ODAC Votes in Favor of Pembrolizumab Approval in Frontline Metastatic Urothelial Cancer

In a 5 to 3 vote, the FDA’s Oncologic Drugs Advisory Committee voted to uphold the accelerated approval of pembrolizumab for the frontline treatment of patients with cisplatin-ineligible and carboplatin-ineligible locally advanced or metastatic urothelial carcinoma.

In a 5 to 3 vote, the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted to uphold the accelerated approval of pembrolizumab (Keytruda) for the frontline treatment of patients with cisplatin-ineligible and carboplatin-ineligible locally advanced or metastatic urothelial carcinoma.

“Based on the unmet need that [pembrolizumab] addresses, we consider that the existing accelerated approval for pembrolizumab should be maintained and, with the data from our development program, we’ll be able to provide confirmatory evidence of the benefit of pembrolizumab,” said Scot Ebbinghaus, MD, Therapeutic Area Head of Oncology at Merck & Co., Inc., in the hearing.

Such trials will include long-term follow-up from KEYNOTE-052, as well as primary findings from LEAP-011, KEYNOTE-866, and KEYNOTE-905.

The meeting roster comprised ODAC members: Susan Halabi, PhD; Philip C. Hoffman, MD; Christopher H. Lieu, MD; and David E. Mitchell; temporary voting members, Andrea B. Apolo, MD; Colette Johnston; Ravi Madan, MD; and Mohummad M. Siddiqui, MD, FACS.

Voting members, Andrea B. Apolo, MD; Philip C. Hoffman, MD; Susan Halabi, PhD; Colette Johnston; and Christopher H. Lieu, MD, voted for the continued approval of pembrolizumab.

In explaining her decision, Apolo said, “Pembrolizumab is active as a second-line treatment for patients with platinum-refractory urothelial carcinoma, and I would argue that pembrolizumab is also active in the first-line treatment setting for patients that have PD-L1–high cisplatin-ineligible [disease]. I personally favor chemotherapy in the first-line setting followed by immunotherapy maintenance or second-line therapy, but there is also a small population of patients that cannot receive any kind of chemotherapy, and as a treating medical oncologist and bladder cancer specialist, I vote to keep pembrolizumab available as a treatment option for patients in the first-line setting that are PD-L1 high.”

Non-voting members included acting designated federal officer of ODAC, Joyce Yu, PharmD, acting industry representative to the committee; Albert L. Kraus, PhD; and FDA participants Richard Pazdur, MD; Julia Beaver, MD; and Laleh Amiri-Kordestani, MD.

The meeting represents the second day of a 3-day public review of 6 indications for checkpoint inhibitors granted under the agency’s accelerated approval process that later failed to reach thresholds for statistical significance for key end points in confirmatory clinical trials.

With regard to pembrolizumab, the PD-1 inhibitor demonstrated an objective response rate of 28.6% and a median duration of response of 30.1 months in treatment-naïve patients with locally advanced or metastatic urothelial carcinoma in primary findings from the phase 2 KEYNOTE-052 trial.

Primary findings from the trial served as the basis for the May 2017 accelerated approval of the agent for the frontline treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy.

“Prior to the accelerated approval of pembrolizumab in 2017, there were no approved drugs for the cisplatin-ineligible patient population. Patients were routinely treated with carboplatin-based chemotherapy, which is associated with inferior outcomes relative to cisplatin-based chemotherapy and treatment options were even more limited for patients who were not eligible to receive any platinum-containing chemotherapy,” said Arjun V. Balar, MD, in the hearing.

In June 2018, the FDA incorporated PD-L1 status into the label for pembrolizumab for the existing frontline approval for cisplatin-ineligible patients with urothelial carcinoma, based on lower overall survival (OS) with the PD-1 inhibitor compared with platinum-based chemotherapy for patients with PD-L1–low expressing platinum-eligible urothelial carcinoma.

Specifically, the label was restricted to cisplatin-ineligible patients with PD-L1 combined positive scores (CPS) of 10 or greater. However, the label remained broad for patients who are ineligible for any platinum-based agent, unconstrained by PD-L1 status.

The FDA decision was based on an assessment conducted by a data monitoring committee for the confirmatory phase 3 KEYNOTE-361 study, which evaluated pembrolizumab alone, pembrolizumab plus chemotherapy, and chemotherapy alone.

The final analysis of the trial failed to verify the clinical benefit of pembrolizumab as frontline therapy in patients with platinum-eligible advanced or metastatic urothelial carcinoma, instead demonstrating a similar OS with chemotherapy in the intention-to-treat and CPS of 10 or greater populations.

“Patients with advanced urothelial carcinoma, the most common type of bladder cancer, remain in critical need of additional treatment options. We are pleased with today’s positive outcome, which supports the continued use of [pembrolizumab] in these patients. We have an extensive clinical development program in bladder cancer, and we look forward to working closely with the FDA as we progress our research to help more patients. We thank all of the patients, advocates and health care providers who participated in today’s discussion,” concluded Ebbinghaus.


Oncologic Drugs Advisory Committee (ODAC) Meeting. FDA. April 28, 2021. Accessed April 28, 2021. https://collaboration.fda.gov/ODAC04282021?disclaimer-consent=true&proto=true.