title: Phase I Study to Assess the Combination of Afatinib with Trastuzumab in Patients with Advanced or Metastatic HER2-Positive Breast Cancer.
abstract: OBJECTIVE
  The HER2 mAb, trastuzumab, is a standard therapy for patients with HER2-positive breast cancer before acquired resistance. Afatinib, an irreversible, oral, small-molecule ErbB family blocker, shows clinical activity in trastuzumab-refractory HER2-positive breast cancer.
  
  
  METHODS
  This phase I study used a 3+3 dose escalation to determine the MTD of oral once-daily afatinib in combination with the recommended dose of intravenous trastuzumab (4 mg/kg week 1; 2 mg/kg/wk thereafter). Adult women with confirmed advanced/metastatic HER2-positive breast cancer were eligible.
  
  
  RESULTS
  Of 18 patients treated, 16 received daily afatinib 20 mg and two 30 mg. Overall, 4 of 13 and 2 of 2 patients receiving afatinib 20 mg and 30 mg, respectively, experienced dose-limiting toxicity (DLT; all CTCAE grade 3 diarrhea). Most frequent treatment-related adverse events were diarrhea (94%), rash (56%), and fatigue (56%). Overall, pharmacokinetic profiles of afatinib and trastuzumab in combination were consistent with the known characteristics of each alone. Overall, objective response and disease control rates were 11% and 39%, respectively, with median progression-free survival 111.0 days (95% confidence interval, 56.0-274.0).
  
  
  CONCLUSIONS
  The MTD of afatinib was 20 mg daily combined with the recommended weekly dose of trastuzumab, with 1 of 6 patients showing DLTs in the dose escalation. However, additional DLTs occurred in the dose-expansion phase meaning that this MTD cannot be recommended for phase II development without strict diarrhea management. There was no evidence suggesting relevant pharmacokinetic drug-drug interactions. Signs of clinical activity were seen in trastuzumab-resistant HER2-positive breast cancer, suggesting further investigation with optimal diarrhea management is warranted.
authors.affiliation: Royal Marsden NHS Foundation Trust, Sutton, United Kingdom and Brighton and Sussex Medical School, Brighton, United Kingdom. alistair.ring@rmh.nhs.uk.
authors.forename: Alistair
authors.initials: A
authors.lastname: Ring
authors.affiliation: Royal Cornwall Hospitals NHS Trust, RCH Treliske, Truro, Cornwall, United Kingdom.
authors.forename: Duncan
authors.initials: D
authors.lastname: Wheatley
authors.affiliation: The Oncology Centre, Addenbrooke's Hospital, Cambridge, United Kingdom.
authors.forename: Helen
authors.initials: H
authors.lastname: Hatcher
authors.affiliation: The Royal Surrey County Hospital NHS Trust, Guildford, Surrey, United Kingdom.
authors.forename: Robert
authors.initials: R
authors.lastname: Laing
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, United Kingdom.
authors.forename: Ruth
authors.initials: R
authors.lastname: Plummer
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Uttenreuther-Fischer
authors.affiliation: Boehringer Ingelheim Ltd., Bracknell, United Kingdom.
authors.forename: Graham
authors.initials: G
authors.lastname: Temple
authors.affiliation: Boehringer Ingelheim Ltd., Bracknell, United Kingdom.
authors.forename: Katy
authors.initials: K
authors.lastname: Pelling
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Schnell
mesh_terms: D000328:Adult; D000077716:Afatinib; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011799:Quinazolines / Q000008:administration & dosage; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism* / Q000494:pharmacology; D019233:Retreatment; D000068878:Trastuzumab / Q000008:administration & dosage
chemical_list: D000077716:Afatinib; D014408:Biomarkers, Tumor; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab