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Title: Standard dose osimertinib for erlotinib refractory T790M-negative EGFR-mutant non-small cell lung cancer with leptomeningeal disease.
Austin Authors: Arulananda, Surein;Do, Hongdo;Rivalland, Gareth;Loh, Zoe ;Musafer, Ashan;Lau, Eddie ;Mitchell, Paul;Dobrovic, Alexander ;John, Thomas 
Affiliation: Cancer Immunobiology Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
Department of Medical Oncology, Olivia Newton-John Cancer and Wellness Centre, Austin Health, Heidelberg, Victoria, Australia
Department of Medicine, University of Melbourne, Parkville, Victoria, Australia
Department of Radiology, Austin Health, Heidelberg, Victoria, Australia
Department of Clinical Pathology, University of Melbourne, Parkville, Victoria, Australia
Translational Genomics and Epigenomics Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
School of Cancer Medicine, La Trobe University, Bundoora, Victoria, Australia
Issue Date: May-2019
Publication information: Journal of thoracic disease 2019; 11(5): 1756-1764
Abstract: Leptomeningeal spread in non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations who experience disease progression on TKIs portends a poor prognosis. Mutation profiling of tumour DNA in cerebrospinal fluid (CSF) samples can be used to determine the presence of the EGFR T790M resistance mutation, indicating that osimertinib, a CNS-penetrating 3rd generation TKI may be efficacious. Eight patients on EGFR TKIs who progressed with cytology-proven leptomeningeal disease at our institution were studied. EGFR mutations were profiled in CSF using droplet digital PCR (ddPCR) and compared to matched plasma samples. Clinical characteristics and survival outcomes on subsequent therapies tailored to ddPCR analysis were reported. None of the four patients who developed leptomeningeal disease while receiving 1st generation EGFR TKIs developed the EGFR T790M mutation in CSF. One patient who did not have extra-cranial disease and was EGFR T790M-negative in both plasma and CSF was nevertheless treated with standard-dose osimertinib, and achieved a rapid and durable response lasting 9 months to date. Three patients developed leptomeningeal disease on osimertinib, with one patient developing the EGFR C797S mutation in a cis-allelic conformation with the EGFR T790M mutation in plasma. Standard-dose osimertinib resulted in a clinically meaningful response in a patient with EGFR T790M-negative 1st generation EGFR TKI refractory leptomeningeal disease. Next generation sequencing and ddPCR has a role at identifying the C797S mutation and its allelic conformation with the T790M mutation with clinical implications.
DOI: 10.21037/jtd.2019.05.41
ORCID: 0000-0003-3414-112X
Journal: Journal of thoracic disease
PubMed URL: 31285867
ISSN: 2072-1439
Type: Journal Article
Subjects: Leptomeningeal disease
T790M negative
epidermal growth factor receptor mutation (EGFR mutation)
non-small cell lung cancer (NSCLC)
Appears in Collections:Journal articles

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