The combination of Merck's Keytruda and Pfizer and Astellas' Padcev recently made waves in bladder cancer—and the broader oncology world—by delivering a massive life-extension benefit against chemotherapy. Now, Merck can claim another positive readout for Keytruda in bladder cancer, although this one is short of a home run.
This time, Keytruda showed its benefit when used after surgery in high-risk patients with localized muscle-invasive bladder cancer and locally advanced bladder cancer. The PD-1 inhibitor pared down the risk of disease recurrence or death by 31% compared with observation in the phase 3 AMBASSADOR trial, which was organized by the National Cancer Institute.
Keytruda more than doubled the median time that patients were alive and disease-free to 29 months, compared with the control arm’s 14 months. The data are being presented at the 2024 American Society of Clinical Oncology Genitourinary Cancers Symposium.
If the AMBASSADOR results eventually lead to an FDA approval, Keytruda would be able to cover an even broader spectrum of bladder cancer patients. In 2020, the drug won a go-ahead to treat certain patients with non-muscle invasive bladder cancer. More recently, the FDA endorsed the drug—alongside Padcev—as a first-line treatment for advanced bladder cancer.
But unlike the Padcev combo approval, which was backed by a 53% reduction in the risk of death versus chemotherapy, Keytruda can’t yet claim an overall survival win in AMBASSADOR.
At an interim analysis, Keytruda showed no benefit toward prolonging patients’ lives. The risk of death marginally favored Keytruda by 2%, but patients who took the PD-1 drug were alive for a median 50.9 months, which was worse than the 55.8 months for their counterparts in the control group.
Overall survival data remained immature, Marjorie Green, M.D., head of oncology global clinical development at Merck Research Laboratories, told Fierce Pharma. The current overall survival readout counts 257 deaths, and the final analysis will be triggered at about 320 deaths, she said. Disease-free survival and overall survival are dual primary endpoints of the AMBASSADOR trial.
Some factors may have put Keytruda at a disadvantage, Green noted. A higher percentage of patients in the control group dropped out mid-study compared with the Keytruda arm. The rates were 27.2% and 17.4%, respectively.
Green declined to comment on Merck’s regulatory plan because it’s confidential. Still, she argued that the disease-free survival data represent an important clinical endpoint, and that Keytruda holds a potential to be a new adjuvant therapy option for patients with earlier stages of resectable muscle-invasive bladder cancer.
Keytruda’s disease-free survival benefit looks consistent across patient subgroups. In patients who had or hadn’t received presurgical neoadjuvant therapy, Keytruda’s improvements were nearly identical. In patients whose tumors expressed PD-L1, Keytruda reduced the risk of recurrence or death by 23%, and in PD-L1-negative disease, the improvement was 39%.
Despite radical surgery, up to half of patients with muscle-invasive bladder cancer still experience high rates of cancer recurrence, Andrea Apolo, M.D., a principal investigator at the Center for Cancer Research of the National Cancer Institute, said in a statement. The current data show the promise of using Keytruda after surgery for certain high-risk patients with persistent muscle-invasive or locally advanced urothelial carcinoma, she said.
Keytruda has enjoyed much fanfare in bladder cancer following the high-profile success of its combination with the antibody-drug conjugate Padcev in previously untreated advanced patients. The Keynote-905 trial, also coded EV303, is now testing the same Keytruda-Padcev pairing—or Keytruda alone—for use both before and after surgery in patients who are ineligible for cisplatin or decline cisplatin with muscle-invasive bladder cancer. Separately, Keynote-866 is adding perioperative Keytruda to neoadjuvant chemo in cisplatin-eligible disease.
Editor's Note: The story now includes the most up to date patient withdrawal rates in the AMBASSADOR trial.