation application for the same indication in March 2026.
Implications for Clinical Practice
1. Debate over the neoadjuvant approach reopens
Neoadjuvant GC has been accepted as the gold standard for years. The EFS and OS data from KEYNOTE-B15 are powerful enough to unsettle that balance fundamentally.
2. The pCR rate emerges as a clinical marker
The 23-point increase in pCR rate (32.5% → 55.8%) further reinforces the prognostic value of cystectomy pathology. It has again been demonstrated that treatments improving pathological response also improve long-term OS.
3. The importance of multidisciplinary tumour boards increases
Treatment planning requires collaboration between urology, medical oncology, radiology and pathology more than ever.
4. The pre-approval period
Since the PDUFA date is 17 August 2026, this combination is not expected to enter routine clinical use before the FDA decision. Clinicians are advised to evaluate their patients through clinical trial opportunities and hospital-based protocols.
Conclusion
KEYNOTE-B15 is on its way to being recorded as one of the most important clinical trials of recent years in the treatment of muscle-invasive bladder cancer. A 47% risk reduction in EFS, a 35% reduction in OS and a 23-point improvement in pCR rate - significant improvement in three strong endpoints simultaneously - is not a statistical coincidence but a sign of genuine clinical superiority.
The FDA decision is expected in August 2026. If approval is granted, neoadjuvant cisplatin-based chemotherapy will face the risk of losing its position as the standard of care held for at least 30 years.
Important note: The treatment combination used in the KEYNOTE-B15 trial has not yet received FDA approval in this indication. Please consult your physician regarding individual treatment decisions.
References
- Journal of Clinical Oncology. Neoadjuvant and adjuvant enfortumab vedotin (EV) plus pembrolizumab (pembro) for participants with MIBC who are eligible for cisplatin: Randomized, open-label, phase 3 KEYNOTE-B15 study. Abstract LBA630. ASCO 2026. - ascopubs.org
- UroToday. ASCO GU 2026: Neoadjuvant and Adjuvant Enfortumab Vedotin + Pembrolizumab for Participants with MIBC Who Are Eligible for Cisplatin. - urotoday.com
- ASCO Post. Perioperative Enfortumab Vedotin Plus Pembrolizumab May Reduce Risk of Recurrence in Patients With Muscle-Invasive Bladder Cancer. February 2026. - ascopost.com
- OncLive. Perioperative Pembrolizumab Plus Enfortumab Vedotin Nets FDA Priority Review in Cisplatin-Eligible MIBC. - onclive.com
- Targeted Oncology. Enfortumab Vedotin/Pembrolizumab Redefines Neoadjuvant Therapy for MIBC. - targetedonc.com
- Astellas Newsroom. EMA Validates Type II Variation Application for PADCEV plus Keytruda in Cisplatin-Eligible Patients with Muscle-Invasive Bladder Cancer. March 2026. - newsroom.astellas.com
Important Note: This article is compiled from scientific publications for general information purposes only and does not constitute individual medical advice. Always consult your physician regarding treatment decisions.
Dr. Murat Binbay - Urology, Uro-Oncology and Robotic Surgery
