Osimertinib Overcomes Alectinib Resistance Caused by Amphiregulin in a Leptomeningeal Carcinomatosis Model of EML4-ALK Lung Cancer

Background: Central nervous system (CNS) metastasis, such as brain metastasis and leptomeningeal carcinomatosis (LMC), occurs in 20–40% of all patients with cancer. Anaplastic lymphoma kinase (ALK) is a clinically validated drug target and ALK rearrangements are found in approximately 3-5% of non-small cell lung cancer (NSCLC). ALK tyrosine kinase inhibitor (TKI) shows dramatic clinical efficacy in ALK-rearranged NSCLC patients, and the second-generation ALK-TKI alectinib is effective against CNS metastasis of ALK-rearranged NSCLC. However, the patients with ALK-rearrangement acquire resistance to alectinib over time and develop recurrent LMC metastasis. This study aimed to clarify the mechanism of resistance to alectinib in LMC and seek a novel therapeutic strategy. Conclusion: We demonstrated that EML4-ALK lung cancer cells acquired moderate resistance to alectinib in the leptomeningeal space due to amphiregulin-triggered EGFR activation. Moreover, combined use of alectinib and EGFR..... READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.08.1841

Authors: S. Arai, S. Takeuchi, K. Fukuda, A. Nishiyama, A. Tanimoto, H. Taniguchi, M. Satouchi, S. Nanjo, R. Katayama, M. Nishio, M. Zheng, Y. Wu, S. Yano

Conference PaperKirk SmithOctober 1, 2019Leptomeningeal carcinomatosis, alectinib resistance, Osimertinib

Intra-cranial efficacy of brigatinib in an ALK-positive non-small cell lung cancer patient presenting leptomeningeal carcinomatosis

Objectives: Brigatinib is a second-generation ALK inhibitor which demonstrated activity over crizotinib-resistance, especially on brain metastasis by increased blood-brain penetration. However, its activity on lepto-meningeal disease is unknown and scarcely reported. Conclusion: Our case provides additional data on brigatinib’s intracranial activity, not only on brain metastasis but also on leptomeningeal disease, after experiencing resistance to both crizotinib and ceretinib, 1st and 2nd generation ALK inhibitors. READ ARTICLE

Lung Cancer
DOI:10.1016/j.lungcan.2019.04.013

Authors: Elisabeth Gaye, Margaux Geier, Paul Bore, Marine Guilloïque, Francois Lucia, Gilles Quéré, Sylvie Gouva, Gilles Robinet, Renaud Descourt

Case StudyKirk SmithApril 20, 2019Leptomeningeal carcinomatosis, Brigatinib, Tyrosine kinase inhibitor (TKI), NSCLC