The combination of Keytruda and Padcev is taking another major step toward securing its position as a leading therapy in the treatment of bladder cancer.
The PD-1/antibody-drug conjugate pairing significantly extended the lives of patients with muscle-invasive bladder cancer (MIBC) who are eligible for cisplatin-based chemotherapy compared with chemotherapy, according to results from the phase 3 Keynote-B15 (EV-304) trial. The study evaluated Keytruda and Padcev, given both before and after surgery in what’s known as a perioperative treatment, and compared the regimen with neoadjuvant chemotherapy followed by surgery.
Keytruda developer Merck & Co. sponsored the study in collaboration with Padcev makers Astellas and Pfizer. The three firms announced the positive top-line readout from an interim analysis Wednesday.
Besides meeting the overall survival goal, a key secondary endpoint of the trial, the trial also hit its primary endpoint of event-free survival, defined as the time to an initial negative event, including tumor recurrence, certain progression of disease, gross residual disease left behind at the time of surgery or death. Pathologic complete response, another secondary endpoint that measures the number of patients who have no sign of cancer in removed tissue following presurgical neoadjuvant treatment, was also met.
For all three endpoints, the companies described the improvements as clinically meaningful and statistically significant. Results from the phase 3 trial will be presented at a future medical meeting and shared with regulators for potential applications for approval.
The positive perioperative results from a cisplatin-eligible MIBC population comes less than a month after a historic FDA approval that made the combo the first perioperative treatment for MIBC patients who can’t receive cisplatin chemo. That green light was based on the Keynote-905 (EV-303) trial, which showed Padcev and Keytruda used around surgery significantly reduced patients’ risk of death by 50% versus surgery alone.
The efficacy bar for the current Keynote-B15 trial is higher because the control group received chemotherapy—given that they’re eligible for cisplatin—rather than simple observation.
“The persistent risk of recurrence in cis-eligible patients with muscle-invasive bladder cancer, despite recent advances, underscores the continued need for effective perioperative treatments,” Matthew Galsky, M.D., director of genitourinary medical oncology at Mount Sinai and a Keynote-B15 principal investigator, said in a Dec. 17 statement.
Nearly half of MIBC patients would progress to metastatic disease within three years of diagnosis while on existing treatment options, Christopher Hoimes, another principal investigator of the trial hailing from Duke Cancer Institute, said in a separate statement.
“Together, the EV-303 and EV-304 results show that perioperative [Padcev] plus [Keytruda] 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,” Hoimes said.
The latest cisplatin-eligible MIBC results reinforce Padcev and Keytruda’s status as one of the most powerful tools in the treatment of bladder cancer following the landmark 2023 FDA approval of the combo in first-line metastatic bladder cancer regardless of cisplatin eligibility.
Keytruda by itself is also cleared to treat patients with high-risk non-muscle invasive bladder cancer (NMIBC) that’s unresponsive to standard BCG treatment, while a separate Keynote-676 trial is evaluating the PD-1 inhibitor in combination with BCG in high-risk NMIBC that’s either persistent following BCG induction or naïve to BCG.
Astellas had a phase 1 trial evaluating Padcev in NMIBC, but the company recently nixed the study. Its ClinicalTrials.gov entry shows the trial was discontinued for “strategic reasons,” not because of safety, futility or regulatory causes.