Firmonertinib 160mg in EGFR-Mutated NSCLC with Brain Metastases After EGFR-TKI Resistance (iFORCE): Clinical Outcomes and Mechanistic Insights

Background Brain metastases (BM) are frequent in EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC) and remain challenging after prior EGFR tyrosine kinase inhibitor (TKI) therapy. This exploratory study evaluated high-dose fimmonertinib and explored subtype-specific spatial biology. Methods iFORCE was a prospective, single-center, single-arm study. Eligible patients had advanced NSCLC harboring EGFR mutations with previously treated BM following EGFR-TKI therapy, or intracranial disease progression. Patients received 160 mg firmonertinib once daily. The primary endpoint was intracranial progression-free survival (iPFS). Archival paired primary tumors and BM specimens from an independent retrospective cohort underwent exploratory digital spatial profiling (DSP). Results Twenty-three patients were enrolled. At a median follow-up of 19.7 months (95% CI, 14.5-25.3), median iPFS was 14.6 months (95% CI, 4.2-not estimable [NE]), with 12- and 18-month iPFS rates of 53.8% and 46.1%, respectively. Based on the best intracranial overall response, intracranial objective response and disease control rates were 34.8% (95% CI, 16.4-57.3) and 91.3% (95% CI, 72.0-98.9). Median systemic PFS was 10.7 months (95% CI, 3.9-NE). Treatment-related adverse events occurred in 13 (56.5%) patients, mostly grade 1; one patient (4.3%) developed grade 3 stomatitis. No treatment discontinuations or treatment-related deaths were observed. DSP revealed distinct EGFR subtype–specific BM ecosystems: exon 19 deletion tumors retained immune-enriched inflammatory programs, whereas L858R-mutated tumors showed tumor-intrinsic cell-cycle, DNA-repair, RNA-splicing, apoptosis-resistance, and immune-evasion features. Conclusions Fimonertinib 160 mg showed promising intracranial activity with a manageable safety profile in EGFR-TKI-treated EGFRm NSCLC with BM. L858R BM displayed tumor-intrinsic, microenvironment-independent biology, suggesting preferential sensitivity to high-dose firmonertinib.