Clinical and molecular characteristics of early progressors (EPs) and long-term progression-free survivors (LTPs) from the phase 3 ADRIATIC trial of consolidation durvalumab (D) vs placebo (P) after concurrent chemoradiotherapy (cCRT) in limited-stage small-cell lung cancer (LS-SCLC).

8014 Background: At the first planned interim analysis of ADRIATIC, consolidation D significantly improved the dual primary endpoints of overall and progression-free survival (PFS) vs P in patients (pts) with LS-SCLC and no progression after cCRT. We assess clinical characteristics, patterns of progression, and associated molecular biomarkers in EPs (pts with PFS <6 mos) and LTPs (PFS or censored after >12 mos) in the D and P arms. Methods: Pts with stage I–III LS-SCLC, WHO performance status (PS) 0/1, and no progression after cCRT were randomized to D (n=264), D + tremelimumab (n=200; arm still blinded), or P (n=266) for up to 24 months. Pre-cCRT tumor samples were collected at screening and immune-related biomarkers (CD8, MHC I, PD-L1, T-cell inflamed signature [TIS], CD8A , and STING pathway) were assessed by immunohistochemistry or RNA sequencing for their role in response to immunotherapy (IO). Results: At data cutoff (15 Jan 2024), 83 (31.4%) and 113 (42.8%) pts in the D arm and 97 (36.5%) and 100 (37.6%) in the P arm were EPs and LTPs, respectively. For EPs and LTPs, respectively: 67.5% and 61.1% in the D arm and 74.2% and 72.0% in the P arm were male; 44.6% and 54.9% in the D arm and 51.5% and 48.0% in the P arm had WHO PS 0; and 90.4% and 89.4% in the D arm and 91.8% and 89.0% in the P arm were current/former smokers. Among EPs, 47.0% vs 45.4% had extrathoracic (ET) only progression, 43.4% vs 43.3% had intrathoracic (IT) only progression, and 6.0% vs 1.0% died without progression in the D vs P arms, respectively. Among LTPs, 16.8% and 25.0% of pts in the D and P arms had progression events, which were mostly IT (D: 14.2%; P: 16.0%). Similar rates of PD-L1+ tumors were observed in EPs and LTPs in both arms (Table). Trends for higher TIS and STING pathway expression were seen in LTPs vs EPs in the D arm but not the P arm. CD8 density, and CD8A and MHC I expressions were lower in EPs vs LTPs in both arms, regardless of D vs P (Table). Conclusions: Exploratory analyses suggest similar rates of IT and ET progression with D and P in EPs, but mostly IT progression in LTPs. Compared with EPs, LTPs were generally characterized by a pre-cCRT tumor microenvironment more conducive to fostering an IO response, with higher antigen presentation and cytotoxic marker expression potentially enhancing D’s mechanism of action. Clinical trial information: NCT03703297 . D, EPs P, EPs D, LTPs P, LTPs PD-L1 TC or IC ≥1%, n (%) 25 (52.1) 32 (55.2) 40 (56.3) 42 (61.8) MHC I n, median TC score* (%) 42, 65.0 46, 75.0 66, 77.5 56, 80.0 CD8 density n, median cells/mm 2 39, 46.7 43, 50.7 57, 94.2 53, 78.7 RNASeq BEP, n 17 27 29 24 CD8A expression † 1.1 1.1 1.3 1.7 TIS value † 2.3 3.1 3.2 3.4 STING signature value † 0.28 1.4 0.90 1.4 *% MHC I-positive TCs in the total tumor area. † Median. BEP, biomarker-evaluable population; TC, tumor cell; IC, immune cell.

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