FDA panel suggests revamp of perioperative lung cancer trials

The US Food and Drug Administration’s (FDA) Oncologic Drugs Advisory Committee (ODAC) has recommended modifications in the design of clinical trials for treatments involving surgery for early-stage non-small cell lung cancer (NSCLC). During their meeting on July 25, the committee underscored the need for separate evaluations of the effectiveness of treatment components in both pre-operative and post-operative phases.

This recommendation followed AstraZeneca's proposal to use Imfinzi (durvalumab) combined with chemotherapy before and after surgery. This proposal was backed by findings from the Phase III AEGEAN study (NCT03800134). Although the committee did not vote on approving Imfinzi for this specific use, the majority opinion leaned towards approval. Dr. Ravi Madan from the National Cancer Institute noted the complexity and potential difficulty for patients and providers if another trial were to be initiated.

The perioperative period encompasses the time before, during, and after surgery. The AEGEAN study demonstrated that using the treatment during this period dropped the likelihood of cancer recurrence, progression, or death by 32% in comparison to chemotherapy alone. However, the study's design did not allow for separate evaluations of the treatment’s effectiveness before and after surgery, leaving ambiguity about which phase was most beneficial.

In a briefing document preceding the meeting, the FDA indicated it had advised AstraZeneca to structure the study to assess the individual benefits in both pre-surgery and post-surgery settings, advice that was not heeded. This oversight raised concerns about potential unnecessary side effects without clear benefits.

Furthermore, the FDA expressed worries about the possibility of overtreatment with perioperative immune checkpoint inhibitor (ICI) regimens in the same document.

Imfinzi initially received approval for bladder cancer treatment in 2017 and its label has since been expanded to include several other indications, such as unresectable NSCLC, small-cell lung cancer, metastatic NSCLC, and endometrial cancer, the latter approved in June 2024. The FDA accepted a supplemental Biologics License Application (sBLA) for Imfinzi in the perioperative setting in September 2023. The drug is already approved for this indication in the UK and Switzerland based on the AEGEAN trial. AstraZeneca emphasized these approvals and noted that while the ODAC’s recommendations are influential, they are not binding on the FDA.

Susan Galbraith, executive vice president of oncology R&D at AstraZeneca, expressed the company's commitment to collaborate with the FDA to make this innovative immunotherapy option available to patients, highlighting its flexible chemotherapy backbone.

In a related development, MSD’s Keytruda (pembrolizumab), combined with chemotherapy, gained FDA approval as a perioperative treatment for NSCLC in October 2023 based on the KEYNOTE-671 Phase III study (NCT03425643). Similar to AEGEAN, this study evaluated the drug’s use in both neoadjuvant and adjuvant settings. KEYNOTE-671 achieved its coprimary endpoints of overall survival (OS) and investigator-assessed event-free survival (EFS). In contrast, AEGEAN focused on EFS and pathological Complete Response (pCR) as its coprimary endpoints within a modified intent-to-treat (mITT) population.