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Anaplastic lymphoma kinase inhibition in metastatic non-small cell lung cancer: clinical impact of alectinib

Authors Muller IB, de Langen AJ, Giovannetti E, Peters GJ

Received 26 May 2017

Accepted for publication 11 August 2017

Published 13 September 2017 Volume 2017:10 Pages 4535—4541


Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Lucy Goodman

Peer reviewer comments 2

Editor who approved publication: Dr Tohru Yamada

Ittai B Muller,1 Adrianus J de Langen,2,3 Elisa Giovannetti,4,5 Godefridus J Peters4

1Department of Clinical Chemistry, 2Department of Pulmonology, VU University Medical Center, 3Department of Thoracic Oncology, Netherlands Cancer Institute, 4Department of Medical Oncology, VU University Medical Center, Amsterdam, the Netherlands; 5Cancer Pharmacology Lab, AIRC Start-Up Unit, University of Pisa, Pisa, Italy

Abstract: A subset of non-small cell lung cancer (NSCLC) tumors (5%) harbors an anaplastic lymphoma kinase (ALK) translocation that drives tumorigenesis. The clinically approved first-line treatment crizotinib specifically inhibits ALK and improves progression-free survival (PFS) in treated and untreated patients by 4 months compared to standard chemotherapy. While some patients relapse after crizotinib treatment due to resistance mutations in ALK, second-generation ALK inhibitors effectively induce tumor response and prolong PFS. Alectinib, a second-generation ALK inhibitor, has recently been approved for ALK-rearranged NSCLC after patients progressed on crizotinib. Alectinib is able to inhibit several crizotinib- and ceritinib-resistant ALK mutations in vitro. Furthermore, alectinib is a more potent tyrosine kinase inhibitor (TKI), with favorable safety profile, and has increased penetration into the central nervous system, inhibiting crizotinib-resistant brain metastases. The discovery of effective personalized therapies to combat ALK-rearranged NSCLC such as alectinib is an example of the importance of genomic profiling of NSCLC and provides an excellent template for future discoveries in managing these tumors.

Keywords: crizotinib, acquired resistance, alectinib, anaplastic lymphoma kinase, tyrosine kinase inhibitors, non-small cell lung cancer

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