The pathologic complete response rate with durvalumab was 17.2% vs 4.3% with placebo, reflecting an absolute difference of 12.9%.
Perioperative durvalumab (Imfinzi), along with neoadjuvant platinum-based chemotherapy, induced statistically significant improvements in pathologic complete response (pCR) and event-free survival (EFS) among patients with resectable non–small cell lung cancer (NSCLC) vs placebo plus chemotherapy, according to preliminary findings from the first interim analysis of the phase 3 AEGEAN trial (NCT03800134) presented at the 2023 AACR Annual Meeting.1,2
The pCR rate with durvalumab (n = 366) was 17.2% vs 4.3% with placebo (n = 374), reflecting an absolute difference of 12.9% (95% CI, 8.7%-17.6%; P = .000036). The major pathologic response (MPR) rates with durvalumab and placebo were 33.3% and 12.3%, respectively, reflecting an absolute difference of 21.0% (95% CI, 15.1%-26.9%; P = .000002).
At a median follow-up of 11.7 months (range, 0.0-46.1) with 31.9% maturity, the median EFS was not reached (NR; 95% CI, 31.9-NR) with durvalumab vs 25.9 months (95% CI, 18.9-NR) with placebo (stratified HR, 0.68; 95% CI, 0.53-0.88; P = .003902). The 12- and 24-month EFS rates with durvalumab were 73.4% and 63.3%, respectively, vs 64.5% and 52.4% with placebo.
“NSCLC remains the leading cause of cancer mortality, and historically, about half of patients who undergo resection experience recurrence,” lead study author John V. Heymach, MD, PhD, chair of Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston, said in a press release. “Anything we can do to increase cure rates for these patients could potentially be a tremendous advance. AEGEAN is the first phase 3 study to describe the benefit of perioperative immunotherapy plus neoadjuvant chemotherapy, [representing] a potential new treatment for patients with resectable NSCLC,” Heymach said.
Surgery is the primary curative-intent intervention for eligible patients with early-stage NSCLC. Recent phase 3 trials including CheckMate 816 (NCT02998528), IMpower010 (NCT02486718), and KEYNOTE-091 (NCT02504372) have shown the benefit of using PD-1/PD-L1 inhibitors in the neoadjuvant or adjuvant setting for resectable NSCLC,3-5 leading to the FDA approvals of nivolumab (Opdivo) and atezolizumab (Tecentriq) in the neoadjuvant and adjuvant settings, respectively.6,7
However, perioperative treatment combining neoadjuvant and adjuvant immunotherapy to prime antitumor activity could result in the eradication of micrometastases and enhance long-term outcomes.
This approach was evaluated in the global, double-blinded, placebo-controlled AEGEAN trial. The study population consisted of patients with treatment-naïve, resectable stage IIA to IIIB NSCLC per American Joint Committee on Cancer 8th edition criteria with plans to undergo lobectomy, sleeve resection, or bilobectomy. In addition to an ECOG performance status of 0 or 1, patients had to have confirmed PD-L1 status and no documented EGFR or ALK aberrations.
Between January 2, 2019, and April 19, 2022, 802 patients were randomly assigned 1:1 to neoadjuvant therapy consisting of 1500 mg of intravenous (IV) durvalumab plus platinum-based chemotherapy every 3 weeks for 4 cycles, or IV placebo plus platinum-based chemotherapy on the same schedule. After surgery, patients received an additional 12 cycles of durvalumab or placebo every 4 weeks, depending on randomization. Post-operative radiotherapy was permitted in accordance with local guidance.
Primary end points were pCR by central laboratory per IASLC 2020 criteria and EFS using blinded independent central review (BICR) per RECIST v1.1 criteria. Secondary end points were MPR by central laboratory per IASLC 2020 criteria, disease-free survival (DFS) using BICR per RECIST v1.1 criteria, and overall survival (OS).
The study protocol was amended during enrollment to exclude patients with tumors classified as T4 for any reason other than size, those with planned pneumonectomy, and those with documented EGFR or ALK aberrations. All efficacy analyses were performed on a modified intention-to-treat population, which excluded patients with EGFR and ALK aberrations.
Minimum follow-up was 6.7 months. Baseline characteristics were largely balanced between the study arms, Heymach said. Most patients were male, White, enrolled in Asia or Europe, and former smokers. Most patients had stage IIIA disease, nonsquamous histology, and PD-L1 expression between 1% and 49% on tumor cells. Regarding tumor, node, and metastasis classification, most patients had T3 and N2 disease. Additionally, more than 70% of patients planned to receive a carboplatin-based regimen as neoadjuvant chemotherapy.
In the neoadjuvant phase, most patients in the experimental arm completed 4 cycles of chemotherapy (84.7%) and durvalumab (86.9%). In the control arm, 87.2% of patients completed 4 cycles of chemotherapy and 88.5% of patients completed 4 cycles of placebo. Approximately 80% of patients in both arms underwent surgery; 94.7% and 91.3% of patients who completed surgery (durvalumab, 77.6%; placebo, 76.7%) achieved R0 resection with durvalumab and placebo, respectively. In the adjuvant phase, 65.8% and 63.4% of patients started durvalumab vs placebo, respectively, and approximately 23% of patients in both arms remained on adjuvant therapy at data cutoff.
“Before the study started, there was a concern that giving neoadjuvant immunotherapy might make it harder for some patients to get to surgery. But in fact, we were happy to see that almost an identical number of patients were able to get surgery in both arms, suggesting that the inclusion of neoadjuvant immunotherapy does not reduce the number of patients who can go on to complete surgery,” Heymach said.
Additional results indicated that benefits in pCR and EFS were largely consistent across predefined subgroups, Heymach said. Additionally, EFS was improved with durvalumab regardless of whether cisplatin (HR, 0.59; 95% CI, 0.35-1.00) or carboplatin (HR, 0.73; 95% CI, 0.54-0.98) was selected for neoadjuvant chemotherapy.
Regarding safety during the overall study period, any-grade, all-cause adverse effects (AEs) occurred in 96.5% of patients in the durvalumab arm vs 94.7% of patients in the placebo arm; grade 3 or 4 events occurred in 42.3% and 43.4% of patients in the durvalumab and placebo arms, respectively. Treatment discontinuation with durvalumab or placebo occurred in 12.0% and 6.0% of patients, respectively, and cancelled surgery in 1.8% and 1.0% of patients, respectively. Deaths due to all-cause AEs occurred in 5.8% and 3.8% of patients on durvalumab vs placebo, respectively.
Any-grade AEs deemed possibly related to durvalumab, placebo, or chemotherapy occurred in 86.5% of patients who received durvalumab vs 80.7% of patients who received placebo; grade 3 or 4 events occurred in 32.3% vs 33.1% of patients on durvalumab vs placebo, respectively. Deaths due to potential treatment-related AEs occurred in 1.8% and 0.5% of patients.
Any-grade immune-mediated AEs were reported in 23.5% of patients on durvalumab vs 9.8% of patients on placebo; grade 3 or 4 events occurred in 4.0% and 2.5% of patients, respectively. Any-grade pneumonitis occurred in 3.8% and 1.8% of patients on durvalumab and placebo, respectively.
“We are excited to see that the trial has achieved both its primary end points of improving pCR and significantly reducing the likelihood of disease progression, recurrence, or death,” Heymach said. “The good news for patients with NSCLC is there are now multiple different regimens that have shown improvements in outcomes. This study has laid the foundation that we can build on by designing new combination regimens on top of this effective backbone.
“This is a new treatment paradigm for this patient population, but one that requires investment from multidisciplinary teams—a greater integration of medical oncology, molecular pathology, and surgical oncology teams all working together to improve clinical outcomes.”
Study investigators will continue to monitor data for long-term EFS, as well as DFS and OS.
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.