Firmonertinib 160mg in EGFR-Mutated NSCLC with Brain Metastases After EGFR-TKI Resistance (iFORCE): Clinical Outcomes and Mechanistic Insights
Mengxing You, Tongji Xie, Lige Wu, Jiayu Liu, Yan Li, Qi Wang, Jie Zhang, Zihe Wang, Ran Gao, Xuezhi Hao, Junling Li, Puyuan XingAbstract
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.