Salvage dacomitinib plus intraventricular pemetrexed for leptomeningeal metastasis after failure of third‑generation EGFR‑TKIs in EGFR‑mutant NSCLC: an ambispective cohort study.

BACKGROUND: In patients with EGFR-mutant non–small cell lung cancer (NSCLC), leptomeningeal metastasis (LM) following progression on third-generation EGFR tyrosine kinase inhibitors (TKIs) remains a life-threatening complication. METHODS: In this ambispective cohort study, we included 21 patients with LM who progressed after third-generation EGFR-TKI therapy and subsequently received salvage treatment with dacomitinib combined with intraventricular chemotherapy (IVC) via an Ommaya reservoir. The primary outcome was intracranial progression-free survival (iPFS); secondary outcomes included intracranial disease control rate (iDCR), intracranial objective response rate (iORR), overall survival (OS), and safety. RESULTS: According to RANO-LM criteria, the median iPFS was 4.44 months, the iDCR was 81.0% (17/21), and the iORR was 19.0% (4/21). Patients harboring uncommon or compound EGFR mutations (n = 11) demonstrated longer median iPFS compared with those carrying L858R or exon 19 deletions (7.98 vs. 3.12 months). The 6-month OS rate was 78.1%. Improvements in performance status, neurological examination findings, and clinical symptoms were observed in 42.9%, 57.1%, and 71.4% of patients, respectively. The regimen was tolerable; the most common adverse events were diarrhea (61.9%, including one grade 3 event) and neutropenia (52.4%, with 19.0% grade ≥ 3), and no treatment-related deaths occurred. CONCLUSION: These findings suggest that dacomitinib combined with IVC may represent a feasible salvage therapy for TKI-resistant LM in patients with NSCLC, with potentially enhanced benefits in those with uncommon or compound EGFR genotypes.