Multimodality salvage treatment incorporating ivonescimab plus chemotherapy for EGFR-mutated NSCLC with leptomeningeal metastases after dose-escalated third-generation EGFR-TKI failure: a retrospective study

Background Leptomeningeal metastasis (LM) is among the most devastating modes of progression in EGFR-mutated non-small cell lung cancer (NSCLC). Although dose escalation of third-generation EGFR-TKIs has been an important central nervous system (CNS)-directed salvage strategy, therapeutic options after progression on this intensification approach remain limited. Methods This single-center retrospective study included consecutive patients treated between September 2024 and December 2025. Eligible patients were adults (≥18 years) with histologically confirmed lung adenocarcinoma, a documented EGFR mutation, and LM diagnosed by gadolinium-enhanced MRI or positive cerebrospinal fluid (CSF) cytology. Patients received ivonescimab plus chemotherapy after documented intracranial or extracranial progression on a dose-escalated third-generation EGFR-TKI regimen used for LM management, with or without concurrent CSF-directed therapy. Ivonescimab was given intravenously at 20 mg/kg every 3 weeks with chemotherapy selected according to prior treatment and clinical status. The primary endpoints were overall survival (OS) and LM progression-free survival (LM-PFS). Results Of 517 screened patients, 33 initiated ivonescimab plus chemotherapy and comprised the overall treated cohort. Concurrent intrathecal or intraventricular chemotherapy was administered to 29 of 33 patients (87.9%). The median age was 61 years (IQR 56–62); 24 (72.7%) were female; 24 (72.7%) had baseline ECOG performance status of 2–3. The median number of prior therapy lines was 4 (IQR 3–6). At a median follow-up of 8.28 months, median OS was 8.54 months (95% CI 5.75–14.32), median LM-PFS was 6.54 months (95% CI 3.42–11.86), and median systemic PFS was 4.83 months (95% CI 2.79–7.56). Three-month treatment persistence was 64.4% (95% CI 44.9–78.6). Among 29 patients evaluable for LM response, 6 achieved a response, yielding an LM response rate of 20.7% (95% CI 8.0–39.7) and an LM disease control rate of 82.8% (95% CI 64.2–94.2). Among 31 patients with evaluable safety documentation, grade ≥3 treatment-related adverse events occurred in 14 (45.2%), most commonly hematologic toxicities. No permanent ivonescimab discontinuation due to toxicity was documented. Conclusions This cohort provides real-world outcome data for patients with EGFR-mutated NSCLC and LM receiving multimodality salvage treatment incorporating ivonescimab plus chemotherapy after dose-escalated third-generation EGFR-TKI failure.