title: Co-clinical quantitative tumor volume imaging in ALK-rearranged NSCLC treated with crizotinib.
abstract: OBJECTIVE
  To evaluate and compare the volumetric tumor burden changes during crizotinib therapy in mice and human cohorts with ALK-rearranged non-small-cell lung cancer (NSCLC).
  
  
  METHODS
  Volumetric tumor burden was quantified on serial imaging studies in 8 bitransgenic mice with ALK-rearranged adenocarcinoma treated with crizotinib, and in 33 human subjects with ALK-rearranged NSCLC treated with crizotinib. The volumetric tumor burden changes and the time to maximal response were compared between mice and humans.
  
  
  RESULTS
  The median tumor volume decrease (%) at the maximal response was -40.4% (range: -79.5%-+11.7%) in mice, and -72.9% (range: -100%-+72%) in humans (Wilcoxon p=0.03). The median time from the initiation of therapy to maximal response was 6 weeks in mice, and 15.7 weeks in humans. Overall volumetric response rate was 50% in mice and 97% in humans. Spider plots of tumor volume changes during therapy demonstrated durable responses in the human cohort, with a median time on therapy of 13.1 months.
  
  
  CONCLUSIONS
  The present study described an initial attempt to evaluate quantitative tumor burden changes in co-clinical imaging studies of genomically-matched mice and human cohorts with ALK-rearranged NSCLC treated with crizotinib. Differences are noted in the degree of maximal volume response between the two cohorts in this well-established paradigm of targeted therapy, indicating a need for further studies to optimize co-clinical trial design and interpretation.
authors.affiliation: Department of Radiology, Brigham and Women's Hospital, 450 Brookline Ave., Boston MA, 02215, USA; Department of Imaging, Dana-Farber Cancer Institute, 450 Brookline Ave., Boston MA, 02215, USA. Electronic address: Mizuki_Nishino@DFCI.HARVARD.EDU.
authors.forename: Mizuki
authors.initials: M
authors.lastname: Nishino
authors.affiliation: Department of Medical Oncology and Department of Medicine Dana-Farber Cancer Institute and Brigham and Women's Hospital 450 Brookline Ave., Boston MA, 02215, USA.
authors.forename: Adrian G
authors.initials: AG
authors.lastname: Sacher
authors.affiliation: Department of Medical Oncology and Department of Medicine Dana-Farber Cancer Institute and Brigham and Women's Hospital 450 Brookline Ave., Boston MA, 02215, USA.
authors.forename: Leena
authors.initials: L
authors.lastname: Gandhi
authors.affiliation: Department of Medical Oncology and Department of Medicine Dana-Farber Cancer Institute and Brigham and Women's Hospital 450 Brookline Ave., Boston MA, 02215, USA.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Medical Oncology and Department of Medicine Dana-Farber Cancer Institute and Brigham and Women's Hospital 450 Brookline Ave., Boston MA, 02215, USA.
authors.forename: Esra
authors.initials: E
authors.lastname: Akbay
authors.affiliation: Department of Radiology, Brigham and Women's Hospital, 450 Brookline Ave., Boston MA, 02215, USA.
authors.forename: Andriy
authors.initials: A
authors.lastname: Fedorov
authors.affiliation: Department of Radiology, Brigham and Women's Hospital, 450 Brookline Ave., Boston MA, 02215, USA.
authors.forename: Carl F
authors.initials: CF
authors.lastname: Westin
authors.affiliation: Department of Radiology, Brigham and Women's Hospital, 450 Brookline Ave., Boston MA, 02215, USA.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Hatabu
authors.affiliation: Department of Medical Oncology and Department of Medicine Dana-Farber Cancer Institute and Brigham and Women's Hospital 450 Brookline Ave., Boston MA, 02215, USA.
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Johnson
authors.affiliation: Department of Medical Oncology and Department of Medicine Dana-Farber Cancer Institute and Brigham and Women's Hospital 450 Brookline Ave., Boston MA, 02215, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Hammerman
authors.affiliation: Department of Medical Oncology and Department of Medicine Dana-Farber Cancer Institute and Brigham and Women's Hospital 450 Brookline Ave., Boston MA, 02215, USA.
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology*; D000077547:Crizotinib; D004195:Disease Models, Animal; D005260:Female; D015321:Gene Rearrangement / Q000187:drug effects*; D006801:Humans; D008175:Lung Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011720:Pyrazoles / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D020794:Receptor Protein-Tyrosine Kinases; D047368:Tumor Burden
chemical_list: 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
keywords: Anaplastic lymphoma kinase inhibitor; Co-clinical trial; Computed tomography; Non-small-cell lung cancer; Targeted therapy; Tumor volume