Abstract 1138: Clinical grade circulating tumor DNA methylation predicts outcome to brigatinib plus local consolidative therapy in patients with ALK rearranged NSCLC - Liquid biopsy correlates from the BRIGHTSTAR trial

Abstract Background: The phase II BRIGHTSTAR trial assessing the combination of brigatinib with local consolidative therapy in patients with ALK rearranged non-small cell lung cancer demonstrated promising clinical activity with a 5-year progression-free survival rate of 51% (Elamin et al. WCLC. 2025). To better characterize patients that would benefit of this treatment regimen, we performed clinical grade ctDNA methylation analysis for the detection of residual disease and prognostic. Methods: We profiled 84 samples from 29 patients with stage IV or recurrent non-small cell lung cancer (NSCLC) and confirmed ALK rearrangement that were treated with local consolidative therapy (LCT) and brigatinib (BRIGHTSTAR; NCT03707938). Sample timepoints included baseline prior to therapy, at 8 weeks of brigatinib induction prior to local consolidative therapy (Pre-LCT) as well as after local consolidative therapy (Post-LCT) and at progression. Samples were profiled using the Guardant INFINITY platform for the detection of ctDNA using DNA methylation. Data was correlated to progression-free survival on treatment using Kaplan-Meier analysis and cox proportional hazard ratio. Results: Circulating tumor DNA was persistently detected across timepoints with detection rates of 72% (N = 21/29) at baseline, 39% Pre-LCT (N = 11/28), 29% Post-LCT (N = 7/24) and 80% at progression (N = 4/5) demonstrating insufficient ctDNA clearing by brigatinib plus LCT treatment regimen. However, patients without detectable ctDNA at baseline using the DNA methylation classifier (ctDNAMETH) had significantly longer progression-free survival compared to patients with detectable ctDNA (38.2 months versus not reached; log-rank p = 0.04; HR = 0.16 (95% CI: 0.02-1.19)). No statistically significant difference in outcome was reported for patients who clear ctDNA Pre- or Post-LCT and patients with persistently detected ctDNA compared to pretreatment timepoint. Conclusions: Clinical grade ctDNA methylation analysis allows the sensitive detection of ctDNA in patients with ALK rearranged NSCLC and is prognostic of outcome to brigatinib plus LCT therapy. Citation Format: Simon Heeke, Saumil Gandhi, Hai T. Tran, Lauren Averett Byers, Don Gibbons, Carl M. Gay, Mehmet Altan, Mara B. Antonoff, Xiuning Le, Janet Tu, Anne S. Tsao, Tina Cascone, Marcelo V. Negrao, George R. Blumenschein, John V. Heymach, Yasir Y. Elamin. Clinical grade circulating tumor DNA methylation predicts outcome to brigatinib plus local consolidative therapy in patients with ALK rearranged NSCLC - Liquid biopsy correlates from the BRIGHTSTAR trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1138.