Astellas Pharma Inc. and Pfizer Inc. recently announced positive topline results from an interim analysis of the Phase 3 EV-304 clinical trial (also known as KEYNOTE-B15) for PADCEV (enfortumab vedotin), a Nectin-4 directed antibody-drug conjugate, in combination with Keytruda (pembrolizumab), a PD-1 inhibitor. This pivotal study is evaluating the combination as neoadjuvant and adjuvant treatment (before and after surgery) versus standard of care neoadjuvant chemotherapy (gemcitabine and cisplatin) in patients with muscle-invasive bladder cancer (MIBC) who are eligible for cisplatin-based chemotherapy. The trial met its primary endpoint, demonstrating clinically meaningful and statistically significant improvements in event-free survival (EFS), and overall survival (OS), a key secondary endpoint.

An additional secondary endpoint of pathologic complete response (pCR) rate for neoadjuvant PADCEV plus pembrolizumab versus neoadjuvant chemotherapy was also met, and a clinically meaningful and statistically significant improvement was observed. The safety profile for PADCEV plus pembrolizumab was consistent with the known profile of the treatment regimen.

“Despite available treatment options, nearly half of patients with muscle-invasive bladder cancer progress to metastatic disease within three years of diagnosis. The EV-304 results represent a key milestone in the new era of urothelial cancer treatment. Together, the EV-303 and EV-304 results show that perioperative enfortumab vedotin plus pembrolizumab can positively impact the treatment journey for patients with muscle-invasive bladder cancer, offering significant survival gains across cisplatin-ineligible and cisplatin-eligible patients, signaling a shift from conventional platinum-based chemotherapy and the potential to transform the standard of care,” said Christopher Hoimes, DO, Director of the Bladder Cancer Program and Center for Cancer Immunotherapy at Duke Cancer Institute, an EV-304 Principal Investigator.

“Building on the recent U.S. approval for cisplatin-ineligible patients living with MIBC, these positive EV-304 findings reinforce the potential of PADCEV plus pembrolizumab to improve survival outcomes for a broad population of patients living with muscle-invasive bladder cancer. Together with the EV-303 data, these results strengthen the evidence supporting this combination regimen as a treatment option for patients regardless of cisplatin eligibility. We are committed to bringing forth much-needed advancements and hope to more patients,” added Moitreyee Chatterjee-Kishore, PhD, MBA, Head of Oncology Development, Astellas.

“For the first time, patients with muscle-invasive bladder cancer are seeing significant survival benefits from combination therapy in a perioperative setting without the need for platinum-based chemotherapy, signaling the potential for a new standard of care for this community. The EV-304 results, combined with the recent unprecedented results from the EV-303 trial, showcase the promising future of this regimen as a cornerstone of care for bladder cancer regardless of cisplatin eligibility,” also added Jeff Legos, PhD, MBA, Chief Oncology Officer, Pfizer.

Bladder cancer is the ninth most common cancer worldwide, diagnosed in more than 614,000 patients each year globally, including an estimated 85,000 people in the U.S. MIBC represents approximately 30% of all bladder cancer cases. The standard treatment for eligible patients with MIBC is neoadjuvant cisplatin-based chemotherapy followed by surgery. However, even after undergoing surgery, half of patients with MIBC experience disease recurrence.

PADCEV plus pembrolizumab is not currently approved for use as neoadjuvant and adjuvant treatment in cisplatin-eligible patients with MIBC. These results will be submitted for presentation at an upcoming medical congress and will be discussed with global health authorities for potential regulatory filings.

PADCEV plus pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph was recently approved by the U.S. Food and Drug Administration in cisplatin-ineligible patients with MIBC, as neoadjuvant treatment and then continued after cystectomy as adjuvant treatment based on results from the Phase 3 EV-303 clinical trial (also known as KEYNOTE-905).

The EV-304 trial is an ongoing, open-label, randomized, controlled, Phase 3 study evaluating neoadjuvant and adjuvant PADCEV in combination with pembrolizumab versus neoadjuvant chemotherapy (gemcitabine and cisplatin) in patients with MIBC who are eligible for cisplatin-based chemotherapy. Patients were randomized to receive either neoadjuvant and adjuvant (before and after surgery) PADCEV in combination with pembrolizumab (arm A) or neoadjuvant chemotherapy (arm B). Curative-intent surgery (cystectomy) was performed, with patients randomized to either arm after completion of pre-operative systemic treatment.

The primary endpoint of this trial is EFS, defined as the time from randomization to the first occurrence of any of the following events: progression of disease that precludes radical cystectomy (RC) or failure to undergo RC in participants with residual disease, gross residual disease left behind at the time of surgery, local or distant recurrence based on blinded independent central review (BICR) or death due to any cause. Key secondary endpoints include OS and pCR rate. For more information on the global EV-304 trial, go to clinicaltrials.gov.

PADCEV (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. Nonclinical data suggest the anticancer activity of PADCEV 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).

PADCEV plus pembrolizumab is approved for the treatment of adult patients with locally advanced or metastatic urothelial cancer (la/mUC) in the United States, the European Union, Japan and a number of other countries around the world. PADCEV 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.