ODAC recommends pulling 2 of 6 accelerated approvals

Regulatory NewsRegulatory News | 30 April 2021 |  By 

Richard Pazdur, MD

“Dangling” accelerated approvals of cancer immunotherapies were on the docket for a 3-day session of the US Food and Drug Administration’s oncology advisory committee that wrapped up on 29 April. After 2 days of relatively smooth sailing for the first half of the six indications on the docket, the final day saw two recommendations for withdrawal – and unexpected fireworks from FDA staff.
Of six indications put before ODAC, just two were recommended for withdrawal, despite all six indications having failed to show clinical benefit in pre-agreed confirmatory studies. Hearings for these two indications were the only times during the marathon three-day meeting when Richard Pazdur, MD, head of FDA’s Oncology Center of Excellence, weighed in. (RELATED: FDA adcomm declines to yank accelerated approvals for cancer immunotherapies, Regulatory Focus 28 April 2021)
On Day 3 of the ODAC meeting, the committee first heard Merck Sharp & Dohme representatives’ perspectives on why Keytruda (pembrolizumab) should retain its accelerated approval to treat patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma whose tumors express PD-L1, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy.
For this indication, further confirmatory trials are not close to readouts, and applicability may be limited since they are all examining Keytruda in combination with chemotherapy. Pazdur lent his perspective, asking “Would we grant this indication at this time?” in the context of a changed treatment landscape and first- and second-line trials that did not confirm benefit. “The definitive answer is no.”
FDA and other committee members were largely agreed on these and other issues with the accelerated approval, including an overall low response rate of 13% in the third-line setting. In the end, the committee voted 6-2 against maintaining the Keytruda’s accelerated approval for the third-line gastric cancer indication.
The final two accelerated approvals reviewed by ODAC were both for immunotherapy used as monotherapy to treat hepatocellular carcinoma (HCC) in patients previously treated with sorafenib. Here, Keytruda received a favorable recommendation, with all 8 committee members voting in favor of maintaining accelerated approval for the indication, pending a confirmatory trial.
Though the response rate for Keytruda as monotherapy post-sorafenib was low and benefit had not been confirmed in another study in the same post-sorafenib setting, the confirmatory trial came just shy of being able to proceed down a statistical hierarchy that might have shown benefit. Further, ongoing trials will soon yield more information “sooner rather than later,” noted Duke biostatistician Susan Halabi, PhD.
Also, other available treatments include combination therapy with bevacizumab, which will not be suitable for many patients with bleeding or clotting risks, noted committee chair Philip Hoffman, MD, of the University of Chicago.
Bristol-Myers Squibb’s Opdivo (nivolumab), however, received a thumbs down from ODAC in a 5-4 vote for the same indication; many committee members voting on each side of the decision said their choice had not been easy. 
Among the factors FDA asked the committee to consider in its decision were the relatively low response rate that HCC patients saw with Opdivo monotherapy after sorafenib treatment, as well as negative results as compared to sorafenib in the first-line setting.
Also, response rates in HCC patients to first-line treatment with another checkpoint inhibitor, Genentech’s Tecentriq (atezolizumab) in combination with bevacizumab have been encouraging, changing the treatment landscape for these patients.
Finally, an approval already exists for Opdivo in combination with ipilimumab to treat HCC, an option that would remain after withdrawal of accelerated approval for Opdivo monotherapy, and an option that has shown higher overall response rates than Opdivo monotherapy. The sponsor’s presenters shared clinical information about patients who were intolerant of dual therapy with ipilimumab and Opdivo but benefited from Opdivo alone.
Here, CDER’s Pazdur jumped in. “How are we going to characterize that patient population, if it’s even been studied? Because if it hasn’t been studied, we have no idea about the efficacy in that population. Here again, we can’t just contrive an indication on the fly here, because we want to.
“Was the data there in the single arm [nivolumab] study on patients that could not tolerate [ipilimumab/nivolumab]? That’s what we’re being asked here. Could I see that data?” Pazdur asked.
“If we retain those data for the patients that cannot tolerate [nivolumab and ipilimumab] …were those patients studied?” Pazdur pointed out that when possible, patients should receive the combination therapy, given the higher response rate. “If you’re advocating that there are some patients that cannot tolerate it, and I certainly believe there are – believe me, I do – were these patients studied, and what is the response rate here? That’s a fair question to ask. You’re asking us really to give you a new indication here for patients that cannot tolerate [nivolumab and ipilimumab]."
Ian Waxman, MD, the GI development team lead and a vice president for Bristol Myers Squibb, responded after many seconds. “We don’t have those exact data in front of us today,” said Waxman, then pointing to patients in clinical trials who, based on liver function scores or other functional parameters, would not have been good candidates for combination therapy. Waxman offered to provide more clinical information.
Pazdur brushed aside the offer. “I want to know what the clinical response rate is in people who could not tolerate [nivolumab and ipilimumab]. You’re asking for that indication.” When Waxman again repeated that the sponsor’s team could not provide the data at that moment, Pazdur responded, “Don’t you think you should? If you’re going to ask for that indication?”
Waxman again offered, and Pazdur rebuffed, Waxman’s offer to share clinical information about individuals in liver failure who received Opdivo monotherapy as second-line therapy. As Pazdur pressed on looking for response rate data, he emphasized that a regulatory, rather than a clinical decision was before the committee, and he maintained the line that the sponsor was really seeking a new indication for Opdivo. Waxman, and eventually Mathias Hukkelhoven, PhD, Bristol Myers Squibb’s senior vice president for global regulatory and safety sciences, disagreed that Bristol Myers Squibb was doing any such thing.
In the end, the impasse remained. “I think this data does not exist, so let’s just bring this conversation to a close,” said Pazdur, at which point ODAC chair Hoffman jumped in.
“I think, Dr. Pazdur, you’ve made your point,” said Hoffman.
Though FDA is not obligated to follow the recommendations of its advisory committees, it usually does.
ODAC agenda



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