title: Clinical Experience With Crizotinib in Patients With Advanced ALK-Rearranged Non-Small-Cell Lung Cancer and Brain Metastases.
abstract: OBJECTIVE
  Crizotinib is an oral kinase inhibitor approved for the treatment of ALK-rearranged non-small-cell lung cancer (NSCLC). The clinical benefits of crizotinib in patients with brain metastases have not been previously studied.
  
  
  METHODS
  Patients with advanced ALK-rearranged NSCLC enrolled onto clinical trial PROFILE 1005 or 1007 (randomly assigned to crizotinib) were included in this retrospective analysis. Patients with asymptomatic brain metastases (nontarget or target lesions) were allowed to enroll. Tumor assessments were evaluated every 6 weeks using RECIST (version 1.1).
  
  
  RESULTS
  At baseline, 31% of patients (275 of 888) had asymptomatic brain metastases; 109 had received no prior and 166 had received prior brain radiotherapy as treatment. Among patients with previously untreated asymptomatic brain metastases, the systemic disease control rate (DCR) at 12 weeks was 63% (95% CI, 54% to 72%), the intracranial DCR was 56% (95% CI, 46% to 66%), and the median intracranial time to progression (TTP) was 7 months (95% CI, 6.7 to 16.4). Among patients with previously treated brain metastases, the systemic DCR was 65% (95% CI, 57% to 72%), the intracranial DCR was 62% (95% CI, 54% to 70%), and the median intracranial TTP was 13.2 months (95% CI, 9.9 to not reached). Patients with systemic disease control were also likely to experience intracranial disease control at 12 weeks (correlation coefficient, 0.7652; P < .001). Among patients without baseline brain metastases who developed progressive disease (n = 253) after initiation of crizotinib, 20% were diagnosed with brain metastases.
  
  
  CONCLUSIONS
  Crizotinib was associated with systemic and intracranial disease control in patients with ALK-rearranged NSCLC who were ALK inhibitor naive and had brain metastases. However, progression of preexisting or development of new intracranial lesions while receiving therapy was a common manifestation of acquired resistance to crizotinib.
authors.affiliation: Daniel B. Costa, Beth Israel Deaconess Medical Center, Harvard Medical School; Alice T. Shaw, Massachusetts General Hospital, Harvard Medical School, Boston, MA; Sai-Hong I. Ou, Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Irvine; S. Martin Shreeve, Paulina Selaru, and Keith D. Wilner, Pfizer Oncology, La Jolla, CA; Benjamin J. Solomon, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Gregory J. Riely, Memorial Sloan-Kettering Cancer Center; Patrick Schnell, Pfizer Oncology, New York, NY; Myung-Ju Ahn, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea; Caicun Zhou, Shanghai Pulmonary Hospital, Shanghai, People's Republic of China; Anna Polli, Pfizer Oncology, Milan; Lucio Crinò, Perugia University Medical School, Perugia, Italy; Robin Wiltshire, Pfizer Oncology, Tadworth, United Kingdom; and D. Ross Camidge, University of Colorado Denver, Aurora, CO. dbcosta@bidmc.harvard.edu.
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Costa
authors.affiliation: Daniel B. Costa, Beth Israel Deaconess Medical Center, Harvard Medical School; Alice T. Shaw, Massachusetts General Hospital, Harvard Medical School, Boston, MA; Sai-Hong I. Ou, Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Irvine; S. Martin Shreeve, Paulina Selaru, and Keith D. Wilner, Pfizer Oncology, La Jolla, CA; Benjamin J. Solomon, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Gregory J. Riely, Memorial Sloan-Kettering Cancer Center; Patrick Schnell, Pfizer Oncology, New York, NY; Myung-Ju Ahn, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea; Caicun Zhou, Shanghai Pulmonary Hospital, Shanghai, People's Republic of China; Anna Polli, Pfizer Oncology, Milan; Lucio Crinò, Perugia University Medical School, Perugia, Italy; Robin Wiltshire, Pfizer Oncology, Tadworth, United Kingdom; and D. Ross Camidge, University of Colorado Denver, Aurora, CO.
authors.forename: Alice T
authors.initials: AT
authors.lastname: Shaw
authors.affiliation: Daniel B. Costa, Beth Israel Deaconess Medical Center, Harvard Medical School; Alice T. Shaw, Massachusetts General Hospital, Harvard Medical School, Boston, MA; Sai-Hong I. Ou, Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Irvine; S. Martin Shreeve, Paulina Selaru, and Keith D. Wilner, Pfizer Oncology, La Jolla, CA; Benjamin J. Solomon, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Gregory J. Riely, Memorial Sloan-Kettering Cancer Center; Patrick Schnell, Pfizer Oncology, New York, NY; Myung-Ju Ahn, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea; Caicun Zhou, Shanghai Pulmonary Hospital, Shanghai, People's Republic of China; Anna Polli, Pfizer Oncology, Milan; Lucio Crinò, Perugia University Medical School, Perugia, Italy; Robin Wiltshire, Pfizer Oncology, Tadworth, United Kingdom; and D. Ross Camidge, University of Colorado Denver, Aurora, CO.
authors.forename: Sai-Hong I
authors.initials: SH
authors.lastname: Ou
authors.affiliation: Daniel B. Costa, Beth Israel Deaconess Medical Center, Harvard Medical School; Alice T. Shaw, Massachusetts General Hospital, Harvard Medical School, Boston, MA; Sai-Hong I. Ou, Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Irvine; S. Martin Shreeve, Paulina Selaru, and Keith D. Wilner, Pfizer Oncology, La Jolla, CA; Benjamin J. Solomon, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Gregory J. Riely, Memorial Sloan-Kettering Cancer Center; Patrick Schnell, Pfizer Oncology, New York, NY; Myung-Ju Ahn, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea; Caicun Zhou, Shanghai Pulmonary Hospital, Shanghai, People's Republic of China; Anna Polli, Pfizer Oncology, Milan; Lucio Crinò, Perugia University Medical School, Perugia, Italy; Robin Wiltshire, Pfizer Oncology, Tadworth, United Kingdom; and D. Ross Camidge, University of Colorado Denver, Aurora, CO.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Solomon
authors.affiliation: Daniel B. Costa, Beth Israel Deaconess Medical Center, Harvard Medical School; Alice T. Shaw, Massachusetts General Hospital, Harvard Medical School, Boston, MA; Sai-Hong I. Ou, Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Irvine; S. Martin Shreeve, Paulina Selaru, and Keith D. Wilner, Pfizer Oncology, La Jolla, CA; Benjamin J. Solomon, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Gregory J. Riely, Memorial Sloan-Kettering Cancer Center; Patrick Schnell, Pfizer Oncology, New York, NY; Myung-Ju Ahn, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea; Caicun Zhou, Shanghai Pulmonary Hospital, Shanghai, People's Republic of China; Anna Polli, Pfizer Oncology, Milan; Lucio Crinò, Perugia University Medical School, Perugia, Italy; Robin Wiltshire, Pfizer Oncology, Tadworth, United Kingdom; and D. Ross Camidge, University of Colorado Denver, Aurora, CO.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Riely
authors.affiliation: Daniel B. Costa, Beth Israel Deaconess Medical Center, Harvard Medical School; Alice T. Shaw, Massachusetts General Hospital, Harvard Medical School, Boston, MA; Sai-Hong I. Ou, Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Irvine; S. Martin Shreeve, Paulina Selaru, and Keith D. Wilner, Pfizer Oncology, La Jolla, CA; Benjamin J. Solomon, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Gregory J. Riely, Memorial Sloan-Kettering Cancer Center; Patrick Schnell, Pfizer Oncology, New York, NY; Myung-Ju Ahn, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea; Caicun Zhou, Shanghai Pulmonary Hospital, Shanghai, People's Republic of China; Anna Polli, Pfizer Oncology, Milan; Lucio Crinò, Perugia University Medical School, Perugia, Italy; Robin Wiltshire, Pfizer Oncology, Tadworth, United Kingdom; and D. Ross Camidge, University of Colorado Denver, Aurora, CO.
authors.forename: Myung-Ju
authors.initials: MJ
authors.lastname: Ahn
authors.affiliation: Daniel B. Costa, Beth Israel Deaconess Medical Center, Harvard Medical School; Alice T. Shaw, Massachusetts General Hospital, Harvard Medical School, Boston, MA; Sai-Hong I. Ou, Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Irvine; S. Martin Shreeve, Paulina Selaru, and Keith D. Wilner, Pfizer Oncology, La Jolla, CA; Benjamin J. Solomon, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Gregory J. Riely, Memorial Sloan-Kettering Cancer Center; Patrick Schnell, Pfizer Oncology, New York, NY; Myung-Ju Ahn, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea; Caicun Zhou, Shanghai Pulmonary Hospital, Shanghai, People's Republic of China; Anna Polli, Pfizer Oncology, Milan; Lucio Crinò, Perugia University Medical School, Perugia, Italy; Robin Wiltshire, Pfizer Oncology, Tadworth, United Kingdom; and D. Ross Camidge, University of Colorado Denver, Aurora, CO.
authors.forename: Caicun
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Daniel B. Costa, Beth Israel Deaconess Medical Center, Harvard Medical School; Alice T. Shaw, Massachusetts General Hospital, Harvard Medical School, Boston, MA; Sai-Hong I. Ou, Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Irvine; S. Martin Shreeve, Paulina Selaru, and Keith D. Wilner, Pfizer Oncology, La Jolla, CA; Benjamin J. Solomon, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Gregory J. Riely, Memorial Sloan-Kettering Cancer Center; Patrick Schnell, Pfizer Oncology, New York, NY; Myung-Ju Ahn, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea; Caicun Zhou, Shanghai Pulmonary Hospital, Shanghai, People's Republic of China; Anna Polli, Pfizer Oncology, Milan; Lucio Crinò, Perugia University Medical School, Perugia, Italy; Robin Wiltshire, Pfizer Oncology, Tadworth, United Kingdom; and D. Ross Camidge, University of Colorado Denver, Aurora, CO.
authors.forename: S Martin
authors.initials: SM
authors.lastname: Shreeve
authors.affiliation: Daniel B. Costa, Beth Israel Deaconess Medical Center, Harvard Medical School; Alice T. Shaw, Massachusetts General Hospital, Harvard Medical School, Boston, MA; Sai-Hong I. Ou, Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Irvine; S. Martin Shreeve, Paulina Selaru, and Keith D. Wilner, Pfizer Oncology, La Jolla, CA; Benjamin J. Solomon, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Gregory J. Riely, Memorial Sloan-Kettering Cancer Center; Patrick Schnell, Pfizer Oncology, New York, NY; Myung-Ju Ahn, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea; Caicun Zhou, Shanghai Pulmonary Hospital, Shanghai, People's Republic of China; Anna Polli, Pfizer Oncology, Milan; Lucio Crinò, Perugia University Medical School, Perugia, Italy; Robin Wiltshire, Pfizer Oncology, Tadworth, United Kingdom; and D. Ross Camidge, University of Colorado Denver, Aurora, CO.
authors.forename: Paulina
authors.initials: P
authors.lastname: Selaru
authors.affiliation: Daniel B. Costa, Beth Israel Deaconess Medical Center, Harvard Medical School; Alice T. Shaw, Massachusetts General Hospital, Harvard Medical School, Boston, MA; Sai-Hong I. Ou, Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Irvine; S. Martin Shreeve, Paulina Selaru, and Keith D. Wilner, Pfizer Oncology, La Jolla, CA; Benjamin J. Solomon, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Gregory J. Riely, Memorial Sloan-Kettering Cancer Center; Patrick Schnell, Pfizer Oncology, New York, NY; Myung-Ju Ahn, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea; Caicun Zhou, Shanghai Pulmonary Hospital, Shanghai, People's Republic of China; Anna Polli, Pfizer Oncology, Milan; Lucio Crinò, Perugia University Medical School, Perugia, Italy; Robin Wiltshire, Pfizer Oncology, Tadworth, United Kingdom; and D. Ross Camidge, University of Colorado Denver, Aurora, CO.
authors.forename: Anna
authors.initials: A
authors.lastname: Polli
authors.affiliation: Daniel B. Costa, Beth Israel Deaconess Medical Center, Harvard Medical School; Alice T. Shaw, Massachusetts General Hospital, Harvard Medical School, Boston, MA; Sai-Hong I. Ou, Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Irvine; S. Martin Shreeve, Paulina Selaru, and Keith D. Wilner, Pfizer Oncology, La Jolla, CA; Benjamin J. Solomon, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Gregory J. Riely, Memorial Sloan-Kettering Cancer Center; Patrick Schnell, Pfizer Oncology, New York, NY; Myung-Ju Ahn, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea; Caicun Zhou, Shanghai Pulmonary Hospital, Shanghai, People's Republic of China; Anna Polli, Pfizer Oncology, Milan; Lucio Crinò, Perugia University Medical School, Perugia, Italy; Robin Wiltshire, Pfizer Oncology, Tadworth, United Kingdom; and D. Ross Camidge, University of Colorado Denver, Aurora, CO.
authors.forename: Patrick
authors.initials: P
authors.lastname: Schnell
authors.affiliation: Daniel B. Costa, Beth Israel Deaconess Medical Center, Harvard Medical School; Alice T. Shaw, Massachusetts General Hospital, Harvard Medical School, Boston, MA; Sai-Hong I. Ou, Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Irvine; S. Martin Shreeve, Paulina Selaru, and Keith D. Wilner, Pfizer Oncology, La Jolla, CA; Benjamin J. Solomon, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Gregory J. Riely, Memorial Sloan-Kettering Cancer Center; Patrick Schnell, Pfizer Oncology, New York, NY; Myung-Ju Ahn, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea; Caicun Zhou, Shanghai Pulmonary Hospital, Shanghai, People's Republic of China; Anna Polli, Pfizer Oncology, Milan; Lucio Crinò, Perugia University Medical School, Perugia, Italy; Robin Wiltshire, Pfizer Oncology, Tadworth, United Kingdom; and D. Ross Camidge, University of Colorado Denver, Aurora, CO.
authors.forename: Keith D
authors.initials: KD
authors.lastname: Wilner
authors.affiliation: Daniel B. Costa, Beth Israel Deaconess Medical Center, Harvard Medical School; Alice T. Shaw, Massachusetts General Hospital, Harvard Medical School, Boston, MA; Sai-Hong I. Ou, Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Irvine; S. Martin Shreeve, Paulina Selaru, and Keith D. Wilner, Pfizer Oncology, La Jolla, CA; Benjamin J. Solomon, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Gregory J. Riely, Memorial Sloan-Kettering Cancer Center; Patrick Schnell, Pfizer Oncology, New York, NY; Myung-Ju Ahn, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea; Caicun Zhou, Shanghai Pulmonary Hospital, Shanghai, People's Republic of China; Anna Polli, Pfizer Oncology, Milan; Lucio Crinò, Perugia University Medical School, Perugia, Italy; Robin Wiltshire, Pfizer Oncology, Tadworth, United Kingdom; and D. Ross Camidge, University of Colorado Denver, Aurora, CO.
authors.forename: Robin
authors.initials: R
authors.lastname: Wiltshire
authors.affiliation: Daniel B. Costa, Beth Israel Deaconess Medical Center, Harvard Medical School; Alice T. Shaw, Massachusetts General Hospital, Harvard Medical School, Boston, MA; Sai-Hong I. Ou, Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Irvine; S. Martin Shreeve, Paulina Selaru, and Keith D. Wilner, Pfizer Oncology, La Jolla, CA; Benjamin J. Solomon, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Gregory J. Riely, Memorial Sloan-Kettering Cancer Center; Patrick Schnell, Pfizer Oncology, New York, NY; Myung-Ju Ahn, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea; Caicun Zhou, Shanghai Pulmonary Hospital, Shanghai, People's Republic of China; Anna Polli, Pfizer Oncology, Milan; Lucio Crinò, Perugia University Medical School, Perugia, Italy; Robin Wiltshire, Pfizer Oncology, Tadworth, United Kingdom; and D. Ross Camidge, University of Colorado Denver, Aurora, CO.
authors.forename: D Ross
authors.initials: DR
authors.lastname: Camidge
authors.affiliation: Daniel B. Costa, Beth Israel Deaconess Medical Center, Harvard Medical School; Alice T. Shaw, Massachusetts General Hospital, Harvard Medical School, Boston, MA; Sai-Hong I. Ou, Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Irvine; S. Martin Shreeve, Paulina Selaru, and Keith D. Wilner, Pfizer Oncology, La Jolla, CA; Benjamin J. Solomon, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Gregory J. Riely, Memorial Sloan-Kettering Cancer Center; Patrick Schnell, Pfizer Oncology, New York, NY; Myung-Ju Ahn, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea; Caicun Zhou, Shanghai Pulmonary Hospital, Shanghai, People's Republic of China; Anna Polli, Pfizer Oncology, Milan; Lucio Crinò, Perugia University Medical School, Perugia, Italy; Robin Wiltshire, Pfizer Oncology, Tadworth, United Kingdom; and D. Ross Camidge, University of Colorado Denver, Aurora, CO.
authors.forename: Lucio
authors.initials: L
authors.lastname: Crinò
mesh_terms: D000328:Adult; D000368:Aged; D000077548:Anaplastic Lymphoma Kinase; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000556:secondary; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000556:secondary; D016371:Cranial Irradiation; D000077547:Crizotinib; D018572:Disease-Free Survival; D005260:Female; D015321:Gene Rearrangement; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000473:pathology*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011720:Pyrazoles / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D016634:Radiosurgery; D016032:Randomized Controlled Trials as Topic; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D012189:Retrospective Studies; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases