Activity of EGFR Tyrosine Kinase Inhibitors in NSCLC With Refractory Leptomeningeal Metastases

Ronan Flippot, Pamela Biondani, Edouard Auclin, Dingyu Xiao, Lizza Hendriks, Emilie Le Rhun, Charlotte Leduc, Michele Beau-Faller, Radj Gervais, Jordi Remon, Julien Adam, David Planchard, Pernelle Lavaud, Charles Naltet, Caroline Caramella, Cecile Le Pechoux, Ludovic Lacroix, Anas Gazzah, Laura Mezquita, Benjamin Besse*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Introduction: Leptomeningeal metastases (LMs) are associated with dismal prognosis in NSCLC. Optimal management remains unknown in patients with EGFR-mutated NSCLC after initial tyrosine kinase inhibitor (TKI) failure.

Methods: We conducted a multicenter retrospective study including patients with EGFR-mutated NSCLC and LM. TKI failure was defined as diagnosis of LM on TKI, or progression of known LM on TKI.

Results: Ninety-two patients were included, median age of 60 years, predominantly female (68%), never-smokers (74%). EGFR mutations included L858R (45%), exon 19 deletions (28%), or other mutations (14%). Median time to LM diagnosis was 18.5 months after initial diagnosis of advanced NSCLC. LM was diagnosed after a median of 2 (range: 0-9) systemic therapies. Median overall survival from LM diagnosis was 6.1 months (95% confidence interval [ CI]: 4.2-7.6 months). Among 87 patients with TKI failure, patients rechallenged with TKI (n = 50) had a median LM overall survival of 7.6 months (95% CI: 5.7-10.9) compared to 4.2 months (95% CI: 1.6-6.7) in patients without further therapy. Overall, 60% of patients rechallenged with TKI experienced clinical benefit (clinical response or stable disease >2 months), and 23% were treatment failure-free at 6 months. Clinical benefit was reported in 11 of 20 (55%) patients treated with erlotinib after afatinib or gefitinib. Strategies based on increasing dose intensity (n = 17) yielded clinical benefit in 59% of patients. All four patients who received osimertinib after first-and second-generation TKI experienced clinical benefit.

Conclusions: TKI rechallenge strategies, including dosing intensification, may improve clinical outcomes of patients with LM from EGFR-mutated NSCLC after initial TKI failure. (C) 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Original languageEnglish
Pages (from-to)1400-1407
Number of pages8
JournalJournal of Thoracic Oncology
Issue number8
Publication statusPublished - Aug 2019


  • EGFR
  • Tyrosine kinase inhibitor
  • Leptomeningeal metastases

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