Entrectinib: a potent new TRK, ROS1, and ALK inhibitor
Rolfo C (1), Ruiz R (2), Giovannetti E (3), Gil-Bazo I (4), Russo A (5), Passiglia F (1,5), Giallombardo M (1), Peeters M (1), Raez L (6).
(1a) Phase I - Early Clinical Trials Unit, Oncology Department , Antwerp University Hospital and Center for Oncological Research (CORE), Antwerp University , Edegem , Belgium.
(2b) Oncology Department , National Cancer Institute (INEN) , Lima , Peru.
(3c) Department Medical Oncology , VU University Medical Center , Amsterdam , The Netherlands.
(4d) Department of Oncology , Clínica Universidad de Navarra , Pamplona , Spain.
(5e) Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology , University of Palermo , Palermo , Italy.
(6f) Thoracic Oncology Program , Memorial Cancer Institute, Memorial Health Care System , Pembroke Pines , FL , USA.
Receptor tyrosine kinases (RTKs) and their signaling pathways, control normal cellular processes; however, their deregulation play important roles in malignant transformation.
In advanced non-small cell lung cancer (NSCLC), the recognition of oncogenic activation of specific RTKs, has led to the development of molecularly targeted agents that only benefit roughly 20% of patients. Entrectinib is a pan-TRK, ROS1 and ALK inhibitor that has shown potent anti-neoplastic activity and tolerability in various neoplastic conditions, particularly NSCLC.
This review outlines the pharmacokinetics, pharmacodynamics, mechanism of action, safety, tolerability, pre-clinical studies and clinical trials of entrectinib, a promising novel agent for the treatment of advanced solid tumors with molecular alterations of Trk-A, B and C, ROS1 or ALK.
Among the several experimental drugs under clinical development, entrectinib is emerging as an innovative and promising targeted agent. The encouraging antitumor activity reported in the Phase 1 studies, together with the acceptable toxicity profile, suggest that entrectinib, thanks to its peculiar mechanism of action, could play an important role in the treatment-strategies of multiple TRK-A, B, C, ROS1, and ALK- dependent solid tumors, including NSCLC and colorectal cancer. That being said, further evidence for its clinical use is still needed.
CITATION Expert Opin Investig Drugs. 2015;24(11):1493-500. doi: 10.1517/13543784.2015.1096344. Epub 2015 Oct 12