As part of an industry-wide review, the FDA persuaded PD-1/L1 players Merck & Co., Bristol Myers Squibb, Roche and AstraZeneca to remove four indications on the labels of cancer drugs, after the failure of post-marketing studies. But the agency wasn’t so sure about six others, so it’s calling for some external input.
In what promises to be a heated deliberation, the FDA will convene experts on its oncologic drugs advisory committee to a three-day meeting in late April to discuss six indications that had been added to drug labels on an accelerated basis but that ultimately failed confirmatory trials, it said in a public notice (PDF) filed Thursday.
The expert panel will discuss data on three indications for Merck’s Keytruda, two for Roche’s Tecentriq and one for Bristol Myers’ Opdivo. The FDA doesn’t have to follow an advisory committee’s recommendation, but it typically does.
The first item on the agenda will be Tecentriq’s conditional nod in combination with Bristol Myers’ chemotherapy Abraxane in PD-L1-positive triple-negative breast cancer.
The drug earned that go-ahead based on data showing that the regimen could stave off cancer progression. But a confirmatory trial dubbed IMpassion131 found the pairing of Tecentriq with the original paclitaxel drug couldn’t extend the lives of newly diagnosed TNBC patients over solo chemo.
On the second day, the panel will discuss two front-line bladder cancer uses of Keytruda and Tecentriq in patients who are not eligible for cisplatin-based chemo. Those concerns were triggered by lackluster overall survival findings from the Keynote-361 trial for Keytruda and the IMvigor211 study in the second-line setting and IMvigor130 study in the front-line for Tecentriq.
The FDA had previously limited the use of the two drugs in front-line, cisplatin-ineligible bladder cancer to patients who met certain PD-L1 expression standards, after noticing reduced survival rates in patients with low PD-L1 levels.
The third day will focus on conditional second-line liver cancer nods for Keytruda and Opdivo, after their confirmatory trials failed. The use of Keytruda in third-line PD-L1-positive gastric or gastroesophageal junction adenocarcinoma will also be discussed, given that it flunked the Keynote-061 and Keynote-062 trials in previously treated and newly diagnosed patients.
The FDA has persuaded some drugmakers to remove indications after misses in confirmatory trials. These include Keytruda and Opdivo in previously treated small-cell lung cancer, and Tecentriq and AstraZeneca’s Imfinzi in previously treated bladder cancer.
The fact that drugmakers did not voluntarily remove the additional six indications, prompting the advisory committee meeting, indicates some amount of disagreement between the companies and the FDA. There is some precedent here: The FDA removed its approval of Roche’s Avastin in breast cancer after the drug failed to improve patients’ life span in a confirmatory trial. That landmark decision came after a heated public debate among physicians, patients, the drugmaker and the FDA, which culminated in a two-day hearing.
The FDA has long been criticized for inadequate supervision of post-marketing commitments made by drugmakers that have received accelerated conditional approvals. For example, Keytruda has remained on the market in stomach cancer for over three years, despite its first Keynote-061 flop.
The FDA’s internal review document, as well as the agency’s final ruling on the six indications the agency is about to reconsider, may offer a benchmark for drugmakers considering what to do after confirmatory trials fail.