Enfortumab Vedotin Plus Pembro Boosts Survival in Key Groups With Bladder Cancer Before and After Surgery, Phase 3 Study Finds

Patients with muscle-invasive bladder cancer (MIBC) who cannot take or decline cisplatin-based chemotherapy may soon have a new treatment option, as positive topline results were announced today for a pivotal trial evaluating enfortumab vedotin (Padcev; Astellas) plus pembrolizumab (Keytruda; Merck).

At an interim analysis, the phase 3 EV-303 trial demonstrated a clinically meaningful and statistically significant improvement in event free survival (EFS) with neoadjuvant and adjuvant therapy vs surgery alone, the study’s primary endpoint. Also reached: the key secondary end point of overall survival (OS), and pathologic complete response (pCR) rate, another secondary end point.

Enfortumab vedotin is an antibody-drug conjugate that targets nectin-4. It is currently approved to treat locally advanced or metastatic urothelial cancer (mUC) is indicated for patients who have previously received a PD-1 or PD-L1 inhibitor and platinum-containing chemotherapy, or for those who are ineligible for cisplatin-containing chemotherapy and have received at least one prior therapy. Additionally, Padcev is approved in combination with pembrolizumab for first-line treatment of these mUC patients.

Bladder is diagnosed in more than 614,000 patients each year worldwide. MIBC accounts for 30% of all bladder cancer cases, but up to half of these patients are ineligible to receive cisplatin-based chemotherapy with surgery, the standard of care. Not only does this limit options for certain patients, but in 2023, physicians and patients faced severe shortages of cisplatin that took more than a year to resolve.

In a statement released early today, Pfizer and Astellas said the interim analysis showed enfortumab vedotin plus pembrolizumab as neoadjuvant and adjuvant treatment versus surgery alone “demonstrated a clinically meaningful and statistically significant improvement in event-free survival (EFS) and overall survival (OS)—making this combination the first and only regimen to improve survival over the current standard of care.”

The statement said results of the EV-303 study mark the first time systemic treatment has been used both before and after surgery to extend survival over standard-of-care surgery, “demonstrating the potential of this combination to address a critical unmet patient need.”

Investigators are still evaluating secondary EFS, OS and pCR rate end points for neoadjuvant and adjuvant pembrolizumab versus surgery alone as they continue to mature. In the statement, officials said both the combination 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,” said Moitreyee Chatterjee-Kishore, PhD, MBA, head of Oncology Development, Astellas, in the statement. “We look forward to presenting further details on these data at an upcoming medical congress.”

“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," said Johanna Bendell, MD, oncology chief development officer, Pfizer. "Thank you to the patients and investigators who participated in this trial.”

Leaders from both companies will discuss results with regulatory authorities. Results will be submitted for presentation at an upcoming medical congress.