Two Approvals in Urothelial Cancer Survive FDA Panel Scrutiny

May 1, 2021
Mary Caffrey

As hearings of the FDA panel have shown, once a drug is approved and in clinical guidelines, pulling it from the market is not so simple, even if later trials do not confirm phase 2 results.

An FDA panel on Wednesday recommended keeping a pair of accelerated approvals in urothelial cancer, as regulators sort through what to do when cancer drugs reach the market based on early data, but follow-up studies tell a different story.


FDA’s Oncologic Drugs Advisory Committee (ODAC), recommended keeping indications for Tecentriq (azetolizumab), from Genentech, and for Keytruda (pembrolizumab), the immunotherapy that has proved a multipurpose blockbuster for Merck.

Early in the day, panelists voted 5-3 to retain Keytruda’s indication for first-line treatment in patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin-containing therapy. Later in the day, the panel voted 10-1 to retain the same indication for Tecentriq, pending final overall survival (OS) results in a trial where panelists felt the data are not yet mature.

A day prior, a slightly different ODAC committee voted 7-2 to keep Tecentriq’s indication in metastatic triple negative breast cancer, after Genentech representatives said it would hard to replicate the trial that led to the accelerated approval. Complicating that vote was the fact that approval was based on using Tecentriq with nab-paclitaxel, but the confirmatory trial combined Tecentriq with paclitaxel and pretreated patients with steroids.

All three votes are the result of what some see as an evitable result of FDA’s accelerated approval pathway, which allows investigational drugs to reach the market based on phase 2 data, if the therapies might help some patients who lack treatment choices. The process calls for additional trials to confirm the results and keep the drugs on the market.

But as the two days of hearings have shown, once a drug is approved and in clinical guidelines, pulling it from the market is not so simple.

For each session, ODAC rotates in specialists who treat patients who might need the drug under review, and that reality weighed into their votes. For the Keytruda discussion, panelist Andrea B. Apolo, M.D., head of the bladder cancer section at the National Cancer Institute, said that while she prefers chemotherapy in a first-line setting, there are some patients who cannot receive it.

“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],” she said. “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.”

Susan Halabi, Ph.D., a biostatistician at Duke Cancer Institute, described her vote on Keytruda as “a very hard decision for me.” Trends toward longer overall survival (OS) and higher overall response rates seen in the second trial were consistent with early data, but the failure to confirm the early result was still “perplexing.”

In a statement, Merck’s Chief Medical Officer Roy Baynes, M.D., Ph.D., said, “The positive vote from today’s ODAC meeting supports the potential for Keytruda in certain patients with high-risk, non-muscle invasive bladder cancer, who currently have limited non-surgical treatment options approved by the FDA .We are encouraged by today’s productive discussion and look forward to working with the FDA as they continue their review of our supplemental application for KEYTRUDA in this patient population.”

In reviewing Tecentriq’s indication in urothelial carcinoma indication, panelists weighed an interim analysis of the confirmatory trial, which found the OS barely missing statistical significance. The study’s methodology states that if the drug falls short in meeting one benchmark others are not calculated, and this bogged the committee down for some time. In the end, most agreed that the best course was to keep the drug available for patients for now.

“There aren’t enough harms really to pull it and confuse patients and doctors,” Apolo said.

“Today’s positive vote reaffirms that Tecentriq fills a significant unmet need for people with previously untreated metastatic bladder cancer, many of whom cannot tolerate standard of care chemotherapy and need additional options,” Levi Garraway, M.D., Ph.D., chief medical officer and head of Global Product Development for Genentech, said in a statement. “Having now received positive ODAC recommendations in both bladder cancer and triple-negative breast cancer, we will continue to work with the FDA on next steps for Tecentriq in these indications.”

However, other data in a second-line trial in bladder cancer led to Genentech’s decision to voluntarily withdraw that indication for Tecentriq in March 2021. In doing so, company officials acknowledged that other treatments are now available for this particular group.