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The activity, safety, and evolving role of brigatinib in patients with ALK-rearranged non-small cell lung cancers

Authors Sabari JK, Santini FC, Schram AM, Bergagnini I, Chen R, Mrad C, Lai WV, Arbour KC, Drilon A

Received 25 January 2017

Accepted for publication 15 March 2017

Published 6 April 2017 Volume 2017:10 Pages 1983—1992

DOI https://doi.org/10.2147/OTT.S109295

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Colin Mak

Peer reviewer comments 3

Editor who approved publication: Dr Faris Farassati

Joshua K Sabari,1 Fernando C Santini,1,2 Alison M Schram,2 Isabella Bergagnini,1 Ruqin Chen,1 Chebli Mrad,1 W Victoria Lai,1 Kathryn C Arbour,1 Alexander Drilon2,3

1Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, 2Developmetal Therapeutics, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, 3Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY, USA

Abstract: Brigatinib (AP26113) is a dimethylphosphine oxide group-containing tyrosine kinase inhibitor (TKI) constructed around a bisanilinopyrimidine scaffold with potent activity against the anaplastic lymphoma kinase (ALK) and several other targets. Despite the activity of first- and second-generation ALK inhibitors in advanced ALK-rearranged lung cancers, the development of acquired resistance represents an ongoing challenge. Later generation ALK inhibitors such as brigatinib are important potential tools in the management of patients with acquired resistance characterized by continued dependency on ALK. Brigatinib is active in vitro against many ALK kinase domain mutations that may mediate acquired resistance to other ALK TKIs, with reported activity (IC50 <50 nM) against ALK C1156Y, I1171S/T, V1180L, L1196M, L1152R/P, E1210K, and G1269A. In patients with ALK-rearranged lung cancers who receive brigatinib after crizotinib, substantial and durable responses and intracranial disease control can be achieved based on early-phase clinical trial data. The drug is also being explored in TKI-naïve patients. From a safety perspective, early pulmonary toxicity has been observed, prompting the decision to pursue lead-in dosing for the drug. Early data point to ALK G1202R and ALK E1210K as potential mechanisms of clinical resistance to brigatinib.

Keywords: NSCLC, ALK, acquired resistance, tyrosine kinase inhibitor, brigatinib, crizotinib, ceritinib, alectinib, lorlatinib
 

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