title: Durable Clinical Response to Entrectinib in NTRK1-Rearranged Non-Small Cell Lung Cancer.
abstract: BACKGROUND
  Chromosomal rearrangements involving neurotrophic tyrosine kinase 1 (NTRK1) occur in a subset of non-small cell lung cancers (NSCLCs) and other solid tumor malignancies, leading to expression of an oncogenic TrkA fusion protein. Entrectinib (RXDX-101) is an orally available tyrosine kinase inhibitor, including TrkA. We sought to determine the frequency of NTRK1 rearrangements in NSCLC and to assess the clinical activity of entrectinib.
  
  
  METHODS
  We screened 1378 cases of NSCLC using anchored multiplex polymerase chain reaction (AMP). A patient with an NTRK1 gene rearrangement was enrolled onto a Phase 1 dose escalation study of entrectinib in adult patients with locally advanced or metastatic tumors (NCT02097810). We assessed safety and response to treatment.
  
  
  RESULTS
  We identified NTRK1 gene rearrangements at a frequency of 0.1% in this cohort. A patient with stage IV lung adenocrcinoma with an SQSTM1-NTRK1 fusion transcript expression was treated with entrectinib. Entrectinib was well tolerated, with no grade 3-4 adverse events. Within three weeks of starting on treatment, the patient reported resolution of prior dyspnea and pain. Restaging CT scans demonstrated a RECIST partial response (PR) and complete resolution of all brain metastases. This patient has continued on treatment for over 6 months with an ongoing PR.
  
  
  CONCLUSIONS
  Entrectinib demonstrated significant anti-tumor activity in a patient with NSCLC harboring an SQSTM1-NTRK1 gene rearrangement, indicating that entrectinib may be an effective therapy for tumors with NTRK gene rearrangements, including those with central nervous system metastases.
authors.affiliation: *Department of Medicine, Massachusetts General Hospital, Boston, MA; †Department of Pathology, Massachusetts General Hospital, Boston, MA; ‡Memorial Sloan Kettering Cancer Center, New York, NY; ‖Sarah Cannon Research Institute/Florida Cancer Specialists, Sarasota, FL; §Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN; ¶Department of Medicine, Georgetown University Medical Center, Washington, DC; #University of California Irving Health, Orange, CA; **Dana-Farber Cancer Institute, Boston, MA; ††Beth Israel Deaconess Medical Center, Boston, MA; and ‡‡Ignyta, Inc., San Diego, CA.
authors.forename: Anna F
authors.initials: AF
authors.lastname: Farago
authors.forename: Long P
authors.initials: LP
authors.lastname: Le
authors.forename: Zongli
authors.initials: Z
authors.lastname: Zheng
authors.forename: Alona
authors.initials: A
authors.lastname: Muzikansky
authors.forename: Alexander
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authors.lastname: Drilon
authors.forename: Manish
authors.initials: M
authors.lastname: Patel
authors.forename: Todd M
authors.initials: TM
authors.lastname: Bauer
authors.forename: Stephen V
authors.initials: SV
authors.lastname: Liu
authors.forename: Sai-Hong I
authors.initials: SH
authors.lastname: Ou
authors.forename: David
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authors.lastname: Jackman
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Costa
authors.forename: Pratik S
authors.initials: PS
authors.lastname: Multani
authors.forename: Gary G
authors.initials: GG
authors.lastname: Li
authors.forename: Zachary
authors.initials: Z
authors.lastname: Hornby
authors.forename: Edna
authors.initials: E
authors.lastname: Chow-Maneval
authors.forename: David
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authors.lastname: Luo
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Lim
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Iafrate
authors.forename: Alice T
authors.initials: AT
authors.lastname: Shaw
mesh_terms: D001549:Benzamides / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D017321:Clinical Trials, Phase I as Topic; D015331:Cohort Studies; D005260:Female; D015321:Gene Rearrangement; D006801:Humans; D007191:Indazoles / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D020917:Receptor, trkA / Q000235:genetics*
chemical_list: D001549:Benzamides; D007191:Indazoles; D047428:Protein Kinase Inhibitors; D020917:Receptor, trkA; C000607349:entrectinib