Impact of neoadjuvant durvalumab (D) on tumor microenvironment (TME) features and their association with event-free survival (EFS) in patients with resectable NSCLC (R-NSCLC) from the phase 3 AEGEAN trial.

Abstract

8015 Background: In AEGEAN, perioperative D + neoadj CT improved EFS and pathological complete response vs neoadj CT alone in pts with R-NSCLC. Here, we report exploratory transcriptomic analyses of the TME in tumor samples collected at baseline (BL) and surgery (Sx) to investigate the impact of neoadj D on TME features and their association with EFS. 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 neoadj platinum-based CT + D or PBO IV (Q3W, 4 cycles) before Sx followed by D or PBO IV (Q4W, 12 cycles) after Sx. EFS was evaluated by BICR (RECIST v1.1) in the modified ITT (mITT) population, which excluded pts with known EGFR / ALK aberrations. Total RNA was extracted from BL and Sx tumor samples and sequenced (Illumina NovaSeq X Plus). Unsupervised hierarchical clustering of samples was conducted based on previously reported gene signatures reflective of tumor and TME components. Results: Transcriptomic data were available from 366 samples in 292 mITT pts across both arms (at BL, 257 pts; at Sx, 109 pts) whose characteristics and outcomes were broadly representative of the mITT population (74 pts with paired samples). At BL, 3 distinct phenotypic clusters (C) based on TME features were identified: an immune desert (C1, 24.9% of pts), characterized by a predominance of proliferating tumor cells; immune suppressed (C2, 39.3%), by elevated levels of suppressive myeloid cells, angiogenesis, and fibroblasts; and immune activated (C3, 35.8%), by high levels of effector T cells. A higher proportion of pts with squamous vs non-squamous tumors had phenotype C1 (37.5% vs 13.9%, respectively) while a lower proportion had C3 (22.5% vs 47.4%). The addition of perioperative D improved EFS across all BL C (C1: HR, 0.43; 95% CI, 0.19–0.94; C2: HR, 0.90; 95% CI, 0.50–1.63; C3: HR, 0.41; 95% CI, 0.20–0.81), with least improvement in C2. The same clusters were detected at Sx (C1, 32.1%; C2, 33.9%; C3, 33.9%) and pts with C1 tumors had the highest risk of progression; 36-month EFS rates (95% CI) were 27.8% (12.1–46.0), 55.7% (33.7–73.0), and 77.2% (59.3–88.0) for C1, C2, and C3, respectively. Neoadj D was associated with higher proportions of pts with C2 and C3 phenotypes at Sx, such that the proportion with poor prognosis C1 tumors at Sx was 17.9% vs 47.2% in the D vs PBO arms, respectively. Among pts with C3 tumors at Sx, EFS benefit in the D vs PBO arm was striking (HR, 0.16; 95% CI, 0.03–0.79). Conclusions: The TME before and after neoadj Tx impacts EFS in pts with R-NSCLC, with an immune suppressed phenotype associated with reduced perioperative D benefit. The TME differs between squamous and non-squamous tumors and is influenced by neoadj D, which may promote an immune-activated phenotype associated with prolonged EFS benefit with perioperative D. Clinical trial information: NCT03800134 .