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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

2016; Impact Journals LLC; Volume: 7; Issue: 25 Linguagem: Inglês

10.18632/oncotarget.8974

1949-2553

Anthony Kong, Daniel Rea, Samreen Ahmed, J. Thaddeus Beck, Rafael López‐López, Laura Biganzoli, Anne Armstrong, Massimo Aglietta, Emilio Alba, Mario Campone, Shu-Fang Hsu Schmitz, Caroline Lefèbvre, Mikhail Akimov, Soo Chin Lee,

Cancer Treatment and Pharmacology

// Anthony Kong 1, 2 , Daniel Rea 2 , Samreen Ahmed 3 , J. Thaddeus Beck 4 , Rafael López López 5 , Laura Biganzoli 6 , Anne C. Armstrong 7 , Massimo Aglietta 8 , Emilio Alba 9 , Mario Campone 10 , Shu-Fang Hsu Schmitz 11 , Caroline Lefebvre 12 , Mikhail Akimov 13 , Soo-Chin Lee 14 1 Previous address: Churchill Hospital, Oxford University Hospitals NHS Trust and University of Oxford, Oxford, United Kingdom 2 School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom 3 Department of Oncology, University Hospitals of Leicester, Leicester Royal Infirmary, Leicester, United Kingdom 4 Department of Oncology, Highlands Oncology Group, Fayetteville, Arkansas, USA 5 Department of Oncology, Hospital Clinico Universitario, Santiago de Compostela, Spain 6 Department of Medical Oncology, Nuovo Ospedale di Prato, Prato, Italy 7 Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom 8 Department of Medical Oncology, University of Torino, FPO-IRCCS, Candiolo, Italy 9 Department of Medical Oncology, University Hospital, IBIMA, Malaga, Spain 10 Department of Medical Oncology, Institut de Cancérologie de l'ouest René Gauducheau, Nantes, France 11 Early Clinical Biostatistics, Oncology, Novartis Pharma AG, Basel, Switzerland 12 Translational Clinical Oncology, Novartis Pharma AG, Basel, Switzerland 13 Oncology Global Development, Novartis Pharma AG, Basel, Switzerland 14 Department of Hematology-Oncology, National University Cancer Institute Singapore, Singapore Correspondence to: Anthony Kong, e-mail: a.h.kong@bham.ac.uk Keywords: breast cancer, HER2, HSP90 inhibitor, AUY922, trastuzumab Received: January 28, 2016 Accepted: March 31, 2016 Published: April 25, 2016 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/m 2 and 41 in phase 1B/2 with AUY922 at 70 mg/m 2 [7 in phase 1B and 34 in phase 2]). One patient in phase 1B (70 mg/m 2 ) experienced a dose-limiting toxicity (grade 3 diarrhea); the RP2D was weekly AUY922 70 mg/m 2 plus trastuzumab. Of the 41 patients in the 70 mg/m 2 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/m 2 plus trastuzumab standard therapy is well tolerated and active in patients with HER2-positive metastatic breast cancer who progressed on trastuzumab-based therapy.