Durvalumab (anti–PD-L1) reshapes the TME and deepens EFS benefit in resectable NSCLC (AEGEAN)

Durvalumab is a PD-L1–blocking antibody given perioperatively with platinum-based neoadjuvant chemotherapy (4 cycles Q3W) then adjuvantly (12 cycles Q4W) in the Phase 3, double-blind AEGEAN trial (NCT03800134) in treatment-naïve, resectable stage II–IIIB (N2) NSCLC excluding EGFR/ALK-altered tumors. Exploratory RNA-seq (366 samples from 292 mITT patients; 74 paired) defined baseline TME clusters—immune desert (C1, 24.9%), immune suppressed (C2, 39.3%), immune activated (C3, 35.8)—and showed perioperative durvalumab improved EFS across baseline clusters but least in C2 (C1 HR 0.43; C2 HR 0.90; C3 HR 0.41); at surgery, the “immune desert” phenotype carried the worst prognosis (36-mo EFS 27.8% vs 55.7% vs 77.2% for C1 vs C2 vs C3). Neoadjuvant durvalumab shifted surgical specimens away from poor-prognosis C1 (C1 at surgery 17.9% with durvalumab vs 47.2% with placebo), and among patients with immune-activated C3 at surgery, the durvalumab EFS effect was especially large (HR 0.16; 95% CI 0.03–0.79), a biomarker story that could help refine perioperative PD-(L)1 selection beyond “one-size-fits-all” approaches (vs current perioperative anti–PD-1 SOC pembrolizumab EFS HR 0.58 in KEYNOTE-671, and neoadjuvant-only nivolumab+chemo EFS HR 0.63 in CheckMate 816).