title: Phase II Study of Lapatinib in Combination With Trastuzumab in Patients With Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer: Clinical Outcomes and Predictive Value of Early [18F]Fluorodeoxyglucose Positron Emission Tomography Imaging (TBCRC 003).
abstract: OBJECTIVE
  Lapatinib plus trastuzumab improves outcomes relative to lapatinib alone in heavily pretreated, human epidermal growth factor receptor 2-positive metastatic breast cancer (MBC). We tested the combination in the earlier-line setting and explored the predictive value of [(18)F]fluorodeoxyglucose positron emission tomography ([(18)F]FDG-PET) for clinical outcomes.
  
  
  METHODS
  Two cohorts were enrolled (cohort 1: no prior trastuzumab for MBC and ≥ 1 year from adjuvant trastuzumab, if given; cohort 2: one to two lines of chemotherapy including trastuzumab for MBC and/or recurrence < 1 year from adjuvant trastuzumab). The primary end point was objective response rate by RECIST v1.0; secondary end points included clinical benefit rate (complete response plus partial response plus stable disease ≥ 24 weeks) and progression-free survival. [(18)F]FDG-PET scans were acquired at baseline, week 1, and week 8. Associations between metabolic response and clinical outcomes were explored.
  
  
  RESULTS
  Eighty-seven patients were registered (85 were evaluable for efficacy). The confirmed objective response rate was 50.0% (95% CI, 33.8% to 66.2%) in cohort 1 and 22.2% (95% CI, 11.3% to 37.3%) in cohort 2. Clinical benefit rate was 57.5% (95% CI, 40.9% to 73.0%) in cohort 1 and 40.0% (95% CI, 25.7% to 55.7%) in cohort 2. Median progression-free survival was 7.4 and 5.3 months, respectively. Lack of week-1 [(18)F]FDG-PET/computed tomography ([(18)F]FDG-PET/CT) response was associated with failure to achieve an objective response by RECIST (negative predictive value, 91% [95% CI, 74% to 100%] for cohort 1 and 91% [95% CI, 79% to 100%] for cohort 2).
  
  
  CONCLUSIONS
  Early use of lapatinib and trastuzumab is active in human epidermal growth factor receptor 2-positive MBC. Week-1 [(18)F]FDG-PET/CT may allow selection of patients who can be treated with targeted regimens and spared the toxicity of chemotherapy.
authors.affiliation: Nancy U. Lin, Hao Guo, Nicole Ryabin, Julie S. Najita, William T. Barry, Ian E. Krop, Eric P. Winer, and Annick D. Van den Abbeele, Dana-Farber Cancer Institute; Andrea L. Richardson and Annick D. Van den Abbeele, Brigham and Women's Hospital, Boston, MA; Jeffrey T. Yap, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT; Ingrid A. Mayer and Carlos L. Arteaga, Vanderbilt-Ingram Cancer Center, Nashville, TN; Carla I. Falkson, University of Alabama, Birmingham, AL; Timothy J. Hobday, Mayo Clinic, Rochester, MN; E. Claire Dees, University of North Carolina, Chapel Hill, NC; Rita Nanda, University of Chicago, Chicago, IL; Mothaffar F. Rimawi, Baylor College of Medicine, Houston, TX; and Antonio C. Wolff, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD. nlin@partners.org.
authors.forename: Nancy U
authors.initials: NU
authors.lastname: Lin
authors.affiliation: Nancy U. Lin, Hao Guo, Nicole Ryabin, Julie S. Najita, William T. Barry, Ian E. Krop, Eric P. Winer, and Annick D. Van den Abbeele, Dana-Farber Cancer Institute; Andrea L. Richardson and Annick D. Van den Abbeele, Brigham and Women's Hospital, Boston, MA; Jeffrey T. Yap, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT; Ingrid A. Mayer and Carlos L. Arteaga, Vanderbilt-Ingram Cancer Center, Nashville, TN; Carla I. Falkson, University of Alabama, Birmingham, AL; Timothy J. Hobday, Mayo Clinic, Rochester, MN; E. Claire Dees, University of North Carolina, Chapel Hill, NC; Rita Nanda, University of Chicago, Chicago, IL; Mothaffar F. Rimawi, Baylor College of Medicine, Houston, TX; and Antonio C. Wolff, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD.
authors.forename: Hao
authors.initials: H
authors.lastname: Guo
authors.affiliation: Nancy U. Lin, Hao Guo, Nicole Ryabin, Julie S. Najita, William T. Barry, Ian E. Krop, Eric P. Winer, and Annick D. Van den Abbeele, Dana-Farber Cancer Institute; Andrea L. Richardson and Annick D. Van den Abbeele, Brigham and Women's Hospital, Boston, MA; Jeffrey T. Yap, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT; Ingrid A. Mayer and Carlos L. Arteaga, Vanderbilt-Ingram Cancer Center, Nashville, TN; Carla I. Falkson, University of Alabama, Birmingham, AL; Timothy J. Hobday, Mayo Clinic, Rochester, MN; E. Claire Dees, University of North Carolina, Chapel Hill, NC; Rita Nanda, University of Chicago, Chicago, IL; Mothaffar F. Rimawi, Baylor College of Medicine, Houston, TX; and Antonio C. Wolff, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD.
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Yap
authors.affiliation: Nancy U. Lin, Hao Guo, Nicole Ryabin, Julie S. Najita, William T. Barry, Ian E. Krop, Eric P. Winer, and Annick D. Van den Abbeele, Dana-Farber Cancer Institute; Andrea L. Richardson and Annick D. Van den Abbeele, Brigham and Women's Hospital, Boston, MA; Jeffrey T. Yap, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT; Ingrid A. Mayer and Carlos L. Arteaga, Vanderbilt-Ingram Cancer Center, Nashville, TN; Carla I. Falkson, University of Alabama, Birmingham, AL; Timothy J. Hobday, Mayo Clinic, Rochester, MN; E. Claire Dees, University of North Carolina, Chapel Hill, NC; Rita Nanda, University of Chicago, Chicago, IL; Mothaffar F. Rimawi, Baylor College of Medicine, Houston, TX; and Antonio C. Wolff, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD.
authors.forename: Ingrid A
authors.initials: IA
authors.lastname: Mayer
authors.affiliation: Nancy U. Lin, Hao Guo, Nicole Ryabin, Julie S. Najita, William T. Barry, Ian E. Krop, Eric P. Winer, and Annick D. Van den Abbeele, Dana-Farber Cancer Institute; Andrea L. Richardson and Annick D. Van den Abbeele, Brigham and Women's Hospital, Boston, MA; Jeffrey T. Yap, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT; Ingrid A. Mayer and Carlos L. Arteaga, Vanderbilt-Ingram Cancer Center, Nashville, TN; Carla I. Falkson, University of Alabama, Birmingham, AL; Timothy J. Hobday, Mayo Clinic, Rochester, MN; E. Claire Dees, University of North Carolina, Chapel Hill, NC; Rita Nanda, University of Chicago, Chicago, IL; Mothaffar F. Rimawi, Baylor College of Medicine, Houston, TX; and Antonio C. Wolff, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD.
authors.forename: Carla I
authors.initials: CI
authors.lastname: Falkson
authors.affiliation: Nancy U. Lin, Hao Guo, Nicole Ryabin, Julie S. Najita, William T. Barry, Ian E. Krop, Eric P. Winer, and Annick D. Van den Abbeele, Dana-Farber Cancer Institute; Andrea L. Richardson and Annick D. Van den Abbeele, Brigham and Women's Hospital, Boston, MA; Jeffrey T. Yap, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT; Ingrid A. Mayer and Carlos L. Arteaga, Vanderbilt-Ingram Cancer Center, Nashville, TN; Carla I. Falkson, University of Alabama, Birmingham, AL; Timothy J. Hobday, Mayo Clinic, Rochester, MN; E. Claire Dees, University of North Carolina, Chapel Hill, NC; Rita Nanda, University of Chicago, Chicago, IL; Mothaffar F. Rimawi, Baylor College of Medicine, Houston, TX; and Antonio C. Wolff, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Hobday
authors.affiliation: Nancy U. Lin, Hao Guo, Nicole Ryabin, Julie S. Najita, William T. Barry, Ian E. Krop, Eric P. Winer, and Annick D. Van den Abbeele, Dana-Farber Cancer Institute; Andrea L. Richardson and Annick D. Van den Abbeele, Brigham and Women's Hospital, Boston, MA; Jeffrey T. Yap, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT; Ingrid A. Mayer and Carlos L. Arteaga, Vanderbilt-Ingram Cancer Center, Nashville, TN; Carla I. Falkson, University of Alabama, Birmingham, AL; Timothy J. Hobday, Mayo Clinic, Rochester, MN; E. Claire Dees, University of North Carolina, Chapel Hill, NC; Rita Nanda, University of Chicago, Chicago, IL; Mothaffar F. Rimawi, Baylor College of Medicine, Houston, TX; and Antonio C. Wolff, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD.
authors.forename: E Claire
authors.initials: EC
authors.lastname: Dees
authors.affiliation: Nancy U. Lin, Hao Guo, Nicole Ryabin, Julie S. Najita, William T. Barry, Ian E. Krop, Eric P. Winer, and Annick D. Van den Abbeele, Dana-Farber Cancer Institute; Andrea L. Richardson and Annick D. Van den Abbeele, Brigham and Women's Hospital, Boston, MA; Jeffrey T. Yap, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT; Ingrid A. Mayer and Carlos L. Arteaga, Vanderbilt-Ingram Cancer Center, Nashville, TN; Carla I. Falkson, University of Alabama, Birmingham, AL; Timothy J. Hobday, Mayo Clinic, Rochester, MN; E. Claire Dees, University of North Carolina, Chapel Hill, NC; Rita Nanda, University of Chicago, Chicago, IL; Mothaffar F. Rimawi, Baylor College of Medicine, Houston, TX; and Antonio C. Wolff, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Richardson
authors.affiliation: Nancy U. Lin, Hao Guo, Nicole Ryabin, Julie S. Najita, William T. Barry, Ian E. Krop, Eric P. Winer, and Annick D. Van den Abbeele, Dana-Farber Cancer Institute; Andrea L. Richardson and Annick D. Van den Abbeele, Brigham and Women's Hospital, Boston, MA; Jeffrey T. Yap, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT; Ingrid A. Mayer and Carlos L. Arteaga, Vanderbilt-Ingram Cancer Center, Nashville, TN; Carla I. Falkson, University of Alabama, Birmingham, AL; Timothy J. Hobday, Mayo Clinic, Rochester, MN; E. Claire Dees, University of North Carolina, Chapel Hill, NC; Rita Nanda, University of Chicago, Chicago, IL; Mothaffar F. Rimawi, Baylor College of Medicine, Houston, TX; and Antonio C. Wolff, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD.
authors.forename: Rita
authors.initials: R
authors.lastname: Nanda
authors.affiliation: Nancy U. Lin, Hao Guo, Nicole Ryabin, Julie S. Najita, William T. Barry, Ian E. Krop, Eric P. Winer, and Annick D. Van den Abbeele, Dana-Farber Cancer Institute; Andrea L. Richardson and Annick D. Van den Abbeele, Brigham and Women's Hospital, Boston, MA; Jeffrey T. Yap, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT; Ingrid A. Mayer and Carlos L. Arteaga, Vanderbilt-Ingram Cancer Center, Nashville, TN; Carla I. Falkson, University of Alabama, Birmingham, AL; Timothy J. Hobday, Mayo Clinic, Rochester, MN; E. Claire Dees, University of North Carolina, Chapel Hill, NC; Rita Nanda, University of Chicago, Chicago, IL; Mothaffar F. Rimawi, Baylor College of Medicine, Houston, TX; and Antonio C. Wolff, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD.
authors.forename: Mothaffar F
authors.initials: MF
authors.lastname: Rimawi
authors.affiliation: Nancy U. Lin, Hao Guo, Nicole Ryabin, Julie S. Najita, William T. Barry, Ian E. Krop, Eric P. Winer, and Annick D. Van den Abbeele, Dana-Farber Cancer Institute; Andrea L. Richardson and Annick D. Van den Abbeele, Brigham and Women's Hospital, Boston, MA; Jeffrey T. Yap, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT; Ingrid A. Mayer and Carlos L. Arteaga, Vanderbilt-Ingram Cancer Center, Nashville, TN; Carla I. Falkson, University of Alabama, Birmingham, AL; Timothy J. Hobday, Mayo Clinic, Rochester, MN; E. Claire Dees, University of North Carolina, Chapel Hill, NC; Rita Nanda, University of Chicago, Chicago, IL; Mothaffar F. Rimawi, Baylor College of Medicine, Houston, TX; and Antonio C. Wolff, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD.
authors.forename: Nicole
authors.initials: N
authors.lastname: Ryabin
authors.affiliation: Nancy U. Lin, Hao Guo, Nicole Ryabin, Julie S. Najita, William T. Barry, Ian E. Krop, Eric P. Winer, and Annick D. Van den Abbeele, Dana-Farber Cancer Institute; Andrea L. Richardson and Annick D. Van den Abbeele, Brigham and Women's Hospital, Boston, MA; Jeffrey T. Yap, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT; Ingrid A. Mayer and Carlos L. Arteaga, Vanderbilt-Ingram Cancer Center, Nashville, TN; Carla I. Falkson, University of Alabama, Birmingham, AL; Timothy J. Hobday, Mayo Clinic, Rochester, MN; E. Claire Dees, University of North Carolina, Chapel Hill, NC; Rita Nanda, University of Chicago, Chicago, IL; Mothaffar F. Rimawi, Baylor College of Medicine, Houston, TX; and Antonio C. Wolff, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD.
authors.forename: Julie S
authors.initials: JS
authors.lastname: Najita
authors.affiliation: Nancy U. Lin, Hao Guo, Nicole Ryabin, Julie S. Najita, William T. Barry, Ian E. Krop, Eric P. Winer, and Annick D. Van den Abbeele, Dana-Farber Cancer Institute; Andrea L. Richardson and Annick D. Van den Abbeele, Brigham and Women's Hospital, Boston, MA; Jeffrey T. Yap, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT; Ingrid A. Mayer and Carlos L. Arteaga, Vanderbilt-Ingram Cancer Center, Nashville, TN; Carla I. Falkson, University of Alabama, Birmingham, AL; Timothy J. Hobday, Mayo Clinic, Rochester, MN; E. Claire Dees, University of North Carolina, Chapel Hill, NC; Rita Nanda, University of Chicago, Chicago, IL; Mothaffar F. Rimawi, Baylor College of Medicine, Houston, TX; and Antonio C. Wolff, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD.
authors.forename: William T
authors.initials: WT
authors.lastname: Barry
authors.affiliation: Nancy U. Lin, Hao Guo, Nicole Ryabin, Julie S. Najita, William T. Barry, Ian E. Krop, Eric P. Winer, and Annick D. Van den Abbeele, Dana-Farber Cancer Institute; Andrea L. Richardson and Annick D. Van den Abbeele, Brigham and Women's Hospital, Boston, MA; Jeffrey T. Yap, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT; Ingrid A. Mayer and Carlos L. Arteaga, Vanderbilt-Ingram Cancer Center, Nashville, TN; Carla I. Falkson, University of Alabama, Birmingham, AL; Timothy J. Hobday, Mayo Clinic, Rochester, MN; E. Claire Dees, University of North Carolina, Chapel Hill, NC; Rita Nanda, University of Chicago, Chicago, IL; Mothaffar F. Rimawi, Baylor College of Medicine, Houston, TX; and Antonio C. Wolff, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD.
authors.forename: Carlos L
authors.initials: CL
authors.lastname: Arteaga
authors.affiliation: Nancy U. Lin, Hao Guo, Nicole Ryabin, Julie S. Najita, William T. Barry, Ian E. Krop, Eric P. Winer, and Annick D. Van den Abbeele, Dana-Farber Cancer Institute; Andrea L. Richardson and Annick D. Van den Abbeele, Brigham and Women's Hospital, Boston, MA; Jeffrey T. Yap, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT; Ingrid A. Mayer and Carlos L. Arteaga, Vanderbilt-Ingram Cancer Center, Nashville, TN; Carla I. Falkson, University of Alabama, Birmingham, AL; Timothy J. Hobday, Mayo Clinic, Rochester, MN; E. Claire Dees, University of North Carolina, Chapel Hill, NC; Rita Nanda, University of Chicago, Chicago, IL; Mothaffar F. Rimawi, Baylor College of Medicine, Houston, TX; and Antonio C. Wolff, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD.
authors.forename: Antonio C
authors.initials: AC
authors.lastname: Wolff
authors.affiliation: Nancy U. Lin, Hao Guo, Nicole Ryabin, Julie S. Najita, William T. Barry, Ian E. Krop, Eric P. Winer, and Annick D. Van den Abbeele, Dana-Farber Cancer Institute; Andrea L. Richardson and Annick D. Van den Abbeele, Brigham and Women's Hospital, Boston, MA; Jeffrey T. Yap, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT; Ingrid A. Mayer and Carlos L. Arteaga, Vanderbilt-Ingram Cancer Center, Nashville, TN; Carla I. Falkson, University of Alabama, Birmingham, AL; Timothy J. Hobday, Mayo Clinic, Rochester, MN; E. Claire Dees, University of North Carolina, Chapel Hill, NC; Rita Nanda, University of Chicago, Chicago, IL; Mothaffar F. Rimawi, Baylor College of Medicine, Houston, TX; and Antonio C. Wolff, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD.
authors.forename: Ian E
authors.initials: IE
authors.lastname: Krop
authors.affiliation: Nancy U. Lin, Hao Guo, Nicole Ryabin, Julie S. Najita, William T. Barry, Ian E. Krop, Eric P. Winer, and Annick D. Van den Abbeele, Dana-Farber Cancer Institute; Andrea L. Richardson and Annick D. Van den Abbeele, Brigham and Women's Hospital, Boston, MA; Jeffrey T. Yap, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT; Ingrid A. Mayer and Carlos L. Arteaga, Vanderbilt-Ingram Cancer Center, Nashville, TN; Carla I. Falkson, University of Alabama, Birmingham, AL; Timothy J. Hobday, Mayo Clinic, Rochester, MN; E. Claire Dees, University of North Carolina, Chapel Hill, NC; Rita Nanda, University of Chicago, Chicago, IL; Mothaffar F. Rimawi, Baylor College of Medicine, Houston, TX; and Antonio C. Wolff, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD.
authors.forename: Eric P
authors.initials: EP
authors.lastname: Winer
authors.affiliation: Nancy U. Lin, Hao Guo, Nicole Ryabin, Julie S. Najita, William T. Barry, Ian E. Krop, Eric P. Winer, and Annick D. Van den Abbeele, Dana-Farber Cancer Institute; Andrea L. Richardson and Annick D. Van den Abbeele, Brigham and Women's Hospital, Boston, MA; Jeffrey T. Yap, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT; Ingrid A. Mayer and Carlos L. Arteaga, Vanderbilt-Ingram Cancer Center, Nashville, TN; Carla I. Falkson, University of Alabama, Birmingham, AL; Timothy J. Hobday, Mayo Clinic, Rochester, MN; E. Claire Dees, University of North Carolina, Chapel Hill, NC; Rita Nanda, University of Chicago, Chicago, IL; Mothaffar F. Rimawi, Baylor College of Medicine, Houston, TX; and Antonio C. Wolff, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD.
authors.forename: Annick D
authors.initials: AD
authors.lastname: Van den Abbeele
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015331:Cohort Studies; D005260:Female; D019788:Fluorodeoxyglucose F18; D006801:Humans; D000077341:Lapatinib; D008875:Middle Aged; D009362:Neoplasm Metastasis; D049268:Positron-Emission Tomography / Q000379:methods; D011799:Quinazolines / Q000008:administration & dosage; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis; D000068878:Trastuzumab; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D019788:Fluorodeoxyglucose F18; D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human