ODAC Votes in Favor of New Perioperative NSCLC Trial Design Proposals

Members of the committee assessed the sufficiency of efficacy and safety findings from the AEGEAN trial (NCT03800134) while considering the potential uncertainty of emerging data across trials associated with possible overtreatment with perioperative immune checkpoint inhibitor therapy.

The FDA’s Oncologic Advisory Drug Committee (ODAC) cast a 11-to-0 vote in favor of the agency mandating that new clinical trial design proposals should include sufficient within-trial assessments of the contribution of treatment phase in studies evaluating perioperative therapy for resectable non–small cell lung cancer (NSCLC).¹

The ODAC convened to discuss 2 key questions related to the use of perioperative therapy in the aforementioned population. First, members addressed whether results from the phase 3 AEGEAN trial (NCT03800134) sufficiently supported the use of perioperative durvalumab (Imfinzi) injection plus platinum-based chemotherapy followed by durvalumab monotherapy after surgery for adult patients with resectable NSCLC with no known EGFR mutations or ALK rearrangements. Developers previously submitted a supplemental biologics license application (sBLA) to the FDA seeking approval of durvalumab plus chemotherapy for patients with resectable NSCLC in July 2023 based on supporting data from the AEGEAN trial.²

Members of the committee assessed the sufficiency of efficacy and safety findings from the AEGEAN trial while considering the potential uncertainty of emerging data across trials associated with possible overtreatment with perioperative immune checkpoint inhibitor therapy. Additionally, they reviewed the trial findings based on whether the efficacy of durvalumab was attributable to its use in the neoadjuvant and/or adjuvant portions of treatment.

The committee also discussed whether developers should be required to adequately justify the treatment of patients both after and before surgery as part of a resectable NSCLC regimen encompassing both adjuvant and neoadjuvant therapy.

“Moving forward, my hope is that we eliminate some of this ambiguity [by having] additional conversations with the patients,” Pamela L. Kunz, MD, an associate professor of Internal Medicine at Yale School of Medicine, said while explaining her vote in favor of trial designs clarifying the contribution of treatment phases.

“It’s a big burden to put on patients to have them make the [treatment] decision. More [treatment] is not always more [in terms of outcomes]. We owe it to our patients to provide them with some of that clarity and provide them with that high-level evidence,” she added.

According to data from the AEGEAN trial published in The New England Journal of Medicine, the perioperative durvalumab regimen conferred a significant event-free survival (EFS) improvement compared with placebo plus chemotherapy (HR, 0.68; 95% CI, 0.53-0.88; P = .004).³ The EFS rates in each respective arm were 73.4% (95% CI, 67.9%-78.1%) vs 64.5% (95% CI, 58.8%-69.6%) and 63.3% (95% CI, 56.1%-69.6%) vs 52.4% (95% CI, 45.4%-59.0%) at 24 months. Data showed a consistent EFS benefit with durvalumab-based treatment across most patient subgroups.

Based on the final analysis of pathological complete response (pCR), findings showed pCR in 17.2% (95% CI, 13.5%-21.5%) of the durvalumab arm compared with 4.3% (95% CI, 2.5%-6.9%) in the placebo arm. An independent assessment of objective response rate (ORR) prior to surgery indicated rates of 56.3% (95% CI, 51.0%-61.4%) and 38.0% (95% CI, 33.0%-43.1%) in each respective arm.

Grade 3 or 4 adverse effects (AEs) affected 42.4% of patients who received durvalumab and 43.2% of those who received placebo; 32.2% and 36.2% of these toxicities, respectively, occurred during neoadjuvant therapy. Any-grade AEs considered to be related to the study treatment occurred in 86.8% and 80.7% of patients from each respective arm. AEs leading to death were reported in 1.7% and 0.5% of patients, respectively.

In the international, double-blind AEGEAN trial, 802 patients were randomly assigned to receive durvalumab at 1500 mg intravenously (n = 400) or matched placebo (n = 402) every 3 weeks before surgery. Adjuvant treatment consisted of additional durvalumab or placebo every 4 weeks for a maximum of 12 cycles.

The trial’s primary end points were EFS per blinded independent central review and pCR based on central review. Secondary end points included major pathological response, disease-free survival, overall survival, patient-reported outcomes, and safety.

Patients 18 years and older with newly diagnosed, previously untreated, histologically or cytologically confirmed resectable stage IIA to IIIB NSCLC suitable for planned surgery with lobectomy, sleeve resection, or bilobectomy were eligible for enrollment on the trial. Other requirements for enrollment included having an ECOG performance status of 0 or 1, a minimum life expectancy of 12 weeks, documented PD-L1 tumor status, and 1 or more measurable target lesions based on RECIST v1.1 criteria.

References

1. July 25, 2024 Meeting of the Oncologic Drugs Advisory Committee (ODAC). Streamed live July 25, 2024. Accessed July 25, 2024. https://tinyurl.com/yhxkmxmz
2. July 25, 2024, Oncologic Drugs Advisory Committee (ODAC) Meeting. Briefing document. FDA. July 25, 2024. Accessed July 25, 2024. https://tinyurl.com/yskspuys
3. Heymach JV, Harpole D, Mitsudomi T, et al. perioperative durvalumab for resectable non–small-cell lung cancer. N Engl J Med. 2023;389(18):1672-1684. doi:10.1056/NEJMoa2304875