title: Trastuzumab emtansine (T-DM1) plus docetaxel with or without pertuzumab in patients with HER2-positive locally advanced or metastatic breast cancer: results from a phase Ib/IIa study.
abstract: Trastuzumab emtansine (T-DM1) exhibited enhanced antitumor activity when combined with docetaxel or pertuzumab in preclinical studies. This phase Ib/IIa study assessed the feasibility of T-DM1 + docetaxel in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) and T-DM1 + docetaxel ± pertuzumab in patients with HER2-positive locally advanced breast cancer (LABC).
  
  
  
  Phase Ib (part 1) explored dose escalation, with T-DM1 + docetaxel administered for greater than or equal to six cycles in patients with MBC. Phase Ib (part 2) began with the maximum tolerated dose (MTD) identified in part 1. Patients with LABC were administered less than or equal to six cycles of T-DM1 + docetaxel or T-DM1 + docetaxel + pertuzumab. Phase IIa explored the MTDs identified in phase Ib.
  
  
  
  Administered with T-DM1 (3.6 mg/kg), the docetaxel MTD was 60 mg/m(2) in MBC. In LABC, the MTD was 100 mg/m(2) docetaxel in combination with T-DM1 (3.6 mg/kg), given with granulocyte colony-stimulating factor (G-CSF). Administered with T-DM1 (3.6 mg/kg) + pertuzumab (840 mg, cycle 1; 420 mg, subsequent cycles), the docetaxel MTD in LABC was 75 mg/m(2) with G-CSF support. Neutropenia was the most common grade 3-4 adverse event (AE; MBC, 72% and LABC, 29%). In total, 48% (12/25) of MBC patients and 47% (34/73) of LABC patients experienced AEs requiring dose modification. In MBC (median prior systemic agents = 5), the objective response rate was 80.0% (20/25; 95% confidence interval [CI] 59.3-93.2) and the median progression-free survival was 13.8 months (range, 1.6-33.5). The pathologic complete response (ypT0/is, ypN0) rate in LABC was 60.3% (44/73; 95% CI 48.1-71.5). Pharmacokinetic analyses indicated a low risk of drug-drug interaction between T-DM1 and docetaxel.
  
  
  
  T-DM1 combined with docetaxel ± pertuzumab appeared efficacious in MBC or LABC; however, nearly half of patients experienced AEs requiring dose reductions with these T-DM1 combinations.
  
  
  
  NCT00934856.
authors.affiliation: Medical Oncology Service, Hospital General Universitario Gregorio Marañón, Madrid, Spain mmartin@geicam.org.
authors.forename: M
authors.initials: M
authors.lastname: Martin
authors.affiliation: Medical Oncology, Georges Francois Leclerc Centre, Dijon, France.
authors.forename: P
authors.initials: P
authors.lastname: Fumoleau
authors.affiliation: Department of Oncology, Ninewells Hospital, Dundee, UK.
authors.forename: J A
authors.initials: JA
authors.lastname: Dewar
authors.affiliation: Medical Oncology, Hospital del Mar, Barcelona Cancer Research Program, IMIM, Barcelona CEXS, Ponpeu Fabra University, Barcelona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Albanell
authors.affiliation: Hematology -Medical Oncology Department, Levine Cancer Institute, Charlotte, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Limentani
authors.affiliation: Medical Oncology, Institute of Cancer Research (ICO) in Western France, Nantes, France.
authors.forename: M
authors.initials: M
authors.lastname: Campone
authors.affiliation: Houston Methodist Cancer Center, Houston Methodist Hospital, Houston, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Chang
authors.affiliation: Pharma Development Oncology.
authors.forename: M
authors.initials: M
authors.lastname: Patre
authors.affiliation: Department of Biostatistics.
authors.forename: A
authors.initials: A
authors.lastname: Strasak
authors.affiliation: Oncology Biomarker Development, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: S L
authors.initials: SL
authors.lastname: de Haas
authors.affiliation: Department of Clinical Pharmacology, Genentech, Inc., South San Francisco, USA.
authors.forename: J
authors.initials: J
authors.lastname: Xu
authors.affiliation: Medical Oncology Department, Hospital Universitario Clínico San Carlos, Madrid, Spain.
authors.forename: J A
authors.initials: JA
authors.lastname: Garcia-Saenz
mesh_terms: D000080044:Ado-Trastuzumab Emtansine; D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018572:Disease-Free Survival; D000077143:Docetaxel; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000235:genetics; D006801:Humans; D008453:Maytansine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D009367:Neoplasm Staging; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D043823:Taxoids / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000068878:Trastuzumab / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D000080044:Ado-Trastuzumab Emtansine; D061067:Antibodies, Monoclonal, Humanized; D000077143:Docetaxel; D016179:Granulocyte Colony-Stimulating Factor; D008453:Maytansine; D018719:Erb-b2 Receptor Tyrosine Kinases; D043823:Taxoids; D000068878:Trastuzumab; C508053:ERBB2 protein, human; C485206:pertuzumab
keywords: T-DM1; ado-trastuzumab emtansine; breast cancer; docetaxel; pertuzumab; trastuzumab emtansine