Positive topline results from the Phase 3 EV-303 (also known as KEYNOTE-905; NCT03924895) were presented earlier today.
The Phase 3 EV-303 is an ongoing clinical trial evaluating enfortumab vedotin (Padcev™; Pfizer and Astellas Pharma), a Nectin-4 directed antibody-drug conjugate (ADC), in combination with pembrolizumab (Keytruda™; Merck & Co), a PD-1 inhibitor, as neoadjuvant and adjuvant treatment (before and after surgery) versus surgery alone, the current standard of care, in patients with muscle-invasive bladder cancer (MIBC) who are not eligible for or declined cisplatin-based chemotherapy.
Participating patients were randomized to receive either neoadjuvant and adjuvant pembrolizumab (arm A), surgery alone (arm B) or neoadjuvant and adjuvant enfortumab vedotin in combination with pembrolizumab (arm C) [see trial description]
The primary endpoint of this trial is event-free survival (EFS) between arm C versus arm B, defined as the time from randomization to the first occurrence of any of the following events: progression of disease that precludes radical cystectomy (RC) surgery or failure to undergo RC surgery in participants with residual disease, gross residual disease left behind at the time of surgery, local or distant recurrence as assessed by imaging and/or biopsy or death due to any cause. Key secondary endpoints include OS and pCR rate between arm C and arm B, as well as EFS, OS and pCR rate between arm A and arm B.
First in class
Enfortumab vedotin is a first-in-class antibody-drug conjugate (ADC) that is directed against Nectin-4, a protein located on the surface of cells and highly expressed in bladder cancer. [4] Nonclinical data suggest the anticancer activity of enfortumab vedotin is due to its binding to Nectin-4-expressing cells, followed by the internalization and release of the anti-tumor agent monomethyl auristatin E (MMAE) into the cell, which result in the cell not reproducing (cell cycle arrest) and in programmed cell death (apoptosis).
Interim efficacy analysis
At the first interim efficacy analysis, the trial demonstrated a clinically meaningful and statistically significant improvement in event-free survival (EFS), the study’s primary endpoint, and overall survival (OS), a key secondary endpoint, with neoadjuvant and adjuvant enfortumab vedotin plus pembrolizumab versus surgery alone. An additional secondary endpoint of pathologic complete response (pCR) rate was also met.
“Patients with muscle-invasive bladder cancer who are ineligible for cisplatin-based chemotherapy have not seen a significant treatment advance beyond surgery and face high rates of disease recurrence and a poor prognosis, even after having their bladder removed,” said Christof Vulsteke, M.D., Ph.D., Head of Integrated Cancer Center Ghent (IKG, Belgium) and Clinical Trial Unit Oncology Ghent and EV-303 principal investigator
“These EV-303 study results mark the first time a systemic treatment approach, used before and after surgery, significantly extended survival over standard-of-care surgery in this population, demonstrating the potential of this combination to address a critical unmet patient need.”
The trial is continuing to evaluate the secondary EFS, OS and pCR rate endpoints for neoadjuvant and adjuvant pembrolizumab versus surgery alone as they continue to mature. The safety profiles for enfortumab vedotin plus pembrolizumab and pembrolizumab monotherapy were consistent with the known profiles of each treatment regimen.
“These results from EV-303 represent a breakthrough for cisplatin-ineligible patients with muscle-invasive bladder cancer, demonstrating the potential of enfortumab vedotin in combination with pembrolizumab when used before and after surgery as a new standard of care. We look forward to presenting further details on these data at an upcoming medical congress,” explained Moitreyee Chatterjee-Kishore, Ph.D., M.B.A., Head of Oncology Development, Astellas.
A common cancer
Bladder cancer is the ninth most common cancer worldwide, diagnosed in more than 614,000 patients each year globally. [1] MIBC represents approximately 30% of all bladder cancer cases. [2] The standard treatment for patients with MIBC is neoadjuvant cisplatin-based chemotherapy followed by surgery, which has been shown to prolong survival. [2]
However, up to half of patients with MIBC are not eligible to receive cisplatin and face limited treatment options, typically undergoing surgery alone. [3]
A changed treatment paradigm
“Enfortumab vedotin plus pembrolizumab has already changed the treatment paradigm for patients with locally advanced or metastatic urothelial cancer as standard of care. These latest results underscore the practice-changing potential of this combination in earlier stages of bladder cancer, where it has the potential to improve outcomes for even more patients. Thank you to the patients and investigators who participated in this trial,” said Johanna Bendell, M.D., Oncology Chief Development Officer, Pfizer.
The results of this study will be submitted for presentation at an upcoming medical congress and will be discussed with global health authorities for potential regulatory filings. Neoadjuvant and adjuvant enfortumab vedotin plus pembrolizumab is also being evaluated in cisplatin-eligible patients with MIBC in the EV-304 Phase 3 clinical trial (also known as KEYNOTE-B15).
Regulatory status
The combination of enfortumab vedotin plus pembrolizumab is approved for the treatment of adult patients with locally advanced or metastatic urothelial cancer (la/mUC) regardless of cisplatin eligibility in the United States, the European Union, Japan and a number of other countries around the world.
Enfortumab vedotin is also approved as a single agent for the treatment of adult patients with la/mUC who have previously received a PD-1/PD-L1 inhibitor and platinum-containing chemotherapy or are ineligible for cisplatin-containing chemotherapy and have previously received one or more prior lines of therapy.
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Clinical trials
Perioperative Pembrolizumab (MK-3475) Plus Cystectomy or Perioperative Pembrolizumab Plus Enfortumab Vedotin Plus Cystectomy Versus Cystectomy Alone in Participants Who Are Cisplatin-ineligible or Decline Cisplatin With Muscle-invasive Bladder Cancer (MK-3475-905/KEYNOTE-905/EV-303) – ClinicalTrials.gov ID NCT03924895
Highlights of Prescribing Information
Enfortumab vedotin (Padcev™; Pfizer and Astellas Pharma)[Prescribing Information]
Pembrolizumab (Keytruda™; Merck & Co)[Prescribing Information]
Reference
[1] World Bladder Cancer Patient Coalition. GLOBOCAN 2022: Bladder cancer 9th most common worldwide. Online. Last accesses in August 2025. Available at:
[2] Bladder Cancer Awareness Network. What is Muscle Invasive Bladder Cancer? Online. Last accessed in August 2025.
[3] Esteban-Villarrubia J, Torres-Jiménez J, Bueno-Bravo C, García-Mondaray R, Subiela JD, Gajate P. Current and Future Landscape of Perioperative Treatment for Muscle-Invasive Bladder Cancer. Cancers (Basel). 2023 Jan 17;15(3):566. doi: 10.3390/cancers15030566. PMID: 36765525; PMCID: PMC9913718.
[4] Challita-Eid PM, Satpayev D, Yang P, et al. Enfortumab vedotin antibody-drug conjugate targeting nectin-4 is a highly potent therapeutic agent in multiple preclinical cancer models. Cancer Res 2016;76(10):3003-13.
Featured image: Bladder Cancer: © 2010 – 2025. Fotolia/Adobe. Used with permission.
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