title: Ceritinib in ALK-rearranged non-small-cell lung cancer.
abstract: BACKGROUND
  Non-small-cell lung cancer (NSCLC) harboring the anaplastic lymphoma kinase gene (ALK) rearrangement is sensitive to the ALK inhibitor crizotinib, but resistance invariably develops. Ceritinib (LDK378) is a new ALK inhibitor that has shown greater antitumor potency than crizotinib in preclinical studies.
  
  
  METHODS
  In this phase 1 study, we administered oral ceritinib in doses of 50 to 750 mg once daily to patients with advanced cancers harboring genetic alterations in ALK. In an expansion phase of the study, patients received the maximum tolerated dose. Patients were assessed to determine the safety, pharmacokinetic properties, and antitumor activity of ceritinib. Tumor biopsies were performed before ceritinib treatment to identify resistance mutations in ALK in a group of patients with NSCLC who had had disease progression during treatment with crizotinib.
  
  
  RESULTS
  A total of 59 patients were enrolled in the dose-escalation phase. The maximum tolerated dose of ceritinib was 750 mg once daily; dose-limiting toxic events included diarrhea, vomiting, dehydration, elevated aminotransferase levels, and hypophosphatemia. This phase was followed by an expansion phase, in which an additional 71 patients were treated, for a total of 130 patients overall. Among 114 patients with NSCLC who received at least 400 mg of ceritinib per day, the overall response rate was 58% (95% confidence interval [CI], 48 to 67). Among 80 patients who had received crizotinib previously, the response rate was 56% (95% CI, 45 to 67). Responses were observed in patients with various resistance mutations in ALK and in patients without detectable mutations. Among patients with NSCLC who received at least 400 mg of ceritinib per day, the median progression-free survival was 7.0 months (95% CI, 5.6 to 9.5).
  
  
  CONCLUSIONS
  Ceritinib was highly active in patients with advanced, ALK-rearranged NSCLC, including those who had had disease progression during crizotinib treatment, regardless of the presence of resistance mutations in ALK. (Funded by Novartis Pharmaceuticals and others; ClinicalTrials.gov number, NCT01283516.).
authors.affiliation: From Massachusetts General Hospital, Boston (A.T.S., J.A.E.); Seoul National University Hospital, Seoul, South Korea (D.-W.K.); Fox Chase Cancer Center, Philadelphia (R.M.); National Cancer Center and Genome Institute of Singapore, Singapore (D.S.W.T.); Vall d'Hebron University, Barcelona (E.F.); University of Washington, Seattle (L.Q.M.C.); University of Colorado, Denver (D.R.C.); University Hospital KU Leuven, Leuven, Belgium (J.V.); Huntsman Cancer Institute, Salt Lake City (S.S.); Istituto Europeo di Oncologia (T.D.P.) and Istituto di Ricovero e Cura a Carattere Scientifico Istituto Clinico Humanitas (A.S.) - both in Milan; Memorial Sloan-Kettering Cancer Center, New York (G.J.R.); Peter MacCallum Cancer Center, Melbourne, VIC, Australia (B.J.S.); Center for Integrated Oncology, University Hospital Cologne, Cologne (J.W.), Thoraxklinik, University of Heidelberg, Translational Lung Research Center Heidelberg, German Center for Lung Research (M.T.), and German Cancer Consortium (M.S.), Heidelberg, and University Duisburg-Essen, Essen (M.S.) - all in Germany; Princess Margaret Cancer Center, Toronto (G.L.); and Novartis Institutes for BioMedical Research, Cambridge, MA (Y.Y.L., M.G., A.L.B.).
authors.forename: Alice T
authors.initials: AT
authors.lastname: Shaw
authors.forename: Dong-Wan
authors.initials: DW
authors.lastname: Kim
authors.forename: Ranee
authors.initials: R
authors.lastname: Mehra
authors.forename: Daniel S W
authors.initials: DS
authors.lastname: Tan
authors.forename: Enriqueta
authors.initials: E
authors.lastname: Felip
authors.forename: Laura Q M
authors.initials: LQ
authors.lastname: Chow
authors.forename: D Ross
authors.initials: DR
authors.lastname: Camidge
authors.forename: Johan
authors.initials: J
authors.lastname: Vansteenkiste
authors.forename: Sunil
authors.initials: S
authors.lastname: Sharma
authors.forename: Tommaso
authors.initials: T
authors.lastname: De Pas
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Riely
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Solomon
authors.forename: Juergen
authors.initials: J
authors.lastname: Wolf
authors.forename: Michael
authors.initials: M
authors.lastname: Thomas
authors.forename: Martin
authors.initials: M
authors.lastname: Schuler
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Liu
authors.forename: Armando
authors.initials: A
authors.lastname: Santoro
authors.forename: Yvonne Y
authors.initials: YY
authors.lastname: Lau
authors.forename: Meredith
authors.initials: M
authors.lastname: Goldwasser
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Boral
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Engelman
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000077548:Anaplastic Lymphoma Kinase; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D011995:Recombination, Genetic; D013450:Sulfones / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013450:Sulfones; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; C586847:ceritinib