title: Entrectinib: a potent new TRK, ROS1, and ALK inhibitor.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: a Phase I - Early Clinical Trials Unit, Oncology Department , Antwerp University Hospital and Center for Oncological Research (CORE), Antwerp University , Edegem , Belgium.
authors.forename: Christian
authors.initials: C
authors.lastname: Rolfo
authors.affiliation: b Oncology Department , National Cancer Institute (INEN) , Lima , Peru.
authors.forename: Rossana
authors.initials: R
authors.lastname: Ruiz
authors.affiliation: c Department Medical Oncology , VU University Medical Center , Amsterdam , The Netherlands.
authors.forename: Elisa
authors.initials: E
authors.lastname: Giovannetti
authors.affiliation: d Department of Oncology , Clínica Universidad de Navarra , Pamplona , Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Gil-Bazo
authors.affiliation: e Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology , University of Palermo , Palermo , Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Russo
authors.affiliation: a Phase I - Early Clinical Trials Unit, Oncology Department , Antwerp University Hospital and Center for Oncological Research (CORE), Antwerp University , Edegem , Belgium.|e Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology , University of Palermo , Palermo , Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Passiglia
authors.affiliation: a Phase I - Early Clinical Trials Unit, Oncology Department , Antwerp University Hospital and Center for Oncological Research (CORE), Antwerp University , Edegem , Belgium.
authors.forename: Marco
authors.initials: M
authors.lastname: Giallombardo
authors.affiliation: a Phase I - Early Clinical Trials Unit, Oncology Department , Antwerp University Hospital and Center for Oncological Research (CORE), Antwerp University , Edegem , Belgium.
authors.forename: Marc
authors.initials: M
authors.lastname: Peeters
authors.affiliation: f Thoracic Oncology Program , Memorial Cancer Institute, Memorial Health Care System , Pembroke Pines , FL , USA.
authors.forename: Luis
authors.initials: L
authors.lastname: Raez
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D001549:Benzamides / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007191:Indazoles / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D020917:Receptor, trkA / Q000037:antagonists & inhibitors; D020813:Receptor, trkB / Q000037:antagonists & inhibitors; D020812:Receptor, trkC / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D007191:Indazoles; D011518:Proto-Oncogene Proteins; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; C062333:ROS1 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA; D020813:Receptor, trkB; D020812:Receptor, trkC; C000607349:entrectinib
keywords: ALK; Entrectinib; NTRK1; NTRK2; NTRK3; ROS1; TrkA; TrkB; TrkC; colorectal cancer; non-small cell lung cancer; precision medicine; salivary gland cancer