title: Phase III trial of nonpegylated liposomal doxorubicin in combination with trastuzumab and paclitaxel in HER2-positive metastatic breast cancer.
abstract: BACKGROUND
  Nonpegylated liposomal doxorubicin liposomal doxorubicin, (Myocet™; Sopherion Therapeutics, Inc Canada, and Cephalon, Europe) (NPLD; Myocet(®)) in combination with trastuzumabHerceptin(®) (Hoffmann-La Roche) has shown promising activity and cardiac safety. We conducted a randomized phase III trial of first-line NPLD plus trastuzumab and paclitaxel (Pharmachemie B.V.) (MTP) versus trastuzumab plus paclitaxel (TP) in patients with human epidermal growth factor 2 receptor (HER2)-positive metastatic breast cancer.
  
  
  METHODS
  Patients were randomly assigned to NPLD (M, 50 mg/m(2) every 3 weeks for six cycles), trastuzumab (T, 4 mg/kg loading dose followed by 2 mg/kg weekly), and paclitaxel (P, 80 mg/m(2) weekly) or T + P at the same doses until progression or toxicity. The primary efficacy outcome was progression-free survival (PFS).
  
  
  RESULTS
  One hundred and eighty-one patients were allocated to receive MTP, and 183 to TP. Median PFS was 16.1 and 14.5 months with MTP and TP, respectively [hazard ratio (HR) 0.84; two-sided P = 0.174]. In patients with estrogen receptor (ER)- and progesterone receptor (PR)-negative tumors, PFS was 20.7 and 14.0 months, respectively [HR 0.68; 95% confidence interval (CI) 0.47-0.99]. Median overall survival (OS) was 33.6 and 28.9 months with MTP and TP, respectively (HR 0.79; two-sided P = 0.083). In ER- and PR-negative tumors, OS was 38.2 and 27.9 months, respectively (HR 0.63; 95% CI 0.42-0.93). The frequency of adverse events was higher with MTP, but there was no significant difference in cardiac toxicity between treatment arms.
  
  
  CONCLUSIONS
  The trial failed to demonstrate a significant clinical improvement with the addition of M to TP regimen. The clinical benefit observed in an exploratory analysis in the ER- and PR-negative population deserves consideration for further clinical trials.
  
  
  BACKGROUND
  NCT00294996.
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, USA; SOLTI Breast Cancer Research Group, Barcelona, Spain. Electronic address: baselgaj@mskcc.org.
authors.forename: J
authors.initials: J
authors.lastname: Baselga
authors.affiliation: City Clinical Oncology Dispensary, St. Petersburg, Russia.
authors.forename: A
authors.initials: A
authors.lastname: Manikhas
authors.affiliation: SOLTI Breast Cancer Research Group, Barcelona, Spain; Medical Oncology, Vall d'Hebron University Hospital, Barcelona.
authors.forename: J
authors.initials: J
authors.lastname: Cortés
authors.affiliation: SOLTI Breast Cancer Research Group, Barcelona, Spain; Medical Oncology, Arnau de Vilanova Hospital, Valencia, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Llombart
authors.affiliation: Leningrad Regional Oncology Dispensary, St. Petersburg.
authors.forename: L
authors.initials: L
authors.lastname: Roman
authors.affiliation: Department of Tumor of Reproductive System, N.N. Petrov Research Institute of Oncology, St. Petersburg.
authors.forename: V F
authors.initials: VF
authors.lastname: Semiglazov
authors.affiliation: Central Clinical Hospital No. 2 Named After N.A. Semashko, Moskow, Russia.
authors.forename: M
authors.initials: M
authors.lastname: Byakhov
authors.affiliation: Department of Medical Oncology, Kidway Memorial Institute of Oncology, Bangalore, India.
authors.forename: D
authors.initials: D
authors.lastname: Lokanatha
authors.affiliation: Sopherion Therapeutics, East Brunswick.
authors.forename: S
authors.initials: S
authors.lastname: Forenza
authors.affiliation: Sopherion Therapeutics, East Brunswick.
authors.forename: R H
authors.initials: RH
authors.lastname: Goldfarb
authors.affiliation: Sopherion Therapeutics, East Brunswick.
authors.forename: J
authors.initials: J
authors.lastname: Matera
authors.affiliation: Oncology Statistics LLC, Laguna Niguel, USA.
authors.forename: N
authors.initials: N
authors.lastname: Azarnia
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Hudis
authors.affiliation: Sopherion Therapeutics, East Brunswick.
authors.forename: M
authors.initials: M
authors.lastname: Rozencweig
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000009:adverse effects / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000627:therapeutic use*; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy*; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D009362:Neoplasm Metastasis / Q000188:drug therapy; D017239:Paclitaxel / Q000009:adverse effects / Q000627:therapeutic use*; D011092:Polyethylene Glycols / Q000009:adverse effects / Q000627:therapeutic use; D011446:Prospective Studies; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D000068878:Trastuzumab; D016896:Treatment Outcome
chemical_list: D000903:Antibiotics, Antineoplastic; D061067:Antibodies, Monoclonal, Humanized; D000972:Antineoplastic Agents, Phytogenic; D004317:Doxorubicin; D017239:Paclitaxel; D011092:Polyethylene Glycols; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C506643:liposomal doxorubicin; C508053:ERBB2 protein, human
keywords: anthracyclines, HER2, cardiac safety, Myocet, trastuzumab; breast cancer