AEGEAN Subgroup Analysis Fails to Demonstrate Clear Benefit With Perioperative Durvalumab Plus Chemo in EGFR+ NSCLC

David Harpole, MD

Despite the superiority of perioperative durvalumab (Imfinzi) plus neoadjuvant chemotherapy vs neoadjuvant chemotherapy alone in patients with resectable non–small cell lung cancer (NSCLC), no significant survival advantage was seen with the approach in patients with EGFR-mutated disease, according to David Harpole, MD.

At the 2023 IASLC World Conference on Lung Cancer, Harpole presented data from an exploratory analysis of patients with EGFR alterations in the phase 3 AEGEAN trial (NCT03800134). At a median follow-up of 16.6 months (range, 0.0-36.4), the unstratified event-free survival (EFS) hazard ratio (HR) was 0.86 (95% CI, 0.35-2.19) in this patient subgroup (n = 51) vs 0.68 (95% CI, 0.53-0.88; P = .003902) in the modified intention-to-treat (ITT) population (n = 740). Within the EGFR-mutant subgroup, the difference in pathologic complete response (pCR) rate between the durvalumab and placebo arms was 3.8% (95% CI, -10.0% to 19.1%), in favor of durvalumab. Comparatively, pCR rates in the modified ITT population were 17.2% and 4.3% (difference, 13.0%; 95% CI, 8.7%-17.6%), respectively. No new safety signals were observed.

Harpole noted that investigators should be cautious when interpreting these findings due to the small number of patients enrolled in the EGFR-mutant subgroup. Still, coupled with the encouraging survival outcomes produced by adjuvant osimertinib (Tagrisso) in the phase 3 ADAURA trial (NCT02511106), these data indicate that patients harboring EGFR aberrations will likely experience greater benefit with osimertinib over chemoimmunotherapy, and should not be enrolled onto chemoimmunotherapy trials, Harpole emphasized.

“[This research] supports the [signals] that we're getting from other trials [focused on perioperative chemoimmunotherapy in lung cancer]. It allows us to tell our patients who have EGFR-mutated [disease] that we've got better treatments for them,” said Harpole, who is the George Barth Geller Distinguished Professor for Research in Cancer, professor of surgery and pathology, and member at Duke Cancer Institute, Durham, North Carolina.

In an interview with OncLive^®, Harpole discussed key data from the first interim analysis of the AEGEAN trial, changes to the adjuvant treatment landscape that inspired the subgroup analysis of patients with EGFR mutations excluded from the ITT population, and how subsequent findings will influence testing recommendations and clinical trial enrollment in this population.

OncLive: Please provide some background on the main objective and design of the AEGEAN trial.

Harpole: This trial was designed about 5 years ago, before any indication that immunotherapy had a role in the upfront treatment of patients as a part of a tri-modality. We had some data in advanced lung cancer showing that immunotherapy plus chemotherapy or immunotherapy alone was beneficial. The AEGEAN trial was designed using the phase 3 PACIFIC trial [NCT02125461] regimen of durvalumab with platinum-based chemotherapy in patients with locally advanced lung cancer who were candidates for surgery. [Investigators aimed] to see whether this regimen would increase the downstaging of patients and benefit them. In the past 25 years that I’ve been doing this, we typically gave upfront platinum chemotherapy [alone] to patients with locally advanced cancer followed by surgery. The CR rate [with this approach] was around 4% to 5%, and the downstaging of nodes was 15% to 20%, so there was not a very large [improvement in outcomes]. We were hopeful that using immunotherapy plus chemotherapy might increase [these rates] and help patients.

Unlike the other two large [trials of chemoimmunotherapy in lung cancer], which also have been reported, the design of the AEGEAN study was based on the knowledge that durvalumab was [used as] consolidative [therapy] for an extended period after chemoradiation in locally advanced patients. Our design was to give the chemoradiation and durvalumab upfront randomized against chemotherapy alone, and to administer durvalumab after resection for 1 year vs placebo in the other arm. [The goal was to] see if [the addition of immunotherapy] would provide benefit to patients when administered both before and after resection. The trial accrued patients for 4 years.

What primary results from this study were previously reported?

We had a first interim analysis planned in November of last year with 30% of the events. To our surprise, we met both primary end points at that early stage. There was only 11.7 months of median follow-up, so it was early. The two primary end points were the pCR rate and EFS. [The pCR rate] was 13% higher in the durvalumab arm, which was significant, and the EFS showed a significant difference of approximately 12 months between the 2 [arms], with the 2 curves now tailing even farther apart. [These data] were presented by my partner, John V. Heymach, MD, PhD, at the 2023 AACR Annual Meeting. The trial has been accepted by the New England Journal of Medicine.

What was the rationale for conducting this exploratory subgroup analysis of patients with EGFR mutations within the AEGEAN trial?

When we started the trial, adjuvant data for durvalumab and osimertinib were not available. When those data came out, and osimertinib was approved in December of 2020 for patients with EGFR-mutated adenocarcinoma, the disease-free survival was dramatically different, with an amazing hazard ratio of 0.2. We adapted the protocol and put testing for both ALK and EGFR as exclusion criteria up front. There were 51 patients [enrolled] onto AEGEAN prior to that [amendment] who we knew [harbored] EGFR mutations. However, we felt that the osimertinib data was so strong that it would be ethically better to exclude [any more patients with EGFR mutations] from the trial. In fact, we removed those patients from our primary modified ITT [analysis]. These data are looking at what happened to those patients.

According to the data presented from this subgroup analysis, what was the efficacy and safety of perioperative durvalumab plus chemotherapy in patients with EGFR-mutated NSCLC?

First, [these results should be extrapolated with] caution. Of the 51 patients [in this subgroup], 26 received the durvalumab/chemotherapy regimen and 25 just received chemotherapy, so [this is a] small [cohort]. However, there have been signals from the advanced patient setting that patients who have EGFR mutations, and probably those who have ALK rearrangements [benefit less] from immunotherapy than those who [do] not. That was our presumption, and that's what we saw. The survival curves are essentially superimposable for the treatment and non-treatment arms. Again, the follow-up was not long, and they're very small numbers. Importantly, there was no safety signal [with the combination. In fact, adverse effects were uncommon and [observed at] similar [rates] between both arms. We look forward to longer-term data.

The bottom line is that the difference in pCR between the arms was 3%, which was not significant, and EFS rates were [comparable]. [Based on these data], we feel that it's reasonable to recommend that patients with EGFR mutations [should undergo] assessment ahead of [treatment with] neoadjuvant chemoimmunotherapy, and that they should probably be eliminated from trials or treatment approaches that include chemoimmunotherapy.

What other research in the lung cancer space were you excited to see presented at the IASLC 2023 World Conference on Lung Cancer?

I was the president of the 2020 World Conference on Lung Cancer when it was virtual in Denver. It was kind of frustrating not getting together for that due to COVID-19. This is the second meeting we've had back in person, and that's the most important thing. This is an important meeting for all of us who [treat patients with] thoracic cancers. We've always been multidisciplinary and inclusive, so seeing friends from all over the world is important. I [was] most looking forward to the presentation of data from the MARS2 study [NCT02040272] on the effect of chemotherapy alone vs chemotherapy with surgery [in patients with] mesothelioma. There were also several other smaller-outcome studies. The other important use of this meeting is [to spotlight] lots of phase 2 trials that are demonstrating signals for new agents. For 20 years, we were optimistic about cancer care. There were opportunities to treat patients who really didn't have a whole lot [of options]. Now, there are hundreds of potential new therapies for patients with lung cancer. I'm hopeful that over the next 5 to 10 years, we're going to make major inroads in cancer treatment and care.

Reference

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 OA012.06.