451PD - Osimertinib at 80 mg for refractory leptomeningeal metastases in T790M-positive EGFR-mutant non-small cell lung cancer

Date 17 December 2016
Event ESMO Asia 2016 Congress
Session Thoracic cancers
Topics Anticancer Agents
Non-Small-Cell Lung Cancer, Metastatic
Presenter Akito Hata
Citation Annals of Oncology (2016) 27 (suppl_9): ix139-ix156. 10.1093/annonc/mdw594
Authors A. Hata1, S. Nanjo2, C. Okuda1, R. Kaji1, K. Masago1, S. Fujita1, K. Irie3, H. Okada3, H. Okada3, H. Okada4, S. Fukushima5, N. Katakami1
  • 1Division Of Integrated Oncology, Institute of Biomedical Research and Innovation, 650-0047 - Kobe/JP
  • 2Division Of Integrated Oncology, Institute of Biomedical Research and Innovation, Kobe/JP
  • 3Department Of Pharmacology, Institute of Biomedical Research and Innovation, 650-0047 - Kobe/JP
  • 4Department Of Medical Oncology, Kobe Minimally Invasive Cancer Center, 650-0047 - Kobe/JP
  • 5Department Of Pharmaceutics, Faculty Of Pharmaceutical Science, Kobe Gakuin University, 650-0046 - Kobe/JP



There are quite few therapeutic options for refractory leptomeningeal metastases (LM) after failure to classical epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), and prognosis is extremely poor in those with such LM. Preclinical data and clinical data at 160 mg have suggested promising efficacy of Osimertinib (Osime) for refractory LM, but almost no clinical data at 80 mg, which is approved standard dose.


This is a prospective pilot study. We enrolled patients with T790M who were suspected of LM after failure to classical EGFR-TKIs. After 2-4 weeks from initiation of 80 mg Osime, magnetic resonance imaging and lumbar puncture were repeatedly done, and we evaluated radiographical, cytological, and EGFR mutational findings. T790M quantitative analysis was performed in cerebrospinal fluid (CSF). CSF penetration of Osime was estimated, based on plasma and CSF concentrations.


We investigated total 10 patients (4 definitive and 6 possible LM cases) since Osime was approved in Japan (April 2016). Malignant cells and sensitive mutations were confirmed in CSF of all definitive cases. In 2 of 4 definitive cases with T790M in both CNS (central nervous system) and extra-CNS, Osime was markedly effective in both CNS and extra-CNS, resulting in disapearance of sensitive mutations and T790M in CSF, radiographical response, and performance status improvement. In 2 definitive cases with T790M in extra-CNS without T790M in CSF, sensitive mutations in CSF did not disapear by Osime. Disease control of both CNS and extra-CNS was obtained in one case, whereas Osime was ineffective in CNS, despite being effective in lung lesions in another case. Neither sensitive mutations nor T790M in CSF were detected in 6 possible cases with T790M in extra-CNS. Osime has controlled both CNS and extra-CNS diseases in all these 6 patients. Immature results of plasma and CSF concentrations estimated CSF penetration rate of Osime to be approximately one-tenth.


Osime at 80 mg could be an therapeutic option for refractory LM after failure to classical EGFR-TKIs. It might be more effective in CSF T790M-positive cases. We will present mature results of CSF, plasma concentrations, and CSF penetration rate of Osime.

Clinical trial indentification

Legal entity responsible for the study



Foundation of Biomedical Research and Innovation


A. Hata: Lecture fee from Chugai, Astra Zeneca, Boeringer Ingelheim, and Eli Lilly. All other authors have declared no conflicts of interest.