Entrectinib: an orally available, selective tyrosine kinase inhibitor for the treatment of  NTRK ,  ROS1 , and  ALK  fusion-positive solid tumors

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Abstract

Entrectinib is a potent small-molecule tyrosine kinase inhibitor that targets oncogenic rearrangements in NTRK, ROS1, and ALK. The consolidated results of 2 Phase I trials demonstrated activity in tyrosine kinase inhibitor-naïve patients along with substantial intracranial activity. In ROS1-rearranged lung cancers, entrectinib results in durable disease control and prolonged progression-free survival. The drug is well tolerated and has a safety profile that includes adverse events mediated by on-target tropomyosin-related kinase A/B/C inhibition.

Most cited references 27

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Oncogenic kinase signalling.

P Blume-Jensen, T. Hunter (2001)

Protein-tyrosine kinases (PTKs) are important regulators of intracellular signal-transduction pathways mediating development and multicellular communication in metazoans. Their activity is normally tightly controlled and regulated. Perturbation of PTK signalling by mutations and other genetic alterations results in deregulated kinase activity and malignant transformation. The lipid kinase phosphoinositide 3-OH kinase (PI(3)K) and some of its downstream targets, such as the protein-serine/threonine kinases Akt and p70 S6 kinase (p70S6K), are crucial effectors in oncogenic PTK signalling. This review emphasizes how oncogenic conversion of protein kinases results from perturbation of the normal autoinhibitory constraints on kinase activity and provides an update on our knowledge about the role of deregulated PI(3)K/Akt and mammalian target of rapamycin/p70S6K signalling in human malignancies.

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ROS1 rearrangements define a unique molecular class of lung cancers.

Kristin Bergethon, Alice Shaw, Sai-Hong Ignatius Ou … (2012)

Chromosomal rearrangements involving the ROS1 receptor tyrosine kinase gene have recently been described in a subset of non-small-cell lung cancers (NSCLCs). Because little is known about these tumors, we examined the clinical characteristics and treatment outcomes of patients with NSCLC with ROS1 rearrangement. Using a ROS1 fluorescent in situ hybridization (FISH) assay, we screened 1,073 patients with NSCLC and correlated ROS1 rearrangement status with clinical characteristics, overall survival, and when available, ALK rearrangement status. In vitro studies assessed the responsiveness of cells with ROS1 rearrangement to the tyrosine kinase inhibitor crizotinib. The clinical response of one patient with ROS1-rearranged NSCLC to crizotinib was investigated as part of an expanded phase I cohort. Of 1,073 tumors screened, 18 (1.7%) were ROS1 rearranged by FISH, and 31 (2.9%) were ALK rearranged. Compared with the ROS1-negative group, patients with ROS1 rearrangements were significantly younger and more likely to be never-smokers (each P < .001). All of the ROS1-positive tumors were adenocarcinomas, with a tendency toward higher grade. ROS1-positive and -negative groups showed no difference in overall survival. The HCC78 ROS1-rearranged NSCLC cell line and 293 cells transfected with CD74-ROS1 showed evidence of sensitivity to crizotinib. The patient treated with crizotinib showed tumor shrinkage, with a near complete response. ROS1 rearrangement defines a molecular subset of NSCLC with distinct clinical characteristics that are similar to those observed in patients with ALK-rearranged NSCLC. Crizotinib shows in vitro activity and early evidence of clinical activity in ROS1-rearranged NSCLC.

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Alectinib in Crizotinib-Refractory ALK-Rearranged Non-Small-Cell Lung Cancer: A Phase II Global Study.

Sai-Hong Ignatius Ou, Jin Seok Ahn, Luigi De Petris … (2016)

Crizotinib confers improved progression-free survival compared with chemotherapy in anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC), but progression invariably occurs. We investigated the efficacy and safety of alectinib, a potent and selective ALK inhibitor with excellent CNS penetration, in patients with crizotinib-refractory ALK-positive NSCLC.

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Author and article information

Journal

Journal ID (nlm-ta): Ther Clin Risk Manag

Journal ID (iso-abbrev): Ther Clin Risk Manag

Journal ID (publisher-id): Therapeutics and Clinical Risk Management

Title: Therapeutics and Clinical Risk Management

Publisher: Dove Medical Press

ISSN (Print): 1176-6336

ISSN (Electronic): 1178-203X

Publication date Collection: 2018

Publication date (Electronic): 20 July 2018

Volume: 14

Pages: 1247-1252

Affiliations

[1 ]Department of Pharmacy, Memorial Sloan Kettering Cancer Center, New York, NY, USA

[2 ]Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY, USA, drilona@ 123456mskcc.org

Author notes

Correspondence: Alexander Drilon, Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, 885 2nd Avenue, 10th Floor, New York, NY 10017, USA, Tel +1 646 888 4206, Email drilona@ 123456mskcc.org

Article

Publisher ID: tcrm-14-1247

DOI: 10.2147/TCRM.S147381

PMC ID: 6055893

PubMed ID: 30050303

SO-VID: b69b5546-bf71-4167-8a60-b97326109d05

License:

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