Association of post-surgical MRD status with neoadjuvant ctDNA dynamics, genomic mutations, and clinical outcomes in patients with resectable NSCLC (R-NSCLC) from the phase 3 AEGEAN trial.

8009 Background: In AEGEAN, perioperative durvalumab (D) + neoadj CT significantly improved the primary endpoints of event-free survival (EFS) and pathological complete response (pCR) vs neoadj CT alone in pts with R-NSCLC. Prior analyses of AEGEAN suggest that pts without ctDNA clearance during neoadj Tx or with molecular residual disease (MRD; i.e. ctDNA detected) at a landmark timepoint after Sx (adj C1D1) had worse outcomes. Using data from all biomarker-evaluable pts, we report exploratory analyses for associations of post-Sx MRD status with pt characteristics, neoadj ctDNA dynamics, pathological response, genomic mutations and outcomes. Methods: AEGEAN is a double-blind PBO-controlled study (NCT03800134). Adults with Tx-naïve R-NSCLC (stage II–IIIB[N2]) and ECOG PS 0/1 were randomized 1:1 to receive neoadj platinum-based CT + D or PBO IV (Q3W, 4 cycles) before Sx followed by D or PBO IV (Q4W, 12 cycles) after Sx. Efficacy was assessed in the mITT population, which excluded pts with known EGFR / ALK aberrations. ctDNA analysis was performed on plasma collected before each neoadj Tx cycle, Sx, and adj C1, C3/4 and C10/11 using pt-specific tumor-informed assays. Whole exome sequencing analysis of diagnostic tumor biopsies was performed to identify mutations associated with MRD status at the post-Sx landmark. Results: Among MRD-evaluable pts, 10% (17/168) were MRD-positive (D, n=10; PBO, n=7) and 90% (151/168) were MRD-negative (D, n=78; PBO, n=73) at the landmark timepoint (median 6.9 wk post-Sx). 88% [15/17] of MRD-positive pts were initially diagnosed with stage III disease. In the D arm, the majority of MRD-positive pts (9/10) also had ctDNA detected at the pre-Sx visit. No MRD-positive pts in the D arm had pCR or major pathological response. As expected, overall disease-free survival (DFS) rates at 12 mo were worse in MRD-positive (14.3%; 95% CI, 2.4–36.3) vs MRD-negative pts (89.3%; 95% CI, 82.6–93.5). In both arms, MRD-positive pts had worse DFS outcomes vs MRD-negative pts (D: HR, 21.28; 95% CI, 7.70–58.83; PBO: HR, 14.29; 95% CI, 4.94–41.36) with DFS trends favoring the D vs PBO arm, particularly in pts with no ctDNA detected (MRD-negative: HR, 0.56; 95% CI, 0.26–1.20; MRD-positive: HR, 0.78; 95% CI, 0.26–2.36). Mutated genes associated with MRD-positive status in the D arm included KEAP1 and KMT2C ; despite small pt numbers, EFS benefit in the D vs PBO arm was not evident in pts with the mutations (m) (KEAP1 m: HR, 1.39; 95% CI, 0.29–6.77; KMT2C m : HR, 2.03; 95% CI, 0.70–5.91). In contrast, EFS benefit was evident in pts with wild type (wt) ( KEAP1 wt: HR, 0.54; 95% CI, 0.36–0.79; KMT2C wt: HR, 0.52; 95% CI, 0.35–0.78). Conclusions: Exploratory analyses based on post-Sx MRD status and genomic analysis identified a small high-risk subgroup of pts with markedly worse prognosis with potentially reduced benefit from the AEGEAN regimen. Clinical trial information: NCT03800134 .