title: Phase 1B/2 study of the HSP90 inhibitor AUY922 plus trastuzumab in metastatic HER2-positive breast cancer patients who have progressed on trastuzumab-based regimen.
abstract: This open-label, multicenter, phase 1B/2 trial assessed AUY922 plus trastuzumab in patients with locally advanced or metastatic HER2-positive breast cancer previously treated with chemotherapy and anti-HER2 therapy. This study was composed of a dose-escalation part with AUY922 administered weekly at escalating doses with trastuzumab 2 mg/kg/week (phase 1B), followed by a phase 2 part using the same regimen at recommended phase 2 dose (RP2D). The primary objectives were to determine the maximum tolerated dose (MTD) and/or RP2D (phase 1B), and to evaluate preliminary antitumor activity (phase 2) of AUY922 plus trastuzumab at MTD/RP2D. Forty-five patients were treated with AUY922 plus trastuzumab (4 in phase 1B with AUY922 at 55 mg/m2 and 41 in phase 1B/2 with AUY922 at 70 mg/m2 [7 in phase 1B and 34 in phase 2]). One patient in phase 1B (70 mg/m2) experienced a dose-limiting toxicity (grade 3 diarrhea); the RP2D was weekly AUY922 70 mg/m2 plus trastuzumab. Of the 41 patients in the 70 mg/m2 cohort, the overall response rate (complete or partial responses) was 22.0% and 48.8% patients had stable disease. Study treatment-related adverse events occurred in 97.8% of patients; of these, 31.1% were grade 3 or 4. Forty-one patients (91.1%) reported ocular events (82.3% had grade 1 or 2 events). Two patients (4.4%) had ocular events leading to the permanent discontinuation of study treatment. AUY922 at 70 mg/m2 plus trastuzumab standard therapy is well tolerated and active in patients with HER2-positive metastatic breast cancer who progressed on trastuzumab-based therapy.
authors.affiliation: Previous address: Churchill Hospital, Oxford University Hospitals NHS Trust and University of Oxford, Oxford, United Kingdom.|School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Anthony
authors.initials: A
authors.lastname: Kong
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Daniel
authors.initials: D
authors.lastname: Rea
authors.affiliation: Department of Oncology, University Hospitals of Leicester, Leicester Royal Infirmary, Leicester, United Kingdom.
authors.forename: Samreen
authors.initials: S
authors.lastname: Ahmed
authors.affiliation: Department of Oncology, Highlands Oncology Group, Fayetteville, Arkansas, USA.
authors.forename: J Thaddeus
authors.initials: JT
authors.lastname: Beck
authors.affiliation: Department of Oncology, Hospital Clinico Universitario, Santiago de Compostela, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: López López
authors.affiliation: Department of Medical Oncology, Nuovo Ospedale di Prato, Prato, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Biganzoli
authors.affiliation: Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom.
authors.forename: Anne C
authors.initials: AC
authors.lastname: Armstrong
authors.affiliation: Department of Medical Oncology, University of Torino, FPO-IRCCS, Candiolo, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Aglietta
authors.affiliation: Department of Medical Oncology, University Hospital, IBIMA, Malaga, Spain.
authors.forename: Emilio
authors.initials: E
authors.lastname: Alba
authors.affiliation: Department of Medical Oncology, Institut de Cancérologie de l'ouest René Gauducheau, Nantes, France.
authors.forename: Mario
authors.initials: M
authors.lastname: Campone
authors.affiliation: Early Clinical Biostatistics, Oncology, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Shu-Fang
authors.initials: SF
authors.lastname: Hsu Schmitz
authors.affiliation: Translational Clinical Oncology, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Caroline
authors.initials: C
authors.lastname: Lefebvre
authors.affiliation: Oncology Global Development, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Akimov
authors.affiliation: Department of Hematology-Oncology, National University Cancer Institute Singapore, Singapore.
authors.forename: Soo-Chin
authors.initials: SC
authors.lastname: Lee
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001499:Bayes Theorem; D001943:Breast Neoplasms / Q000188:drug therapy*; D015331:Cohort Studies; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007555:Isoxazoles / Q000008:administration & dosage*; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009362:Neoplasm Metastasis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D012118:Resorcinols / Q000008:administration & dosage*; D000068878:Trastuzumab / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018841:HSP90 Heat-Shock Proteins; D007555:Isoxazoles; D018719:Erb-b2 Receptor Tyrosine Kinases; D012118:Resorcinols; D000068878:Trastuzumab; C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; C508053:ERBB2 protein, human
keywords: AUY922; HER2; HSP90 inhibitor; breast cancer; trastuzumab