title: A phase Ib, dose-finding study of erlotinib in combination with a fixed dose of pertuzumab in patients with advanced non-small-cell lung cancer.
abstract: BACKGROUND
  Pertuzumab, a dimerization inhibitor of human epidermal growth factor receptor 2 (HER2), has demonstrated pharmacodynamic activity, with stable disease in non-small-cell lung cancer. Combining erlotinib and pertuzumab may enhance antitumor activity. This study aimed to establish the recommended dosing of the erlotinib and pertuzumab combination; assess safety, preliminary efficacy, and pharmacokinetics; and analyze biomarkers.
  
  
  METHODS
  Fifteen patients with stage IIIb/IV non-small-cell lung cancer who failed chemotherapy were recruited. The patients received erlotinib (days -8 to -1), then combination therapy (21-day cycles for 6 cycles). Pertuzumab was given intravenous at 840 mg, then 420 mg once every three weeks, with erlotinib given daily (100 or 150 mg).
  
  
  RESULTS
  No dose-limiting toxicities were observed. Adverse events were generally grade 1/2 and manageable. The objective response rate was 20% (3/15 patients; 2 responders had mutant HER1, 1 responder had wild-type HER1), median overall progression-free survival was 9.3 weeks. High HER1, HER2, and HER3 messenger RNA expression correlated with increased progression-free survival. Combination therapy did not affect erlotinib's pharmacokinetics; however, pertuzumab mean exposures (maximum concentration, 231 mg/L; area under the concentration-time curve from 0 to 21 days, 1780 mg*d/L) were slightly higher than in previous studies.
  
  
  CONCLUSIONS
  Combination therapy was well tolerated in patients with good performance status, with encouraging efficacy. A loading dose of pertuzumab 840 mg followed by 420 mg once every three weeks plus daily erlotinib 150 mg appears to be the most appropriate regimen for this combination.
authors.affiliation: Medical Oncology Service, Vall d'Hebron University Hospital, Barcelona, Spain. efelip@vhebron.net
authors.forename: Enriqueta
authors.initials: E
authors.lastname: Felip
authors.forename: Malcolm
authors.initials: M
authors.lastname: Ranson
authors.forename: Susana
authors.initials: S
authors.lastname: Cedrés
authors.forename: Emma
authors.initials: E
authors.lastname: Dean
authors.forename: Mike
authors.initials: M
authors.lastname: Brewster
authors.forename: Pablo
authors.initials: P
authors.lastname: Martínez
authors.forename: Virginia
authors.initials: V
authors.lastname: McNally
authors.forename: Graham
authors.initials: G
authors.lastname: Ross
authors.forename: Danny
authors.initials: D
authors.lastname: Galdermans
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D019540:Area Under Curve; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D015331:Cohort Studies; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000235:genetics; D000069347:Erlotinib Hydrochloride; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011799:Quinazolines / Q000008:administration & dosage; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D020893:Receptor, ErbB-3 / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C485206:pertuzumab