title: A phase II trial of trabectedin in triple-negative and HER2-overexpressing metastatic breast cancer.
abstract: Trabectedin is an alkylating agent that binds to the minor groove of DNA. Early studies with trabectedin suggested efficacy in triple-negative and HER2-overexpressing metastatic breast cancer (MBC). The efficacy and safety of trabectedin in pretreated patients with these tumors were evaluated in this parallel-cohort phase II trial. Patients received a 3-h infusion of trabectedin 1.3 mg/m(2) intravenously every 3 weeks until progression or unmanageable/unacceptable toxicity. The primary objective was to evaluate the efficacy using the objective response rate (ORR) as per Response Evaluation Criteria In Solid Tumors (RECIST). Secondary objectives comprised time-to-event endpoints and safety assessed with the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v.3.0. Patients with heavily pretreated triple-negative (n = 50) or HER2-overexpressing (n = 37) MBC were enrolled. No confirmed responses were found in triple-negative MBC patients, with median progression-free survival (PFS) of 2.2 months (95 % CI 1.3-2.7 months). Confirmed partial responses occurred in 4 of 34 evaluable HER2-overexpressing MBC patients (ORR = 12 %; 95 % CI 3-27 %) and lasted a median of 12.5 months (95 % CI, 6.2-14.7 months); median PFS was 3.8 months (95 % CI, 1.8-5.5 months). Most trabectedin-related adverse events were mild or moderate, and the most frequent were fatigue, nausea, vomiting, constipation, and anorexia. Severe neutropenia and transaminase increases were non-cumulative and transient and were mostly managed by infusion delays or dose reductions. Single-agent trabectedin is well tolerated in aggressive MBC and has moderate activity in HER2-overexpressing tumors. Further studies are warranted to evaluate trabectedin combined with HER2-targeted treatments in this subtype.
authors.affiliation: Baylor-Charles A. Sammons Cancer Center, Texas Oncology, US Oncology, 3410 Worth St., Suite 400, Dallas, TX, 75246, USA. joanne.blum@usoncology.com.
authors.forename: Joanne L
authors.initials: JL
authors.lastname: Blum
authors.affiliation: Institut Paoli Calmettes, Marseille, France.
authors.forename: Anthony
authors.initials: A
authors.lastname: Gonçalves
authors.affiliation: Kaplan Medical Center, Rehovot, Israel.
authors.forename: Noa
authors.initials: N
authors.lastname: Efrat
authors.affiliation: Institute Bergonie, Bordeaux, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Debled
authors.affiliation: Azienda Ospedaliero, Università di Modena, Modena, Italy.|Istituto Oncologico Veneto, IRCCS, Università di Padova, Padua, Italy.
authors.forename: Pierfranco
authors.initials: P
authors.lastname: Conte
authors.affiliation: Oncology/Hematology Associates of SW Virginia, US Oncology, Salem, VA, USA.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Richards
authors.affiliation: Texas Oncology - Tyler, US Oncology, Tyler, TX, USA.
authors.forename: Donald
authors.initials: D
authors.lastname: Richards
authors.affiliation: Pharma Mar, S.A., Clinical R&D, Colmenar Viejo, Madrid, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Lardelli
authors.affiliation: Pharma Mar, S.A., Clinical R&D, Colmenar Viejo, Madrid, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Nieto
authors.affiliation: Pharma Mar, S.A., Clinical R&D, Colmenar Viejo, Madrid, Spain.
authors.forename: Martin
authors.initials: M
authors.lastname: Cullell-Young
authors.affiliation: Gustave Roussy Cancer Campus, Villejuif, France.
authors.forename: Suzette
authors.initials: S
authors.lastname: Delaloge
mesh_terms: D000328:Adult; D000368:Aged; D004149:Dioxoles / Q000009:adverse effects / Q000627:therapeutic use*; D018572:Disease-Free Survival; D006801:Humans; D008875:Middle Aged; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D044005:Tetrahydroisoquinolines / Q000009:adverse effects / Q000627:therapeutic use*; D000077606:Trabectedin; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D055815:Young Adult
chemical_list: D004149:Dioxoles; D018719:Erb-b2 Receptor Tyrosine Kinases; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin; C508053:ERBB2 protein, human
keywords: Breast cancer; HER2; Trabectedin; Triple negative