AEGEAN Trial Demonstrates Benefit and Viability of Novel Perioperative Treatment Approach in NSCLC

John V. Heymach, MD

Administering neoadjuvant durvalumab (Imfinzi) with platinum-based chemotherapy followed by curative-intent surgery and adjuvant durvalumab bolstered antitumor activity and decreased recurrence risk in patients with non–small cell lung cancer (NSCLC), according to John V. Heymach, MD, PhD, who added that this approach may possess the potential to enhance long-term outcomes for these patients.^1,2

The first interim analysis of the phase 3 AEGEAN trial (NCT03800134) was presented at the 2023 AACR Annual Meeting. At a median follow-up of 11.7 months, with 31.9% maturity, the median event-free survival (EFS) in patients with treatment-naïve, resectable stage IIA to IIIB NSCLC who were given perioperative durvalumab was not reached (NR; 95% CI, 31.9-NR) vs 25.9 months (95% CI, 18.9-NR) with placebo/chemotherapy alone (HR, 0.68; 95% CI, 0.53-0.88; P = .003902). Perioperative durvalumab also improved pathologic complete response (pCR) rate by an absolute difference of 12.9% vs placebo.¹ No new safety signals were seen with the regimen, and it did not prevent patients from undergoing resection vs chemotherapy alone.²

“This [study] is a tremendous step forward,” said Heymach, who is the chair of Thoracic/Head and Neck Medical Oncology and the David Bruton Endowed Chair in Cancer Research at The University of Texas MD Anderson Cancer Center, in Houston, Texas. “In the decades that we researched adjuvant or neoadjuvant chemotherapy, we reduced the chance of [recurrence] by about 5%. In this study, we’ve improved it by 11% at 2 years.”

This study builds on several pivotal trials showing the clinical benefit of either neoadjuvant or adjuvant chemoimmunotherapy regimens in NSCLC. Data from the phase 3 IMPOWER 010 trial (NCT02486718) supported the FDA approval of adjuvant atezolizumab (Tecentriq) following resection and chemotherapy in October 2021.³ In March 2022, nivolumab (Opdivo) plus platinum-based chemotherapy subsequently gained approval in the neoadjuvant setting based on findings from the phase 3 CheckMate 816 trial (NCT02998528).⁴

In an interview with OncLive®, Heymach expanded on the efficacy of perioperative durvalumab in the AEGAN trial, the significance of this unique approach for the NSCLC treatment paradigm, and future research examining opportunities to build on or intensify the benefit achieved with this regimen. 

OncLive: Could you describe the rationale for combining neoadjuvant and adjuvant durvalumab with neoadjuvant chemotherapy in patients with NSCLC?

Heymach: Lung cancer is the leading cause of cancer deaths. Historically, chemotherapy has been the standard for early-stage NSCLC, but it only [provides] a modest benefit. Recently, [research in NSCLC] has shown benefit [with] neoadjuvant immunotherapy, which is where you give immunotherapy with chemotherapy before surgery, as well as adjuvant immunotherapy, [which is] when you give [immunotherapy] after surgery. The AEGEAN study is the first reported randomized study that combines neoadjuvant and adjuvant immunotherapy, [which] we call perioperative immunotherapy, with neoadjuvant chemotherapy to see what benefit [this approach provides].

Could you expand on the primary objectives of the AEGEAN study?

The potential benefits of this combined preoperative therapy approach are that you can induce improved antitumor immunity while the tumor and lymph nodes are still in place. After surgery, you [administer] sustained PD-1 inhibitors to eradicate [any] microscopic metastases. The AEGEAN study had two main end points. One was to improve pCR; [that measures whether] we eliminated all the visible tumor under the microscope [during resection]. The second was to improve EFS, [which is] the likelihood of the cancer progressing, recurring, or [leading to] death from any cause.

What antitumor activity was observed with perioperative durvalumab and neoadjuvant chemotherapy in this trial?

The AEGEAN study achieved both of its primary end points. In terms of pCR, the response rate improved from [4.3% with] chemotherapy alone to [17.2%] with the combined durvalumab approach. EFS [rate] showed a statistically significant improvement, as well. The hazard ratio for EFS was 0.68. That means that so far, there was a 32% lower risk of an EFS event [with the combined approach] during the study. Notably, the results are still early.

This positive study came out of the first planned interim analysis. A lot of patients are still getting durvalumab, so it’s possible that the benefits we see are going to grow over time as more patients receive the full course of treatment.

Were any results from this study particularly notable?

One [key] thing to report is that we saw benefit across virtually all the subgroups that were tested. What’s particularly important is that patients whose tumors were PD-L1 negative, or [had a PD-L1 expression of] less than 1%, still experienced substantial benefit [with the perioperative combination]. The hazard ratio was 0.76, [which] means there was a 24% reduction in the risk of an EFS event in patients whose tumors were PD-L1 negative. When we think about adjuvant immunotherapy, that group typically does not [experience] benefit, so it’s wonderful to see that this group does benefit [from this kind of approach]. We also saw benefit regardless of which platinum-based chemotherapy we used and regardless of tumor stage.

Given these findings, what future directions exist for the investigation of perioperative immunotherapy approaches in NSCLC?

The rates of cancer [recurrence] are still much higher than we would like. In [about] 37% of patients [with regional NSCLC], the cancer still comes back [within 5] years. The question is how do we raise the [EFS] rate and have a smaller percentage of patients whose tumors come back?

The approach that will be most effective going forward [involves using this regimen] as a starting point and looking for ways to intensify that [treatment] in patients who don’t have a pCR. [That means] adding something [to] adjuvant therapy, because we know that group is much more likely to recur. Moving forward, this [regimen] will serve as a platform, and then we’ll develop more tailored therapies [based on this] platform, or some of the other therapies that are coming [down the pike].

What main message would you like to impart to your colleagues regarding this presentation?

For patients with resectable NSCLC, it’s important to do molecular profiling early on [in the treatment course]. At minimum, I would strongly advocate for [patients to receive] neoadjuvant therapy, and potentially perioperative therapy like [this regimen], if it is approved. [This is] because it looks like the benefits of giving immunotherapy and chemotherapy before resecting the tumor are substantial. That’s shown not only here in the AEGEAN study, but earlier with the [phase 3] Checkmate 816 study [NCT02998528].

That’s really a change in practice. For some time, the [standard] practice was [that] surgeons would initially [perform resection], and then send [patients] to medical oncologists to [potentially receive] adjuvant therapy. Now, we must work together in a multidisciplinary team earlier [on in the treatment course], [start] therapy before surgery, and then evaluate the best treatment [approach] after surgery.

Disclosures: Dr Heymach participated in advisory committees for Genentech, Mirati Therapeutics, Eli Lilly & Co, Janssen, Boehringer-Ingelheim, Regeneron, Takeda, BerGenBio, Jazz Pharmaceutics, Curio Science, Novartis, AstraZeneca, BioAlta, Sanofi, Spectrum, GlaxoSmithKline, EMD Serono, BluePrint Medicine, and Chugai Pharmaceuticals; research support from AstraZeneca, Boehringer-Ingelheim, Spectrum, Mirati, Bristol Myers Squibb, and Takeda; and licensing/royalties from Spectrum.

​​References

1. Imfinzi significantly improved event-free survival in AEGEAN Phase III trial for patients with resectable non-small cell lung cancer. Press release. AstraZeneca. March 9, 2023. Accessed May 17, 2023. https://www.astrazeneca.com/media-centre/press-releases
2. Heymach JV, Harpole D, Mitsudomi T, et al. AEGEAN: a phase 3 trial of neoadjuvant durvalumab + chemotherapy followed by adjuvant durvalumab in patients with resectable NSCLC. Presented at: 2023 AACR Annual Meeting; April 14-19, 2023; Orlando, FL. Abstract CT005.
3. FDA approves neoadjuvant nivolumab and platinum-doublet chemotherapy for early-stage non-small cell lung cancer. News release. FDA. March 4, 2022. Accessed May 17, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-neoadjuvant-nivolumab-and-platinum-doublet-chemotherapy-early-stage-non-small-cell-lung
4. FDA approves atezolizumab as adjuvant treatment for non-small cell lung cancer. News release. FDA. October 15, 2021. Accessed May 17, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-atezolizumab-adjuvant-treatment-non-small-cell-lung-cancer