Abstract A049: Impact of Actionable Genomic Alterations (AGA) on the Efficacy of Durvalumab in Patients with Locally Advanced NSCLC Treated with Concurrent Chemoradiotherapy

Abstract Introduction: Durvalumab improves survival after platinum-based chemoradiotherapy in stage III NSCLC. However, conflicting data exist regarding its efficacy across molecular subgroups not evaluated in the PACIFIC trial. We analyzed whether the presence of distinct actionable genomic alterations (AGA) influences progression-free survival (PFS) with durvalumab, adjusting for key clinical factors. Methods: This single-institution retrospective study included patients with unresectable, non-metastatic, locally advanced non–small cell lung cancer (NSCLC) diagnosed between June 2017 and September 2024. All received platinum-based concurrent chemoradiotherapy followed by durvalumab, an anti–PD-L1 immune checkpoint inhibitor (ICI). Only patients with NGS data were included. Based on historical data from metastatic NSCLC cohorts (as the IMMUNOTARGET registry), patients with AGA were grouped by IO sensitivity based on ORR: IO-sensitive with ORR ≥20% (KRAS, BRAF) with consistent benefit; IO-intermediate with ORR 10–19% (FGFR, ERBB2, MET) with mixed evidence; and IO-resistant with ORR <10% (EGFR, RET, ROS1, ALK), generally linked to poor or negative recommendations of ICI. PFS was calculated from the first durvalumab dose to progression, death, or last follow-up. Survival was analyzed using the Kaplan–Meier method. A multivariable Cox model adjusted for age, sex, stage, and PD-L1 was used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). Proportional hazards assumptions were assessed. Results: A total of 384 patients were analyzed, with the most frequent alterations among AGA patients being KRAS (54.3%), FGFR (17.3%), MET (8.7%), BRAF (7.2%), ERBB2 (5.8%), EGFR (2.9%), RET (2.4%), ROS1 (1%), and ALK (0.5%). Significant differences were observed between AGA and non-AGA groups in age, ECOG status, or tumor mutational burden (TMB), while sex, smoking history, race, histology and PD-L1 levels were differed significantly. Median PFS was 24.3 months (95% CI: 15.2–36.1 in the non-AGA group, versus 19.2 months (95% CI: 13.5-24.3) in the IO-sensitive group, 10.2 months (95% CI: 7.4-19.7) in the IO-intermediate group, and 5.3 months (95% CI: 4.3–NA) in the IO-resistant group. In the multivariable Cox model, the risk of progression was significantly higher in IO-resistant patients (HR 3.49; 95% CI: 1.73–7.07; p < 0.001), IO-intermediate patients (HR 1.75; 95% CI: 1.22–2.5; p < 0.01), and IO-sensitive patients (HR 1.72; 95% CI: 1.20–2.46; p < 0.01) compared with non-AGA patients. No significant differences in OS were found between groups. Conclusions: The presence of AGA predicted PFS in patients treated with chemoradiotherapy followed by durvalumab, identifying a subgroup (IO-resistant) with no apparent benefit from immunotherapy. IO-sensitive alterations and absence of AGA were associated with improved outcomes, supporting their potential role as predictive markers for durvalumab benefit. Citation Format: Jaime Rubio-Perez, Sameh Daher, Kathryn Arbour, Alexander Drilon. Impact of Actionable Genomic Alterations (AGA) on the Efficacy of Durvalumab in Patients with Locally Advanced NSCLC Treated with Concurrent Chemoradiotherapy [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A049.