FDA panel positive on approval of Imfinzi, but votes for changes to perioperative lung cancer trials

2024-07-26

An FDA advisory panel voted unanimously that the design of future clinical studies for perioperative regimens in resectable non-small-cell lung cancer (NSCLC) should be changed, but committee members appeared to favour approval of AstraZeneca’s Imfinzi (durvalumab) in this setting, despite limitations of supporting data.

At the heart of the issue is whether the FDA should require new trial designs for perioperative regimens that can tease out the contribution from both the neoadjuvant and adjuvant treatment phase. While the pivotal Phase III AEGEAN study of Imfinzi met its primary endpoints, questions have arisen about the respective contributions from the use of the PD-L1 inhibitor in both the neoadjuvant and adjuvant settings, and whether the latter is necessary.

Went against advice

Indeed, ahead of the advisory panel meeting, FDA documents noted that while the agency “has recommended within trial evaluation of contribution of sequence, including for AEGEAN, sponsors have not heeded this advice."

Results from the trial demonstrated that patients with resectable NSCLC who were treated with Imfinzi plus chemotherapy before and after surgery had a 32% reduced risk of disease recurrence or progression events. The data also showed that the rate of Grade 3-4 adverse events from any cause were similar for the two groups, although the FDA briefing documents said the safety profile of Imfinzi “in the prolonged adjuvant setting…are concerning given that the contribution of this phase of treatment to the efficacy of the regimen remains unclear.”

Comparable efficacy to neoadjuvant Opdivo

The AEGEAN results must also be viewed through the lens of the earlier CheckMate-816 study, in which Bristol Myers Squibb’s PD-1 inhibitor PD-1 inhibitor Opdivo (nivolumab) demonstrated broadly comparable efficacy when used only as a neoadjuvant treatment, leading to FDA approval in 2022. Indeed, a key opinion leader (KOL) previously suggested to FirstWord that doctors are likely to stick with Opdivo given the lack of compelling differentiation between the two drugs and Imfinzi’s added treatment burden.

Opdivo is currently under review by the FDA as a perioperative NSCLC regimen after demonstrating a 42% reduction in the risk of disease progression, recurrence or death in the CheckMate-77T study; a decision is expected by October 8. Meanwhile, Merck & Co.’s Keytruda (pembrolizumab) gained FDA approval last year in the perioperative setting based on findings from the KEYNOTE-671 study, which along with significantly improving event-free survival, also demonstrated an overall survival benefit.

Over to the FDA

While a vote was not taken at the panel meeting on whether Imfinzi should be authorised in perioperative NSCLC, many committee members urged for approval. “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? My answer is no we shouldn’t,” remarked consumer representative David Mitchell.

Susan Galbraith, executive vice president of oncology R&D at AstraZeneca, said “the committee’s discussion of the AEGEAN data highlighted the significant benefit delivered by this Imfinzi-based regimen for patients with resectable lung cancer. We are committed to working closely with the FDA to bring this novel immunotherapy option to patients that offers a flexible chemotherapy backbone.”

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