Furmonertinib in uncommon <scp>EGFR</scp>‐mutated non‐small cell lung cancer with central nervous system metastases: A retrospective cohort study

Uncommon EGFR mutations constitute 10%-20% of all EGFR mutations in non-small cell lung cancer (NSCLC), forming a molecularly distinct and clinically heterogeneous subgroup. This retrospective cohort study evaluated the efficacy and safety of furmonertinib in managing central nervous system (CNS) metastases among NSCLC patients with uncommon EGFR mutations (excluding exon 20 insertion variants). Thirty-one eligible patients treated at the Affiliated Brain Hospital of Nanjing Medical University between March 2022 and August 2024 were enrolled. Serial cerebrospinal fluid (CSF) samples were subjected to next-generation sequencing for circulating tumor DNA (ctDNA) profiling. Clinical endpoints included CNS objective response rate (ORR), disease control rate (DCR), intracranial progression-free survival (iPFS), overall survival (OS), and safety parameters. The cohort demonstrated a CNS ORR of 38.7% (95% CI, 21.8%-57.8%) and DCR of 64.5% (95% CI, 45.4%-80.8%), with a median iPFS of 6.97 months. Median OS remained immature at data cutoff. A total of 21 patients with leptomeningeal metastases had baseline EGFR-mutant ctDNA detected in their CSF, with ctDNA analysis indicating intracranial responses corresponded to decreased or cleared ctDNA abundance. Longitudinal CSF ctDNA monitoring in a representative case demonstrated significant temporal correlation between molecular response and radiographic/clinical improvement. The safety profile was favorable, with no grade ≥4 adverse events or treatment-related mortality. These findings suggest that furmonertinib provides clinically meaningful CNS activity with acceptable toxicity in uncommon EGFR-mutant NSCLC, particularly when integrated with CSF ctDNA dynamics as a potential pharmacodynamic biomarker. This study highlights the therapeutic implications of third-generation EGFR-TKIs in molecularly defined NSCLC subpopulations.