FDA ODAC Votes Unanimously to Mandate Phase Assessments in NSCLC Perioperative Regimens

In an 11 to 0 vote, the FDA’s Oncologic Drugs Advisory Committee (ODAC) agreed that the FDA should mandate that new trial design proposals for perioperative regimens for resectable non–small cell lung cancer (NSCLC) include an adequate trial assessment of the contribution of each treatment phase.¹

The ODAC met to discuss the supplemental biologics license application (sBLA) 761069/S-043 for durvalumab (Imfinzi) injection, submitted by AstraZeneca UK Limited. The proposed use for durvalumab is in combination with platinum-containing chemotherapy as neoadjuvant treatment, followed by durvalumab as monotherapy after surgery, for the treatment of adult patients with resectable NSCLC with no known EGFR mutations or anaplastic lymphoma kinase (ALK) rearrangements.

The Committee examined key issues arising from the AEGEAN trial (NCT03800134) and debated whether an additional trial needs to be conducted to clarify the contribution of the treatment phase for the durvalumab perioperative regimen prior to approval. This discussion was due to the uncertainty around the need for both phases of treatment. The results from AEGEAN were evaluated to determine if they sufficiently support the proposed use of durvalumab in both the neoadjuvant and adjuvant settings.

The focus was on evaluating the adequacy of the efficacy and safety data from AEGEAN to support the proposed perioperative indication and the broader implications for future trial designs involving immune checkpoint inhibitors and novel therapies.

In addition, the Committee also discussed whether drug sponsors should be required to adequately justify treatment of patients both before and after surgery for resectable NSCLC prior to an approval that would include both neoadjuvant and adjuvant therapy. This requirement would ensure that the proposed treatment regimen is necessary and beneficial across all phases of perioperative care.

The objective was to ensure future trials can better identify the contributions of neoadjuvant and adjuvant treatments to avoid unnecessary toxicities and improve patient outcomes.

About the Phase 3 AEGEAN Trial

In the phase 3 AEGEAN trial, patients with stage II to IIIB resectable NSCLC were randomly assigned to receive platinum-based chemotherapy plus durvalumab or placebo given via intravenous (IV) infusion every 3 weeks for 4 cycles prior to surgery, followed by adjuvant durvalumab or IV placebo every 4 weeks for 12 cycles. Of the 802 patients included in the study, 400 were randomly assigned to receive durvalumab and 402 to placebo.²

The primary end points explored in the study included event-free survival (EFS) and pathological complete response (pCR).

At the first interim analysis, the EFS duration was significantly longer among those treated with durvalumab (n = 366) vs placebo (n = 374). In this intention-to-treat population and at a median follow-up of 11.7 months (range, 0.0-46.1), the median EFS with durvalumab was not reached (NR; 95% CI, 31.9-NR) vs 25.9 months (95% CI, 18.9-NR) with placebo (HR, 0.68; 95% CI, 0.53-0.88; P =.004). At the 12-month landmark analysis, the EFS rate was 73.4% for patients given durvalumab (95% CI, 67.9%-78.1%) vs 64.5% with placebo (95% CI, 58.8%-69.6%), and 24-month rates were 63.3% and 52.4%, respectively.

Durvalumab yielded a significantly greater incidence of pCR at 17.2% vs 4.3% with placebo(difference, 13.0%; 95% CI, 8.7%-17.6%; P =.000036). Both EFS and pCR benefits were observed regardless of stage and PD-L1 expression.

For safety, adverse events (AEs) deemed grade 3 or 4 were seen in 42.4% of patients in the durvalumab arm and 43.2% in the placebo arm.

However, findings from the phase 3 trial presented at the 2023 IASLC World Conference on Lung Cancer showed that adding durvalumab to chemotherapy prior to surgery, followed by adjuvant durvalumab, did not provide a clear clinical benefit in patients with early-stage NSCLC harboring an EGFR mutation.³ In a subgroup of patients with EGFR-mutated NSCLC who were enrolled in the trial before a protocol amendment (n = 51), the median EFS in the durvalumab arm (n = 26) was 30.8 months (95% CI, 11.4-NR) by blinded independent central review (BICR) and RECIST v1.1 criteria compared with 19.6 months (95% CI, 14.3-NR) in the placebo arm (n = 25; HR, 0.86; 95% CI, 0.35-2.19). This was at a median follow-up of 16.6 months (range, 0.0-36.4). In the investigative and control arms, the estimated 12-month EFS rates were 65.2% and 77.8%, respectively. Further, the estimated 24-month EFS rates were 59.3% and 44.9%, respectively.

For pCR, the rate was 3.8% in the durvalumab arm vs 0% in the placebo arm (difference, 3.8%; 95% CI, –10.0% to 19.1%). In the durvalumab arm, 7.7% of patients achieved a major pathologic response (MPR) vs 4% of those in the placebo arm (difference, 3.7%; 95% CI, –13.2% to 21.0%).

When used alone and in combination with chemotherapy, durvalumab has a well-established and manageable safety profile. Safety findings from the AEGEAN trial are consistent with the established safety profiles of the individual treatment agents. Specifically, in the EGFR-mutated subgroup, any-grade AEs occurred in 96.2% of patients treated with durvalumab arm vs 84% given placebo. These AEs were maximum grade 3 or 4 in 42.3% and 40% of patients, respectively, and serious AEs were seen in 34.6% vs 28% of patients.

“The totality of data from the study support a strong and clinically meaningful benefit from perioperative durvalumab and the trial continues for longer term efficacy data, including overall survival,” said Gary Doherty, MB, BChir, MA, PhD, FRCP, global clinical program lead at AstraZeneca, during the meeting.

The combined FDA and AstraZeneca ODAC briefing document presented data from the first 3 data cutoff dates of the AEGEAN study.1 The first data cutoff date was January 14, 2022, which included a prespecified and primary analysis of pCR and MPR. The second date was November 10, 2022, which consisted of a prespecified and primary analysis of EFS using BICR per RECIST 1.1. The third was August 14, 2023, which was an ad hoc updated analysis of safety data and descriptive overall survival (OS) data, which was provided to fulfill an agreement with FDA.

Applicant’s Stance

Despite recent approvals of immunotherapy for the treatment of resectable NSCLC in various settings, the outlook for many patients remains poor, and there is a need for better data on how to select patients for different immunotherapy strategies. However, there are no phase 3 trials directly comparing these strategies.

According to the applicant, AEGEAN was well-designed and enrolled a large and representative patient population across the globe. The trial aligned with US clinical practice, including cisplatin and carboplatin chemotherapy doublets.

Looking at efficacy, the applicant explained that the AEGEAN trial showed that the combination of perioperative durvalumab with chemotherapy is safe and effective in this patient population, and the study met its primary end points of pCR and EFS. It also demonstrated a meaningful improvement in pCR and MPR. While OS data were immature, there was a trend favoring the durvalumab combination. Further, EFS data were statistically significant with less follow-up compared with other studies.

For safety, the combination, as well as durvalumab as a monotherapy, showed a manageable safety profile during the adjuvant phase. Most immune-related AEs were nonserious and resolved without leading to discontinuation of treatment.

“Durvalumab is the established standard of care with substantial experience as consolidation therapy in stage III unresectable NSCLC,” said Marina Garassino, MD, medical oncologist at the University of Chicago, during the meeting. “AEGEAN is an important study that adds to the treatment choices for patients with resectable NSCLC, with no detriment to patients’ quality of life.”

John V. Heymach, MD, PhD, also emphasized the potential benefits of this approach over neoadjuvant or adjuvant therapy alone, citing data from various studies. He acknowledged the need for further research to optimize treatment strategies and believes that the available evidence supports the use of perioperative regimens like this.

“It is important to remember that the majority of patients today still recur. So, we have a long way to go and need to get there as quickly as possible for patients,” stated Heymach, professor, Department of Cancer Biology; David Bruton, Jr chair in cancer research; and chair, Department of Thoracic/Head and Neck Medical Oncology, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center. .

The applicant states that these updated results confirm the positive benefit-risk profile of durvalumab plus chemotherapy prior to surgery, followed by durvalumab monotherapy post-surgery, in patients with resectable NSCLC with no known EGFR mutations or ALK rearrangements. This shows support for the first ODAC discussion question.

“Part of the discussion today is if additional data are needed prior to approval of the AEGEAN regimen. It is a sponsored position that AEGEAN has already convincingly demonstrated a clinical benefit,” said Leora Horn, MD, MSC, MHPE, FRCPC, during her closing remarks.

“AstraZeneca is committed to address some of the remaining questions in resectable non–small cell lung cancer, with new studies anticipated to enroll first subjects later this year. Future studies in resectable non–small cell lung cancer need to consider the drug’s mechanism of action, trial feasibility, the treatment landscape, patient's preference, and societal burden,” concluded Horn.

FDA’s Position

The FDA expressed significant concerns regarding the design of the AEGEAN trial. Bernardo Haddock Lobo Goulart, MD, clinical reviewer in the Division of Oncology II Office of Oncologic Diseases, presented the agency's clinical perspective on the trial, highlighting key issues and recommendations for future research.

According to the FDA, the efficacy data from AEGEAN showed a statistically significant and clinically meaningful improvement in EFS favoring perioperative durvalumab. However, the disease-free survival (DFS) data was not statistically significant, preventing formal testing of OS. Descriptive analyses of OS did not suggest any negative effects from perioperative durvalumab.

The inability to determine the specific contribution of neoadjuvant and adjuvant therapy to overall treatment outcome raises concerns. This could lead to patients undergoing unnecessary treatment, increasing their risk of AEs without clear benefit.

“Even benefits in OS would not address this issue,” explained Erin Larkins, MD, director (acting), Division of Oncology II, Office of Oncologic Diseases, during her presentation at the meeting.

They explained that the safety profile was consistent with the known toxicities of platinum-based chemotherapy and immune checkpoint inhibitors. However, they raised concerns about unresolved immune-related AEs in 9% of patients at the end of treatment, which could affect those who might achieve long-term survival.

The FDA's main concern centered on the trial's inability to distinguish the effects of neoadjuvant durvalumab from adjuvant durvalumab. The FDA also highlighted the trial's design flaw, which prevents assessing the individual contributions of durvalumab in the neoadjuvant or adjuvant phases. External data did not clearly support the perioperative regimen's superior efficacy over either phase alone, raising concerns about potential overtreatment, particularly in the adjuvant setting.

Goulart outlined the FDA's recommendations for future trial designs, suggesting alternatives like multi-arm, factorial, and re-randomization trials to help characterize the efficacy and contribution of novel drugs in each treatment phase. The FDA also suggested a need for additional trials to clarify the contribution of each treatment phase prior to granting approval for the perioperative regimen.

“Continued use of 2-arm trials designs assessing therapy added to both phases of therapy will further exacerbate the risk of overtreatment. To best serve patients and the oncology community, multi-arm trials are needed to provide evidence of contribution of phase,” added Larkins.

They sought the advisory committee's advice on requiring such designs for future trials to avoid unnecessary toxicities without added clinical benefits.

Conclusions

During a discussion, experts explained that the AEGEAN trial met its primary end point of improved pCR and EFS, though it did not meet the predefined threshold for DFS. Data suggest that, while OS is not worse, there are small survival benefit differences.

“Many of the panel members think that we need answers to this question, probably sooner than later, and that there are suboptimal consequences once a regimen is approved and that it is not simple to go back to optimize sequencing or duration,” explained Daniel Spratt, MD, acting chairperson of the ODAC.

Overall, the Committee voted that the FDA should require that new trial design proposals for perioperative regimens for resectable NSCLC include adequate within trial assessment of contribution of treatment phase.

REFERENCES:

1. Oncologic Drugs Advisory Committee (ODAC) Meeting. FDA. July 25, 2024. Accessed July 25, 2024. https://tinyurl.com/3srwn2uv

2. 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

3. He J, Gao S, Reck M, et al. Neoadjuvant durvalumab + chemotherapy followed by adjuvant durvalumab in resectable EGFR-mutated NSCLC (AEGEAN). Presented at: 2023 IASLC World Conference on Lung Cancer; September 9-12, 2023; Singapore, Republic of Singapore. Abstract OA12.06.