The FDA’s Oncologic Drugs Advisory Committee (ODAC) has unanimously called for a revamp of perioperative clinical trial designs in resectable non-small cell lung cancer (NSCLC) to include assessment of the contribution of each treatment phase.
The 11-0 vote comes in response to AstraZeneca’s application for approval of Imfinzi as a treatment before and after tumor-removal surgery in early-stage NSCLC. The regimen includes pre-operative use of Imfinzi plus chemotherapy, followed by post-operative use of Imfinzi as a monotherapy.
In AZ’s phase 3 AEGEAN study, which met its primary endpoint, the perioperative use of Imfinzi reduced the risk of recurrence, progression or death by 32% when compared to chemotherapy alone. But because of the design of the trial there was no way to individually assess the two stages of the therapy.
In a briefing document released (PDF) earlier, the FDA said that before the trial start AZ had ignored the agency's advice to demonstrate the effectiveness of each phase of the treatment. The FDA also raised the concern that perioperative regimens run the risk of “toxicities due to overtreatment without additional clinical benefit.”
In discussing the value of AZ’s treatment, some doctors on the panel expressed frustration at not being able to inform patients of the benefits and risks.
“My hope is that we eliminate some of this ambiguity with the patient-physician conversation. I think it’s a big burden to put on patients to have them make the decision,” Pamela Kunz, M.D., of the Yale School of Medicine, said during Thursday's ODAC meeting. “We really (want to) provide them with that high-level evidence.”
Kunz added that she hoped the FDA would consider extending the requirement to trials for other solid tumors.
Several committee members agreed that the new requirement would complicate clinical trials and make them more expensive and time-consuming, but potential benefits could accrue.
“Companies may find applications that they were not expecting that will be used by more patients in the long run,” Victor Van Berkel, M.D., Ph.D. of the University of Louisville School of Medicine, said.
As for whether Imfinzi should be approved in the indication, there was no vote taken—just discussion—with many panelists urging for approval, including consumer representative David Mitchell.
“Should we require another study that would extend the time before people get access to this drug that has been shown to meet the primary endpoint?” Mitchell asked. “My answer is no we shouldn’t.”
The FDA, which accepted AZ's submission in September 2023, is not required to follow the recommendation of the ODAC.
“The Committee’s discussion of the AEGEAN data highlighted the significant benefit delivered by this Imfinzi-based regimen for patients with resectable lung cancer," Susan Galbraith, AZ's oncology and R&D chief said in a statmenet Thursday. "We are committed to working closely with the FDA to bring this novel immunotherapy option to patients that offers a flexible chemotherapy backbone."
Bristol Myers Squibb’s Opdivo also is up for a look-alike approval in October, based on a trial that showed perioperative use provided a 42% reduction in the risk of tumor recurrence, progression or death in patients with stage 2 to 3b NSCLC. Based on nearly identical event-free survival results, plus a unique overall survival win, Merck’s Keytruda has already been approved in the indication.
The FDA could risk the criticsm of a double standard if it eventually decided to reject perioperative Imfinzi, because Keytruda's Keynote-671 study also has the same continuous neoadjuvant-adjuvant design that doesn't tease out the contribution of each treatment phase.
Imfinzi was originally approved in 2017 for bladder cancer. It later added endorsements for unresectable NSCLC, small-cell lung cancer, biliary tract cancer, metastatic NSCLC and its most recent indication, endometrial cancer, which was gained last month. AZ reported sales of Imfinzi at $4.2 billion last year.