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In separate votes, an FDA advisory committee recommended that pembrolizumab (Keytruda) and atezolizumab (Tecentriq) hold on to accelerated approval as first-line therapy for advanced bladder cancer, pending additional clinical trial data.

The Oncologic Drugs Advisory Committee (ODAC) voted 5-3 in favor of Merck maintaining accelerated approval status for pembrolizumab as initial treatment for patients with platinum-ineligible (cisplatin and carboplatin) advanced/metastatic urothelial cancer.

By a 10-1 vote the panel favored continuation of accelerated approval for Genentech's atezolizumab for the same indication. The FDA is not bound by advisory committee decisions but usually follows the committees' recommendations.

Despite the disparity in the two votes, panelists indicated that neither decision came easily, as confirmatory trials required for final approval turned out negative or have yet to be completed.

Summarizing the panel's mixed sentiments at the end of the pembrolizumab vote, ODAC chair Philip Hoffman, MD, of the University of Chicago, suggested the vote turned in favor of "the continued unmet need in platinum-ineligible patients, some immaturity of the data still, and not wanting to remove a potential value drug."

"We know that the drug is useful in other settings, second line and maintenance, and we have seen some long-term benefits in patients who were platinum ineligible and tolerated this very well. The people who voted no rightly want to see more mature data and further confirmatory data about the effects on overall survival, and we look forward to seeing those accumulate in the coming years," he said.

Accelerated approval is a contingent approval status the FDA established in 1992 as a means to make promising therapies for HIV available to patients more quickly. As a condition of accelerated approval, sponsors usually are required to conduct additional studies to provide confirmatory data that will open the way to final approval. Over the past decade, oncology drugs the accelerated-approval process.

Pembrolizumab received accelerated approval on the basis of an interim analysis of the phase II , which involved patients with previously untreated advanced, inoperable, or metastatic urothelial cancer ineligible for cisplatin-based chemotherapy. An updated analysis in September 2018 showed an objective response rate (ORR) of 28.6% in 370 cisplatin-ineligible patients and a median response duration of 30.1 months.

In the subgroup of patients with a PD-L1 combined positive score (CPS) ≥10, ORR increased to 47.3%, and duration of response had yet to be reached.

To support a bid for full approval, Merck launched the randomized phase III , which compared pembrolizumab with or without chemotherapy versus chemotherapy alone. The study population comprised patients considered fit enough for platinum-based chemotherapy (cisplatin or carboplatin). The final analysis in April 2020 failed to show a benefit for the dual primary endpoints of progression-free survival (PFS) and overall survival (OS).

"The applicant is not seeking to convert accelerated approval to full approval on the basis of this study, but instead is briefly presenting the key findings from the study that suggest meaningful activity of pembrolizumab," Merck stated in the ODAC report. "The KEYNOTE-361 study efficacy results were generally consistent with results of KEYNOTE-052 and had safety findings that were consistent with both KEYNOTE-052 and the established safety profile of pembrolizumab.

"Therefore, overall, the study is supportive of a continued positive risk-benefit assessment for pembrolizumab and maintaining the existing accelerated approval as first-line treatment for cisplatin-ineligible patients with a PD-L1 CPS ≥10 or platinum-ineligible patients irrespective of PD-L1 expression status," the company said.

The FDA staff noted that KEYNOTE-052 provided early evidence of clinical benefit to support accelerated approval. Whether the response data translates into a clinical benefit, given an OS benefit previously demonstrated in the second-line setting, remains unclear.

As for KEYNOTE-361, the FDA staff report stated: "This trial is not supportive of a continued positive risk-benefit assessment for pembrolizumab and maintaining the existing accelerated approval as first-line treatment for cisplatin-ineligible patients with a PD-L1 CPS ≥10 or platinum-ineligible patients irrespective of PD-L1 expression status."

ODAC panelist Susan Halabi, PhD, remained conflicted, even after voting in favor of continuing the accelerated-approval status.

"This has been a very hard decision for me," said Halabi, a biostatistician at Duke University Medical Center in Durham, North Carolina. "The data is definitely perplexing, but I think even though there was no confirmation from KEYNOTE-361, the trend does indicate prolongation of survival and higher ORR rates that were pretty much consistent, not only in first line but also second line. The other reason I voted yes was the unmet need in carboplatin-ineligible patients."

ODAC consumer representative David Mitchell, a myeloma survivor, also was conflicted but ultimately voted against continuation of accelerated approval.

"While the clinical experience and anecdotes are encouraging and positive, the data aren't there," he said. "I feel strongly for the safety and well-being of patients like myself that we have to rely on data, and I don't see it."

Additional trials have been planned to generate additional data with pembrolizumab in various patient populations with metastatic bladder cancer.

Atezolizumab received accelerated approval for platinum-ineligible advanced bladder cancer on the basis of the . The trial demonstrated "clinically meaningful benefit" in patients with locally advanced/metastatic urothelial cancer in both the overall population (23.5% response rate) and patients with PD-L1 expression ≥5% (28.1%), according to a prepared for ODAC. As of Jan. 31 (5 years from the end of enrollment), 17 of 28 responses were ongoing.

To support the approval, Genentech sponsored the IMvigor130 randomized trial with two stages of enrollment: A comparison of chemotherapy plus atezolizumab or placebo, and a comparison of single-agent atezolizumab and chemotherapy. The trial did not include carboplatin-ineligible patients, "and this study thus does not directly address efficacy or safety in this population," according to FDA staff. Follow-up for OS continues in IMvigor130.

IMvigor130 did show an improvement in investigator-assessed PFS from 1.9 months with placebo plus chemotherapy to 6.3 months with the addition of pembrolizumab. The FDA dismissed the finding as not clinically meaningful for an add-on therapy.

Genentech noted that atezolizumab resulted in clinically meaningful improvement in IMvigor210 as compared with a historical control group of patients treated with carboplatin-based chemotherapy. Although IMvigor130 did not meet the PFS and OS endpoints, the results showed meaningful improvement in OS in the subgroup of patients with high PD-L1 expression.

Without dismissing the limitations of the current data, ODAC panelists generally felt that waiting for mature OS data from IMvigor130 is reasonable.

"I'm optimistic that the data will continue to support the best care for our patients with bladder cancer," said Ravi Madan, MD, of the National Cancer Institute.

As the only member to vote against continuation of accelerated approval for atezolizumab, Hoffman found that the data went against intuitive thinking. In March 2021 withdrawal of its U.S. indication for atezolizumab as second-line therapy for patients with metastatic urothelial cancer previously treated with platinum-based chemotherapy.

"I'm concerned about the fact that a second-line trial was a negative trial that led to the withdrawal of the drug from that indication," he said. "It sort of goes against most of oncologic history where something shows benefit in a later line, more advanced disease, and then it's moved progressively earlier, so that it is equally effective or better. I'm struck by the fact that this is the opposite."

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