Abstract 3776: Association of baseline ctDNA <i>EGFR</i> mutation detection with clinical outcome in the phase II RAMOSE trial assessing ramucirumab plus osimertinib versus osimertinib in <i>EGFR</i> mutant non-small cell lung cancer

Abstract Background: While third-generation EGFR TKIs such as osimertinib have improved outcomes in EGFR-mutant non-small cell lung cancer (NSCLC), responses remain transient, and resistance develops often. We recently reported primary efficacy results from the phase II RAMOSE trial showing that the combination of osimertinib with the VEGFR2 antagonist ramucirumab improved progression-free survival (PFS) over osimertinib monotherapy (24.8 months [mo] vs 15.6 mo, HR 0.55 (95% CI, 0.32-0.93, p=0.023), establishing this regimen as a promising approach to improve clinical outcomes. However, biomarker strategies are needed to guide optimal treatment decisions and allow for personalized therapy stratification. Therefore, we explore EGFR mutation detection from blood plasma at baseline in patients enrolled in the RAMOSE trial. Methods: The randomized, open-label multicenter phase II RAMOSE trial (NCT03909334, HCRN LUN-18-335) compared osimertinib with ramucirumab to osimertinib for frontline treatment of metastatic EGFR-mutant NSCLC. Blood plasma was collected at baseline (BL). Circulating-tumor DNA (ctDNA) for analysis was isolated from up to 4ml of blood plasma using the Genexus purification system. EGFR mutations were analyzed using the Oncomine Precision Assay on the Ion Torrent Genexus System. EGFR mutations were assessed by variant allele frequency (VAF) and correlated to clinical outcomes, including PFS and OS. Results: Eight-six patient samples were sequenced, and 81 (94%) yielded positive sequencing results at BL. No statistically significant differences in BL EGFR detection were detected between the two treatment arms (χ2 p = 0.33). EGFR mutations at any VAF were detected in 68/81 patients (84%). Patients with EGFR VAF &amp;lt; 0.5% had significantly longer PFS (17.9mo vs not reached; p = 0.016; HR = 0.37) and OS (33.4mo vs not reached; p = 0.028; HR = 0.14) compared to patients with VAF &amp;gt; 0.5%. In patients without detectable EGFR mutations at BL, no death occurred during median follow up of 21.4mo (OS p = 0.076). In patients with detectable EGFR mutation at BL, the PFS was 19.9 mo in combination arm versus 16.0 mo in the osimertinib arm (HR = 0.69, p = 0.3). Conclusion: Detection of EGFR mutations from blood plasma at baseline was prognostic of clinical outcome and associated with significantly shorter PFS and OS. Detection of EGFR VAF by liquid biopsy can identify patients with higher risk of treatment progression and warrants further investigation for stratification of patients to future clinical trials. Citation Format: Simon Heeke, Dzifa Duose, Srividya Arjuna, Monique Nilsson, Jyoti Patel, Elaine Shum, Christina Baik, Rachel Sanborn, Catherine Shu, Chul Kim, Mary Jo Fidler, Richard Hall, Jhanelle Gray, Andreas Saltos, John V. Heymach, Xiuning Le. Association of baseline ctDNA EGFR mutation detection with clinical outcome in the phase II RAMOSE trial assessing ramucirumab plus osimertinib versus osimertinib in EGFR mutant non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3776.