{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T05:54:09Z","timestamp":1791179649640,"version":"4.1.0"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T00:00:00Z","timestamp":1791158400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004826","name":"Natural Science Foundation of Beijing Municipality","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004826","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009331","name":"Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100009331","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100018904","name":"Beijing Xisike Clinical Oncology Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100018904","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This single-center retrospective study included consecutive patients treated between September 2024 and December 2025. Eligible patients were adults (\u226518 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).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>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\u201362); 24 (72.7%) were female; 24 (72.7%) had baseline ECOG performance status of 2\u20133. The median number of prior therapy lines was 4 (IQR 3\u20136). At a median follow-up of 8.28 months, median OS was 8.54 months (95% CI 5.75\u201314.32), median LM-PFS was 6.54 months (95% CI 3.42\u201311.86), and median systemic PFS was 4.83 months (95% CI 2.79\u20137.56). Three-month treatment persistence was 64.4% (95% CI 44.9\u201378.6). Among 29 patients evaluable for LM response, 6 achieved a response, yielding an LM response rate of 20.7% (95% CI 8.0\u201339.7) and an LM disease control rate of 82.8% (95% CI 64.2\u201394.2). Among 31 patients with evaluable safety documentation, grade \u22653 treatment-related adverse events occurred in 14 (45.2%), most commonly hematologic toxicities. No permanent ivonescimab discontinuation due to toxicity was documented.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1973923","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T05:32:47Z","timestamp":1791178367000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["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"],"prefix":"10.3389","volume":"17","author":[{"given":"Qichao","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Oncology, Beijing Tiantan Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Qiu","sequence":"additional","affiliation":[{"name":"Department of Oncology, Beijing Tiantan Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"An","sequence":"additional","affiliation":[{"name":"Department of Oncology, Beijing Tiantan Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiran","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Oncology, Beijing Tiantan Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaosheng","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Oncology, Beijing Tiantan Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Oncology, Beijing Tiantan Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yichun","family":"Hua","sequence":"additional","affiliation":[{"name":"Department of Oncology, Beijing Tiantan Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xixi","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Oncology, Beijing Tiantan Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yijia","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Oncology, Beijing Tiantan Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beihe","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Oncology, Beijing Tiantan Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Oncology, Beijing Tiantan Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,10,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2016.06.029","article-title":"Leptomeningeal metastases in patients with NSCLC with EGFR mutations","volume":"11","author":"Li","year":"2016","journal-title":"J Thorac Oncol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/noae103","article-title":"Leptomeningeal metastases from solid tumors: A Society for Neuro-Oncology and American Society of Clinical Oncology consensus review on clinical management and future directions","volume":"26","author":"Wilcox","year":"2024","journal-title":"Neuro Oncol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.esmoop.2023.101624","article-title":"Leptomeningeal metastasis from solid tumours: EANO-ESMO clinical practice guideline for diagnosis, treatment and follow-up","volume":"8","author":"Le Rhun","year":"2023","journal-title":"ESMO Open"},{"key":"B4","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1007\/s11864-020-00759-3","article-title":"Leptomeningeal metastases in non-small cell lung cancer: Optimal systemic management in NSCLC with and without driver mutations","volume":"21","author":"Alexander","year":"2020","journal-title":"Curr Treat Options Oncol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2025.09.140","article-title":"The evolving landscape of leptomeningeal metastases from NSCLC: An international, contemporary, multicenter cohort study","volume":"37","author":"Zheng","year":"2026","journal-title":"Ann Oncol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/noaa298","article-title":"Prognostic validation and clinical implications of the EANO ESMO classification of leptomeningeal metastasis from solid tumors","volume":"23","author":"Le Rhun","year":"2021","journal-title":"Neuro Oncol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1007\/BF02341153","article-title":"Leptomeningeal metastases: Comparison of clinical features and laboratory data of solid tumors, lymphomas and leukemias","volume":"9","author":"Kaplan","year":"1990","journal-title":"J Neuro-Oncol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410170121","article-title":"Leptomeningeal metastases: Reduction in regional cerebral blood flow and cognitive impairment","volume":"17","author":"Siegal","year":"1985","journal-title":"Ann Neurol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1212\/wnl.41.11.1765","article-title":"Leptomeningeal metastases: 111indium-DTPA CSF flow studies","volume":"41","author":"Chamberlain","year":"1991","journal-title":"Neurology"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/noab101","article-title":"Epidemiology of brain metastases and leptomeningeal disease","volume":"23","author":"Lamba","year":"2021","journal-title":"Neuro Oncol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1002\/cncr.30911","article-title":"Leptomeningeal metastasis from systemic cancer: Review and update on management","volume":"124","author":"Wang","year":"2018","journal-title":"Cancer"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctrv.2016.12.006","article-title":"Leptomeningeal carcinomatosis in non-small cell lung cancer patients: A continuing challenge in the personalized treatment era","volume":"53","author":"Remon","year":"2017","journal-title":"Cancer Treat Rev"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(17)30689-7","article-title":"Leptomeningeal metastases in non-small-cell lung cancer","volume":"19","author":"Cheng","year":"2018","journal-title":"Lancet Oncol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1016\/j.jtho.2024.09.1385","article-title":"High-dose furmonertinib in patients with EGFR-mutated NSCLC and leptomeningeal metastases: A prospective real-world study","volume":"20","author":"Chen","year":"2025","journal-title":"J Thorac Oncol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2019.05.007","article-title":"Activity of EGFR tyrosine kinase inhibitors in NSCLC with refractory leptomeningeal metastases","volume":"14","author":"Flippot","year":"2019","journal-title":"J Thorac Oncol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.2886","article-title":"A phase I trial of high dose gefitinib for patients with leptomeningeal metastases from non-small cell lung cancer","volume":"6","author":"Jackman","year":"2015","journal-title":"Oncotarget"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/nor121","article-title":"Pulsatile\" high-dose weekly erlotinib for CNS metastases from EGFR mutant non-small cell lung cancer","volume":"13","author":"Grommes","year":"2011","journal-title":"Neuro Oncol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1007\/s11060-010-0128-6","article-title":"High dose weekly erlotinib achieves therapeutic concentrations in CSF and is effective in leptomeningeal metastases from epidermal growth factor receptor mutant lung cancer","volume":"99","author":"Clarke","year":"2010","journal-title":"J Neuro-Oncol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.19.00457","article-title":"Osimertinib in patients with epidermal growth factor receptor mutation-positive non-small-cell lung cancer and leptomeningeal metastases: The BLOOM study","volume":"38","author":"Yang","year":"2020","journal-title":"J Clin Oncol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.24.00708","article-title":"Phase II efficacy and safety of 80 mg osimertinib in patients with leptomeningeal metastases associated with epidermal growth factor receptor mutation-positive non-small cell lung cancer (BLOSSOM)","volume":"42","author":"Park","year":"2024","journal-title":"J Clin Oncol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.esmoop.2026.107743","article-title":"Furmonertinib-based triplet therapy improves survival in EGFR-mutant NSCLC with leptomeningeal metastases: A large-scale multicenter retrospective study (FURMO-LM)","volume":"11","author":"Chen","year":"2026","journal-title":"ESMO Open"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2024.10613","article-title":"Ivonescimab plus chemotherapy in non-small cell lung cancer with EGFR variant: A randomized clinical trial","volume":"332","author":"Fang","year":"2024","journal-title":"JAMA"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.esmoop.2026.106322","article-title":"15P intracranial (IC) efficacy of ivonescimab (ivo) plus chemotherapy (chemo) in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-resistant, EGFR-mutated non-small cell lung cancer (NSCLC) in the HARMONi study [conference abstract","volume":"11","author":"Le","year":"2026","journal-title":"ESMO Open"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1007\/s11060-020-03617-2","article-title":"Diagnostic accuracy of MR imaging of patients with leptomeningeal seeding from lung adenocarcinoma based on 2017 RANO proposal: Added value of contrast-enhanced 2D axial T2 FLAIR","volume":"149","author":"Seong","year":"2020","journal-title":"J Neuro-Oncol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2019.00838","article-title":"A pilot phase 1 study of intrathecal pemetrexed for refractory leptomeningeal metastases from non-small-cell lung cancer","volume":"9","author":"Pan","year":"2019","journal-title":"Front Oncol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2025.1543416","article-title":"The efficacy and safety of intrathecal pemetrexed for leptomeningeal metastasis from non-small cell lung cancer: A single-arm meta-analysis of Chinese patients","volume":"15","author":"Zhao","year":"2025","journal-title":"Front Oncol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.esmoop.2024.102384","article-title":"Efficacy and safety of intrathecal pemetrexed for TKI-failed leptomeningeal metastases from EGFR+ NSCLC: An expanded, single-arm, phase II clinical trial","volume":"9","author":"Fan","year":"2024","journal-title":"ESMO Open"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1007\/s11060-024-04716-0","article-title":"High-dose furmonertinib combined with intraventricular chemotherapy as salvage therapy for leptomeningeal metastasis from EGFR exon 20 insertion-mutated lung cancer","volume":"169","author":"Yu","year":"2024","journal-title":"J Neuro-Oncol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2021.04.018","article-title":"Efficacy and safety of intrathecal pemetrexed combined with dexamethasone for treating tyrosine kinase inhibitor-failed leptomeningeal metastases from EGFR-mutant NSCLC-a prospective, open-label, single-arm phase 1\/2 clinical trial (Unique Identifier: ChiCTR1800016615)","volume":"16","author":"Fan","year":"2021","journal-title":"J Thorac Oncol"},{"key":"B30","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1097\/JTO.0b013e318287c943","article-title":"Analysis of treatment outcomes of intraventricular chemotherapy in 105 patients for leptomeningeal carcinomatosis from non-small-cell lung cancer","volume":"8","author":"Gwak","year":"2013","journal-title":"J Thorac Oncol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/now183","article-title":"Leptomeningeal metastases: A RANO proposal for response criteria","volume":"19","author":"Chamberlain","year":"2017","journal-title":"Neuro Oncol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(15)70057-4","article-title":"Response assessment criteria for brain metastases: Proposal from the RANO group","volume":"16","author":"Lin","year":"2015","journal-title":"Lancet Oncol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2008.10.026","article-title":"New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1)","volume":"45","author":"Eisenhauer","year":"2009","journal-title":"Eur J Cancer"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2019.12.113","article-title":"Osimertinib for patients with leptomeningeal metastases associated with EGFR T790M-positive advanced NSCLC: The AURA leptomeningeal metastases analysis","volume":"15","author":"Ahn","year":"2020","journal-title":"J Thorac Oncol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2020.06.018","article-title":"Osimertinib improves overall survival in patients with EGFR-mutated NSCLC with leptomeningeal metastases regardless of T790M mutational status","volume":"15","author":"Lee","year":"2020","journal-title":"J Thorac Oncol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.3779\/j.issn.1009-3419.2025.106.23","article-title":"Efficacy and safety evaluation of intrathecal pemetrexed in EGFR-mutated NSCLC patients with leptomeningeal metastases","volume":"28","author":"Zhang","year":"2025","journal-title":"Zhongguo Fei Ai Za Zhi"},{"key":"B37","doi-asserted-by":"publisher","first-page":"651","DOI":"10.1186\/s12885-026-15915-5","article-title":"Real-world evidence for first-line intrathecal pemetrexed in leptomeningeal metastases from solid tumors: A retrospective cohort study","volume":"26","author":"Wang","year":"2026","journal-title":"BMC Cancer"},{"key":"B38","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1016\/j.annonc.2023.10.117","article-title":"Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: Primary results from the phase III MARIPOSA-2 study","volume":"35","author":"Passaro","year":"2024","journal-title":"Ann Oncol"},{"key":"B39","doi-asserted-by":"publisher","first-page":"103505","DOI":"10.1016\/j.jtho.2025.10.012","article-title":"Phase 2 study of amivantamab plus lazertinib in previously treated patients with EGFR-mutant lung cancers with brain and leptomeningeal metastases","volume":"21","author":"Chen","year":"2026","journal-title":"J Thorac Oncol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1200\/JCO-24-01349","article-title":"Datopotamab deruxtecan in advanced or metastatic non-small cell lung cancer with actionable genomic alterations: Results from the phase II TROPION-Lung05 study","volume":"43","author":"Sands","year":"2025","journal-title":"J Clin Oncol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.22.01148","article-title":"Randomized phase II trial of proton craniospinal irradiation versus photon involved-field radiotherapy for patients with solid tumor leptomeningeal metastasis","volume":"40","author":"Yang","year":"2022","journal-title":"J Clin Oncol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1973923\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T05:32:50Z","timestamp":1791178370000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1973923\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,5]]},"references-count":41,"alternative-id":["10.3389\/fimmu.2026.1973923"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1973923","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,5]]},"article-number":"1973923"}}