title: Exposure-response analysis of pertuzumab in HER2-positive metastatic breast cancer: absence of effect on QTc prolongation and other ECG parameters.
abstract: OBJECTIVE
  The phase III trial of pertuzumab plus trastuzumab plus docetaxel versus placebo plus trastuzumab plus docetaxel for first-line treatment of HER2-positive metastatic breast cancer included a substudy to determine whether pertuzumab affected the corrected QT (QTc) interval or other electrocardiogram parameters.
  
  
  METHODS
  Triplicate 12-lead electrocardiogram measurements and serum samples were collected before (-30 and -15 min) and after (0-15 and 60-75 min) pertuzumab/placebo infusions (Cycles 1 and 3), and at 72 h post-infusion (Cycle 1). Fridericia's correction was applied to QT measurements (QTcF) and change from baseline (ΔQTcF) calculated. Statistical analyses were performed on baseline-adjusted, placebo-corrected QTcF values (ΔΔQTcF). Linear mixed-effects modeling evaluated potential exposure-response relationships between ΔQTcF and observed pertuzumab concentrations.
  
  
  RESULTS
  Thirty-seven female patients participated in the substudy. QTcF values in both groups were within the normal range and below critical thresholds of clinical concern. No pertuzumab-treated patient showed abnormal electrocardiogram morphology. In Cycle 1, mean ΔΔQTcF (90 % CI) values at 0-15 min, 60-75 min, and 72 h post-infusion were -6.96 (-13.69, -0.23), -6.35 (-13.57, 0.88), and -4.08 (-12.64, 4.48), all of which were <5 ms, with upper CI limits <10 ms. One Cycle 3 post-infusion mean ΔΔQTcF value exceeded 5 ms. Other electrocardiogram parameters were within normal ranges. Concentration-QTc modeling showed no apparent relationship between ΔQTcF and pertuzumab concentrations.
  
  
  CONCLUSIONS
  Cardiac monitoring and concentration-QTc modeling demonstrated that pertuzumab, combined with trastuzumab and docetaxel, had no clinically relevant effects on QTcF and other electrocardiogram parameters.
authors.affiliation: Genentech, Inc., 1 DNA Way, MS-463A, South San Francisco, CA, 94080, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Garg
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Emma
authors.initials: E
authors.lastname: Clark
authors.forename: Adam
authors.initials: A
authors.lastname: Knott
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Carrothers
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Marier
authors.forename: Javier
authors.initials: J
authors.lastname: Cortés
authors.forename: Michael
authors.initials: M
authors.lastname: Brewster
authors.forename: Jennifer
authors.initials: J
authors.lastname: Visich
authors.forename: Bert
authors.initials: B
authors.lastname: Lum
mesh_terms: D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000453:epidemiology / Q000503:physiopathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D000077143:Docetaxel; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006801:Humans; D015994:Incidence; D008875:Middle Aged; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D043823:Taxoids / Q000008:administration & dosage / Q000627:therapeutic use; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000077143:Docetaxel; D009363:Neoplasm Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D043823:Taxoids; D000068878:Trastuzumab; C508053:ERBB2 protein, human; C485206:pertuzumab