Abstract CT238: Associations of ctDNA levels during neoadjuvant treatment with pathological response in patients with resectable NSCLC from the phase 3 AEGEAN trial
Authors: Gale Davina , Zhu Zhou , Lai Zhongwu , Reck Martin , Harpole David , Taube Janis M. , Mitsudomi Tetsuya , Hochmair Maximilian , Winder Thomas , Urbán László , Rodriguez-Cid Jeronimo , Chu Quincy , Chaft Jamie , Stewart Ross , Hodgson Darren , Doherty Gary J. , Heymach John V. 
Published: April 2024

Abstract
Background: In AEGEAN, perioperative durvalumab (D) + neoadjuvant (neoadj) chemotherapy (CT) significantly improved pathological complete response (pCR) and event-free survival (primary endpoints), and major pathological response (MPR; key secondary endpoint), with manageable safety vs neoadj CT alone in patients with resectable NSCLC. We report exploratory ctDNA analyses during neoadj treatment (Tx) and associations of ctDNA dynamics and clearance with pathological response, including pCR, MPR and percentage residual viable tumor (%RVT). Methods: AEGEAN is a double-blind placebo (PBO)-controlled study (NCT03800134). Adults with Tx-naïve resectable NSCLC (stage II-IIIB[N2]; AJCC 8th ed) were randomized (1:1) to receive neoadj CT + D or PBO IV (Q3W, 4 cycles) prior to surgery (Sx), followed by D or PBO IV (Q4W, 12 cycles), respectively, after Sx. Evaluable resected samples from patients in the modified intent-to-treat (mITT) population (patients without known EGFR/ALK aberrations) were assessed centrally for %RVT and determination of pCR (absence of any RVT in resection specimen, including primary tumor and all sampled lymph nodes) and MPR (≤10% RVT in primary tumor) per IASLC recommendations. Plasma samples were collected prior to each neoadj Tx cycle (at baseline [BL], C2D1, C3D1, and C4D1) and before Sx. ctDNA analysis was performed using patient-specific, tumor-informed assays, following identification of mutations in Tx-naïve, diagnostic biopsies by whole exome sequencing. ctDNA variant allele fractions (VAFs; mutant sequences as a % of total sequence reads at ctDNA panel sites) and dynamics, including ctDNA clearance, were assessed during neoadj Tx, and their potential associations with pCR, MPR, or %RVT were evaluated. Results: ctDNA was evaluated in 831 samples from 186 patients (D arm, n=90; PBO arm, n=96) in the mITT population from the interim pCR analysis cohort (n=402). ctDNA dynamics were assessed during neoadj Tx in relation to whether patients had a pathological response at surgery; patients without surgery were designated as non-responders. BL VAF levels were not significantly different between patients who had tumors with vs without pCR (D arm, P=0.09; PBO arm, P=0.7) or MPR (D arm, P=0.4; PBO arm, P=0.8); however, on-Tx VAF levels were significantly lower in the D arm from C2D1 onwards in patients with vs without pCR (P≤0.001) or MPR (P≤0.01) and in the PBO arm from C3D1 for pCR (P≤0.003) or C2D1 for MPR (P≤0.002). %RVT was significantly lower in patients with vs without ctDNA clearance from C2D1 onwards in the D arm (median, &lt;5% vs ≥30%, P≤0.01) and from C3D1 onwards in the PBO arm (median, 10% vs ≥50%, P≤0.0004). Conclusions: In AEGEAN, reduced VAF levels during neoadj Tx appeared associated with pCR or MPR. Patients in whom ctDNA clearance was observed tended to have a lower %RVT, from C2D1 in the D arm and from C3D1 in the PBO arm.
Citation Format: Davina Gale, Zhou Zhu, Zhongwu Lai, Martin Reck, David Harpole, Janis M. Taube, Tetsuya Mitsudomi, Maximilian Hochmair, Thomas Winder, László Urbán, Jeronimo Rodriguez-Cid, Quincy Chu, Jamie Chaft, Ross Stewart, Darren Hodgson, Gary J. Doherty, John V. Heymach. Associations of ctDNA levels during neoadjuvant treatment with pathological response in patients with resectable NSCLC from the phase 3 AEGEAN trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT238.