title: Crizotinib in ROS1-rearranged non-small-cell lung cancer.
abstract: BACKGROUND
  Chromosomal rearrangements of the gene encoding ROS1 proto-oncogene receptor tyrosine kinase (ROS1) define a distinct molecular subgroup of non-small-cell lung cancers (NSCLCs) that may be susceptible to therapeutic ROS1 kinase inhibition. Crizotinib is a small-molecule tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK), ROS1, and another proto-oncogene receptor tyrosine kinase, MET.
  
  
  METHODS
  We enrolled 50 patients with advanced NSCLC who tested positive for ROS1 rearrangement in an expansion cohort of the phase 1 study of crizotinib. Patients were treated with crizotinib at the standard oral dose of 250 mg twice daily and assessed for safety, pharmacokinetics, and response to therapy. ROS1 fusion partners were identified with the use of next-generation sequencing or reverse-transcriptase-polymerase-chain-reaction assays.
  
  
  RESULTS
  The objective response rate was 72% (95% confidence interval [CI], 58 to 84), with 3 complete responses and 33 partial responses. The median duration of response was 17.6 months (95% CI, 14.5 to not reached). Median progression-free survival was 19.2 months (95% CI, 14.4 to not reached), with 25 patients (50%) still in follow-up for progression. Among 30 tumors that were tested, we identified 7 ROS1 fusion partners: 5 known and 2 novel partner genes. No correlation was observed between the type of ROS1 rearrangement and the clinical response to crizotinib. The safety profile of crizotinib was similar to that seen in patients with ALK-rearranged NSCLC.
  
  
  CONCLUSIONS
  In this study, crizotinib showed marked antitumor activity in patients with advanced ROS1-rearranged NSCLC. ROS1 rearrangement defines a second molecular subgroup of NSCLC for which crizotinib is highly active. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195.).
authors.affiliation: From the Massachusetts General Hospital Cancer Center (A.T.S., L.P.L., Z.Z., J.W.C., A.J.I.), Dana-Farber Cancer Institute (G.I.S.), and Beth Israel Deaconess Medical Center (D.B.C.) - all in Boston; University of California at Irvine, Irvine (S.-H.I.O.), and Pfizer Oncology, La Jolla (W.T., S.M.S., L.M.T., J.G.C., K.D.W.) - both in California; Seoul National University Hospital, Seoul, South Korea (Y.-J.B.); University of Colorado, Aurora (D.R.C., M.V.-G., R.C.D.); Peter MacCallum Cancer Centre, Melbourne, VIC, Australia (B.J.S.); University of Chicago, Chicago (R.S.); Memorial Sloan Kettering Cancer Center, New York (G.J.R.); Karolinska Institutet, Stockholm (Z.Z.); and Rho, Chapel Hill, NC (P.S.).
authors.forename: Alice T
authors.initials: AT
authors.lastname: Shaw
authors.forename: Sai-Hong I
authors.initials: SH
authors.lastname: Ou
authors.forename: Yung-Jue
authors.initials: YJ
authors.lastname: Bang
authors.forename: D Ross
authors.initials: DR
authors.lastname: Camidge
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Solomon
authors.forename: Ravi
authors.initials: R
authors.lastname: Salgia
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Riely
authors.forename: Marileila
authors.initials: M
authors.lastname: Varella-Garcia
authors.forename: Geoffrey I
authors.initials: GI
authors.lastname: Shapiro
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Costa
authors.forename: Robert C
authors.initials: RC
authors.lastname: Doebele
authors.forename: Long Phi
authors.initials: LP
authors.lastname: Le
authors.forename: Zongli
authors.initials: Z
authors.lastname: Zheng
authors.forename: Weiwei
authors.initials: W
authors.lastname: Tan
authors.forename: Patricia
authors.initials: P
authors.lastname: Stephenson
authors.forename: S Martin
authors.initials: SM
authors.lastname: Shreeve
authors.forename: Lesley M
authors.initials: LM
authors.lastname: Tye
authors.forename: James G
authors.initials: JG
authors.lastname: Christensen
authors.forename: Keith D
authors.initials: KD
authors.lastname: Wilner
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Clark
authors.forename: A John
authors.initials: AJ
authors.lastname: Iafrate
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D000077547:Crizotinib; D018572:Disease-Free Survival; D005260:Female; D015321:Gene Rearrangement; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D011720:Pyrazoles / Q000009:adverse effects / Q000627:therapeutic use*; D011725:Pyridines / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome; D014786:Vision Disorders / Q000139:chemically induced
chemical_list: C000715470:MAS1 protein, human; D047428:Protein Kinase Inhibitors; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; D011505:Protein-Tyrosine Kinases; C062333:ROS1 protein, human