Osimertinib-induced DNA resistance mutations in cerebrospinal fluid of epidermal growth factor receptor-mutated non-small-cell lung carcinoma patients developing leptomeningeal metastases: Osimertinib Resistance Analysis-leptomeningeal metastases study

• Published in: Neuro-oncology (Charlottesville, Va.) Va.), 2024-12, Vol.26 (12), p.2316
• Main Authors: van der Wel, J W Tijmen, Boelens, Mirjam C, Jebbink, Merel, Smulders, Sietske A, Maas, Klaartje W, Luitse, Merel J A, Compter, Annette, Boltjes, Robin P B, Sol, Nik, Monkhorst, Kim, van den Broek, Daan, Smit, Egbert F, de Langen, Adrianus J, Brandsma, Dieta
• Format: Article
• Language: English
• Subjects: Acrylamides - administration & dosage; Acrylamides - therapeutic use; Adult; Aged; Aged, 80 and over; Aniline Compounds - therapeutic use; Antineoplastic Agents - therapeutic use; Carcinoma, Non-Small-Cell Lung - cerebrospinal fluid; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Drug Resistance, Neoplasm; ErbB Receptors - genetics; Female; Follow-Up Studies; Humans; Indoles; Lung Neoplasms - cerebrospinal fluid; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Male; Meningeal Carcinomatosis - cerebrospinal fluid; Meningeal Carcinomatosis - drug therapy; Meningeal Carcinomatosis - genetics; Meningeal Carcinomatosis - secondary; Meningeal Neoplasms - cerebrospinal fluid; Meningeal Neoplasms - drug therapy; Meningeal Neoplasms - genetics; Meningeal Neoplasms - secondary; Middle Aged; Mutation; Prognosis; Protein Kinase Inhibitors - therapeutic use; Pyrimidines
• ISSN: 1522-8517; 1523-5866; 1523-5866
• DOI: 10.1093/neuonc/noae138

Diagnosis and treatment of leptomeningeal metastases (LM) in epidermal growth factor receptor mutation-positive (EGFRm +) non-small-cell lung carcinoma (NSCLC) is challenging. We aimed to identify resistance mechanisms (RM) to osimertinib in cerebrospinal fluid (CSF) and plasma. EGFRm + patients with new or progressive LM during osimertinib were enrolled. NGS Ampliseq was performed on DNA isolated from CSF. Patients were prescribed osimertinib dose escalation (DE, 160 mg QD) following lumbar puncture. Clinical and radiological response was evaluated 4 weeks after osimertinib DE. Twenty-eight patients were included. The driver mutation was identified in 93% of CSF samples (n = 26). Seven (27%) harbored ≥1 RM. Twenty-five patients (89%) were prescribed osimertinib DE. Four weeks afterwards, symptoms improved in 5 patients, stabilized in 9 and worsened in 11 patients. Twenty-one (84%) patients underwent MR imaging. Four showed radiological improvement, 14 stabilization, and 3 worsening. In 27% of patients, an RM was found in CSF ctDNA, none of which are targetable at the time of writing, and the clinical efficacy of osimertinib DE seems limited. There is much to gain in diagnostic as well as therapeutic strategies in EGFRm + NSCLC LM.