Abstract
BACKGROUND: Brain metastases are common in EGFR-mutant NSCLC (EGFR+LC), with >30% of patients experiencing CNS progression despite initial response to first-line Osimertinib. While CNS-penetrant TKIs offer initial intracranial control, the benefit of consolidative stereotactic radiosurgery (SRS) remains uncertain, especially in patients with residual Brain Metastases after TKI induction. Retrospective studies suggest SRS may improve intracranial outcomes in high-risk patients with lesions >1cm. ICON-RT prospectively evaluates this strategy while integrating molecular biomarkers of resistance through serial plasma profiling. METHODS: ICON-RT (Intracranial CONsolidation with RT) is a single-center, randomized phase 2 trial enrolling 56 patients with EGFR+LC and at least one metastasis >1cm who fail to achieve complete response after 3 months of Osimertinib. Eligible patients are randomized 1:1 to: Arm A: Consolidative SRS to residual metastases + continued Osimertinib andArm B: Continued Osimertinib with deferred SRS at salvage. PRIMARY ENDPOINT: Intracranial progression-free survival (iPFS) at 9 months post-randomization (RANO-BM). SECONDARY ENDPOINTS: Overall PFS, time-to-CNS progression, OS, time-to-TKI discontinuation, SRS-related toxicity. TRANSLATIONAL AIMS: Tumor tissue will undergo single-cell whole-genome sequencing (scWGS) using DLP+ to define clonal structure and identify clone-specific SVs. Duplex sequencing of cfDNA enables personalized, longitudinal clonal tracking to identify drug-resistant subclones. Plasma-derived cfRNA will be profiled using RARE-Seq. Differential expression analyses will explore resistance signatures (EMT, MAPK, MET amplification, SCLC transformation). Integrated cfDNA/cfRNA analysis will reveal CNS-specific resistance pathways and biomarkers to personalize SRS timing. TRIAL ACTIVATION: October 2024. Enrollment target: 56 patients over 24 months. Conducted at Memorial Sloan Kettering Cancer Center under IRB#. 24-378