{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T17:26:11Z","timestamp":1793813171137,"version":"4.6.1"},"reference-count":38,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T00:00:00Z","timestamp":1792454400000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"the Medical Oncology Innovation Team of Cancer Hospital Chinese Academy of Medical Sciences"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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 firmonertinib and explored subtype-specific spatial biology.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Twenty-three patients were enrolled. At a median follow-up of 19.7 months (95% CI, 14.5-5.3), 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; 1 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Firmonertinib 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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/neuonc\/noag260","type":"journal-article","created":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T09:43:59Z","timestamp":1792489439000},"source":"Crossref","is-referenced-by-count":0,"title":["Firmonertinib 160 mg in EGFR-mutated non-small cell lung cancer with brain metastases after EGFR-tyrosine kinase inhibitor resistance (iFORCE): Clinical outcomes and mechanistic insights"],"prefix":"10.1093","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5579-3023","authenticated-orcid":false,"given":"Mengxing","family":"You","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, National Cancer Center\/National Clinical Research Center for Cancer\/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College , 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