title: Co-clinical trials demonstrate superiority of crizotinib to chemotherapy in ALK-rearranged non-small cell lung cancer and predict strategies to overcome resistance.
abstract: OBJECTIVE
  To extend the results of a phase III trial in patients with non-small cell lung cancer with adenocarcinomas harboring EML4-ALK fusion.
  
  
  METHODS
  We conducted a co-clinical trial in a mouse model comparing the ALK inhibitor crizotinib to the standard-of-care cytotoxic agents docetaxel or pemetrexed.
  
  
  RESULTS
  Concordant with the clinical outcome in humans, crizotinib produced a substantially higher response rate compared with chemotherapy, associated with significantly longer progression-free survival. Overall survival was also prolonged in crizotinib- compared with chemotherapy-treated mice. Pemetrexed produced superior overall survival compared with docetaxel, suggesting that this agent may be the preferred chemotherapy in the ALK population. In addition, in the EML4-ALK-driven mouse lung adenocarcinoma model, HSP90 inhibition can overcome both primary and acquired crizotinib resistance. Furthermore, HSP90 inhibition, as well as the second-generation ALK inhibitor TAE684, demonstrated activity in newly developed lung adenocarcinoma models driven by crizotinib-insensitive EML4-ALK L1196M or F1174L.
  
  
  CONCLUSIONS
  Our findings suggest that crizotinib is superior to standard chemotherapy in ALK inhibitor-naïve disease and support further clinical investigation of HSP90 inhibitors and second-generation ALK inhibitors in tumors with primary or acquired crizotinib resistance.
authors: Department of Medicine, Harvard Medical School, Boston MA 02115.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.|Ludwig Center at Dana-Farber/Harvard Cancer Center, Dana-Farber Cancer Institute, Boston, MA 02115.
authors: Zhao
authors: Z
authors: Chen
authors: Department of Medicine, Harvard Medical School, Boston MA 02115.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.|Ludwig Center at Dana-Farber/Harvard Cancer Center, Dana-Farber Cancer Institute, Boston, MA 02115.
authors: Esra
authors: E
authors: Akbay
authors: Department of Medicine, Harvard Medical School, Boston MA 02115.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.|Ludwig Center at Dana-Farber/Harvard Cancer Center, Dana-Farber Cancer Institute, Boston, MA 02115.
authors: Oliver
authors: O
authors: Mikse
authors: Lurie Family Imaging Center, Dana-Farber Cancer Institute, Boston, MA 02115.
authors: Tanya
authors: T
authors: Tupper
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.|Ludwig Center at Dana-Farber/Harvard Cancer Center, Dana-Farber Cancer Institute, Boston, MA 02115.
authors: Katherine
authors: K
authors: Cheng
authors: Department of Imaging, Dana-Farber Cancer Institute, Boston, MA 02115.|Department of Radiology, Brigham and Women's Hospital, Boston, MA 02115.
authors: Yuchuan
authors: Y
authors: Wang
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.
authors: Xiaohong
authors: X
authors: Tan
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.
authors: Abigail
authors: A
authors: Altabef
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.
authors: Sue-Ann
authors: SA
authors: Woo
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.
authors: Liang
authors: L
authors: Chen
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.
authors: Jacob B
authors: JB
authors: Reibel
authors: Department of Medicine, Harvard Medical School, Boston MA 02115.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.|Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.
authors: Pasi A
authors: PA
authors: Janne
authors: Department of Genetics, School of Medicine, University of North Carolina, Chapel Hill, NC 27599.
authors: Norman E
authors: NE
authors: Sharpless
authors: Department of Medicine, Harvard Medical School, Boston MA 02115.|Department of Medical Oncology, Massachusetts General Hospital Cancer Center, Boston, MA 02114.
authors: Jeffrey A
authors: JA
authors: Engelman
authors: Department of Medicine, Harvard Medical School, Boston MA 02115.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.|Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.|Early Drug Development Center, Dana-Farber Cancer Institute, Boston, MA 02115.
authors: Geoffrey I
authors: GI
authors: Shapiro
authors: Lurie Family Imaging Center, Dana-Farber Cancer Institute, Boston, MA 02115.|Department of Pediatric Oncology, Dana-Farber Cancer Institute and Children's Hospital, Boston, MA 02115.
authors: Andrew L
authors: AL
authors: Kung
authors: Department of Medicine, Harvard Medical School, Boston MA 02115.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.|Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.|Ludwig Center at Dana-Farber/Harvard Cancer Center, Dana-Farber Cancer Institute, Boston, MA 02115.
authors: Kwok-Kin
authors: KK
authors: Wong
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D000077547:Crizotinib; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D008279:Magnetic Resonance Imaging; D051379:Mice; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D049268:Positron-Emission Tomography; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; C522504:EML4-ALK fusion protein, human; D018841:HSP90 Heat-Shock Proteins; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases