title: Phase IIa trial of trastuzumab emtansine with pertuzumab for patients with human epidermal growth factor receptor 2-positive, locally advanced, or metastatic breast cancer.
abstract: OBJECTIVE
  Our phase IIa study characterized the safety and efficacy of two human epidermal growth factor receptor 2 (HER2) -targeted agents, trastuzumab emtansine (T-DM1) and pertuzumab, in patients with HER2-positive metastatic breast cancer (MBC).
  
  
  METHODS
  Patients with HER2-positive locally advanced breast cancer or MBC were treated with 3.6 mg/kg T-DM1 plus pertuzumab (840-mg loading dose, then 420 mg subsequently) once every 3 weeks. The primary efficacy end point was investigator-assessed objective response rate (ORR).
  
  
  RESULTS
  Sixty-four patients (43 patients in the second-line or greater setting [advanced MBC]; 21 patients in the first-line setting [first-line MBC]) were enrolled. Patients with advanced MBC had received trastuzumab and a median of six prior nonhormonal treatments for MBC; 86% of first-line MBC patients had received trastuzumab in the (neo)adjuvant setting. The ORR was 41% overall, 33% in patients with advanced MBC, and 57% in first-line patients. Median progression-free survival was 6.6, 5.5, and 7.7 months, respectively. The most common adverse events were fatigue (61%), nausea (50%), and diarrhea (39%). The most frequent grade ≥ 3 adverse events were thrombocytopenia (13%), fatigue (11%), and liver enzyme elevations (increased ALT: 9%; increased AST: 9%). One patient had left ventricular ejection fraction of less than 40% after study drug discontinuation. Exploratory biomarker analyses demonstrated that patients with above-median tumor HER2 mRNA levels had a numerically higher ORR than patients with below-median levels (44% v 33%, respectively).
  
  
  CONCLUSIONS
  T-DM1 and pertuzumab can be combined at full doses with no unexpected toxicities. The preliminary efficacy in patients in the first-line and advanced MBC settings warrants further investigation.
authors.affiliation: Kathy D. Miller, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN; Reshma L. Mahtani, Sylvester Comprehensive Cancer Center, Miami, FL; Kathy S. Albain, Loyola University Chicago Stritch School of Medicine, Maywood, IL; Liang Fang, Glenn Michelson, Genentech, South San Francisco, CA; Howard A. Burris, Sarah Cannon Research Institute, Nashville, TN; Véronique Diéras, Institut Curie, Paris; Fabrice Andre, Institut Gustave Roussy, Villejuif, France; Nadia Harbeck, Interdisciplinary Breast Cancer, University of Cologne, Cologne; Nadia Harbeck, Breast Cancer University of Munich, Germany; Luca Gianni, San Raffaele Hospital, Milan; Diana Crivellari, Centro di Riferimento Oncologico, Istituto Nazionale Tumori, Aviano, Italy; Sanne L. de Haas, F. Hoffmann-La Roche, Basel, Switzerland.
authors.forename: Kathy D
authors.initials: KD
authors.lastname: Miller
authors.forename: Véronique
authors.initials: V
authors.lastname: Diéras
authors.forename: Nadia
authors.initials: N
authors.lastname: Harbeck
authors.forename: Fabrice
authors.initials: F
authors.lastname: Andre
authors.forename: Reshma L
authors.initials: RL
authors.lastname: Mahtani
authors.forename: Luca
authors.initials: L
authors.lastname: Gianni
authors.forename: Kathy S
authors.initials: KS
authors.lastname: Albain
authors.forename: Diana
authors.initials: D
authors.lastname: Crivellari
authors.forename: Liang
authors.initials: L
authors.lastname: Fang
authors.forename: Glenn
authors.initials: G
authors.lastname: Michelson
authors.forename: Sanne L
authors.initials: SL
authors.lastname: de Haas
authors.forename: Howard A
authors.initials: HA
authors.lastname: Burris
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* / Q000235:genetics / Q000401:mortality; D018572:Disease-Free Survival; D005260:Female; D018734:Genes, erbB-2; D006801:Humans; D053208:Kaplan-Meier Estimate; D008453:Maytansine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D008453:Maytansine; C485206:pertuzumab; D000068878:Trastuzumab; D000080044:Ado-Trastuzumab Emtansine