FDA adcomm declines to yank accelerated approvals for cancer immunotherapies

Regulatory NewsRegulatory News | 28 April 2021 |  By 

At the halfway mark in its review of six “dangling” accelerated approvals for cancer immunotherapies, an advisory committee to the US Food and Drug Administration has declined to rescind approvals for any of the indications it has reviewed to date, citing immature data and ongoing unmet patient need.
FDA’s Oncologic Drugs Advisory Committee (ODAC), convening virtually, has thus far reviewed two indications for Genentech’s Tecentriq (azetolizumab) and one for Merck, Shape & Dohme’s Keytruda (pembrolizumab).
On 28 April, the committee reviewed Keytruda for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin-containing therapy. Tecentriq was reviewed for the same indication and for use in combination with nab-paclitaxel to treat locally advanced or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1.
All three indications, as well as the three remaining to review during the 3-day ODAC marathon meeting, are before ODAC because confirmatory trials did not verify clinical benefit in the particular indication for which the drugs were granted accelerated approval. (RELATED: Pazdur: Oncology accelerated approvals under review by ODAC, Regulatory Focus 26 April 2021)
The particulars of the development program for each drug and indication differed enough that ODAC’s voting members spent considerable time over the last day and half untangling the statistical plans for the various trials. Many of the committee members are practicing oncologists who treat patients with the conditions under review, so ongoing unmet need in many therapeutic areas weighed heavily in discussions and voting.
Even Duke’s Susan Halabi, PhD, the biostatistician on the committee, acknowledged ongoing unmet need in urothelial carcinoma patients. “This was a very hard decision for me,” she said of her vote to leave Keytruda on the market for its urothelial carcinoma indication.
Halabi noted that the lack of data showing confirmatory benefit for Keytruda for urothelial carcinoma was “definitely perplexing.” She noted a trend toward prolongation in overall survival (OS) along with higher overall response rates in the confirmatory trial “that are pretty much consistent” with earlier data. “The other reason I voted yes was unmet need” in carboplatin resistant bladder cancer, she said. The committee split with a 5-3 vote in favor of Keytruda for this indication.
Tecentriq’s review for the same urothelial carcinoma indication had a slightly different set of issues at hand, since an interim analysis of the confirmatory trial shows OS falling just short of statistical significance, with a hazard ratio of 0.84 favoring Tecentriq and chemotherapy over placebo and chemotherapy. However, the 95% confidence interval ranges from 0.71 to 1.00.
Here, the hierarchical statistical plan held up discussion for some time: only if the drug meets the co-primary endpoint pitting Tecentriq against placebo in combination with chemotherapy for OS will further analysis be completed.
One committee member after another questioned the sponsor about details of the slide depicting the study design. Finally, Richard Pazdur, MD, head of FDA’s Oncology Center of Excellence, injected himself into the conversation. “You guys are making this way too complicated,” said Pazdur. “If they win on the first box [OS for the co-primary endpoint] they get a ‘twofer.’ I don’t know how much clearer I can make it.” Keytruda’s monotherapy accelerated approval would be converted to a regular approval, and the drug would also receive a new indication for its use in combination with chemotherapy.
When the vote was tallied for Tecentriq for its bladder cancer indication, all but committee chair Phillip Hoffman, MD, of the University of Chicago, voted in favor of maintaining the indication pending the final OS results. Many cited the need for study data to mature. “We’ll know soon enough the results” in terms of overall survival, said committee member Andrea Apolo, MD, head of the bladder cancer section at the National Cancer Institute. “There aren’t enough harms really to pull it and confuse patients and doctors.”
Hoffman cited “compelling” data from FDA’s review of the Tecentriq data that highlighted a second-line trial in bladder cancer that was negative, and actually led to Tecentriq’s voluntary withdrawal for that indication earlier this year.
On 27 April, the committee, whose composition differed slightly to include experts in breast rather than bladder cancer, voted seven to two in favor of keeping the accelerated approval for Tecentriq in combination with nab-paclitaxel for TNBC. The meeting started and stopped several times as it was plagued by technical difficulties, and audio cut out as the committee members shared final thoughts on why they cast their votes as they did.
The accelerated approval for Tecentriq in the TNBC indication was granted on the strength of a study showing increased progression-free survival and a numeric, but not statistically significant, increase in overall survival. The benefit was not seen in the confirmatory trial, which showed a “possible detriment” in overall survival, in FDA’s words.
Still to come on ODAC’s docket for the meeting are two more Keytruda indications. The first is for patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma whose tumors express PD-L1 and whose disease has progressed with two or more prior lines of therapy.
Also under review is the accelerated approval for Keytruda to treat patients with hepatocellular carcinoma previously treated with sorafenib. Bristol-Myers Squibb’s Opdivo (nivolumab) is being reviewed for the same indication.
ODAC agenda, meeting materials


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