Interim results from a phase 3 trial of AstraZeneca’s Imfinzi as a treatment before and after surgery in resectable non-small cell lung cancer (NSCLC) were head-scratching as they failed to answer two key questions.

Do both treatment settings optimize the use of the PD-L1 inhibitor? And is Bristol Myers Squibb’s PD-1 Opdivo in the neoadjuvant (before surgery) setting alone a superior choice?

Thursday, the FDA’s Oncologic Drugs Advisory Committee (ODAC) will try to figure these out and determine whether to recommend Imfinzi for approval in the indication.

In a briefing document released by the FDA on Tuesday, the regulator pointed out that the AEGEAN study failed to show how much benefit is derived separately from each phase of the regimen, which utilizes Imfinzi plus chemotherapy ahead of surgery and Imfinzi as a monotherapy after surgery.

The first question the advisory committee will hash out is whether a new trial is needed to clarify the contributions of each phase of the regimen.

The second, bigger-picture question is whether the FDA should require trials for perioperative regimens to be designed to include assessment of the benefit of each treatment phase.

Of particular concern to the FDA is whether perioperative regimens run the risk of “toxicities due to overtreatment without additional clinical benefit,” the regulator's staff wrote.

In the AEGEAN study, the use of Imfinzi before and after tumor-removing surgery reduced the risk of recurrence, progression or death by 32% in patients with resectable stage 2 to stage 3b NSCLC. The regimen’s comparator was chemotherapy alone.

As for Opdivo plus chemotherapy in the CheckMate-816 trial, the BMS blockbuster tallied a 37% risk reduction figure—even though the combo was used only in the preoperative stage.

Last year in an interview with Fierce Pharma, the AEGEAN study’s lead investigator, John Heymatch, M.D., Ph.D., pointed out several differences in the trials that could explain why Imfinzi’s perioperative regimen appeared to be weaker than neoadjuvant Opdivo, most importantly that BMS’ study included patients in earlier stages of the disease—from 1b to 3a.