1. 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
- Author
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Rafael López, Shu Fang Hsu Schmitz, Caroline Lefebvre, Soo-Chin Lee, Anne C Armstrong, Emilio Alba, Mario Campone, Mikhail Akimov, Samreen Ahmed, Massimo Aglietta, J. Thaddeus Beck, Laura Biganzoli, Anthony Kong, Daniel Rea, [Kong, Anthony] Oxford Univ Hosp NHS Trust, Churchill Hosp, Oxford, England, [Kong, Anthony] Univ Oxford, Oxford, England, [Kong, Anthony] Univ Birmingham, Sch Canc Sci, Birmingham, W Midlands, England, [Rea, Daniel] Univ Birmingham, Sch Canc Sci, Birmingham, W Midlands, England, [Ahmed, Samreen] Leicester Royal Infirm, Univ Hosp Leicester, Dept Oncol, Leicester, Leics, England, [Beck, J. Thaddeus] Highlands Oncol Grp, Dept Oncol, Fayetteville, AR USA, [Lopez, Rafael Lopez] Hosp Clin Univ, Dept Oncol, Santiago De Compostela, Spain, [Biganzoli, Laura] Nuovo Osped Prato, Dept Med Oncol, Prato, Italy, [Armstrong, Anne C.] Christie NHS Fdn Trust, Dept Med Oncol, Manchester, Lancs, England, [Aglietta, Massimo] Univ Turin, Dept Med Oncol, FPO IRCCS, Candiolo, Italy, [Alba, Emilio] IBIMA, Univ Hosp, Dept Med Oncol, Malaga, Spain, [Campone, Mario] Inst Canc Ouest Rene Gauducheau, Dept Med Oncol, Nantes, France, [Schmitz, Shu-Fang Hsu] Novartis Pharma AG, Early Clin Biostat, Oncol, Basel, Switzerland, [Lefebvre, Caroline] Novartis Pharma AG, Translat Clin Oncol, Basel, Switzerland, [Akimov, Mikhail] Novartis Pharma AG, Oncol Global Dev, Basel, Switzerland, [Lee, Soo-Chin] Natl Univ Singapore, Canc Inst Singapore, Dept Hematol Oncol, Singapore 117548, Singapore, Novartis Pharma AG, Basel, Switzerland, and Breakthrough Breast Cancer Clinician Scientist fellowship through Holbeck charitable trust
- Subjects
0301 basic medicine ,Oncology ,Gerontology ,Receptor, ErbB-2 ,medicine.medical_treatment ,Kaplan-Meier Estimate ,Docetaxel ,Cohort Studies ,0302 clinical medicine ,Trastuzumab ,Antineoplastic Combined Chemotherapy Protocols ,Medicine ,Open-label ,Neoplasm Metastasis ,skin and connective tissue diseases ,AUY922 ,Middle Aged ,Metastatic breast cancer ,trastuzumab ,Treatment Outcome ,030220 oncology & carcinogenesis ,Toxicity ,Disease Progression ,Ii trial ,Female ,Research Paper ,medicine.drug ,Adult ,medicine.medical_specialty ,HSP90 inhibitor ,Efficacy ,Breast Neoplasms ,Antibodies, Monoclonal, Humanized ,03 medical and health sciences ,Breast cancer ,Her2 ,breast cancer ,Internal medicine ,1st-line treatment ,Dose-escalation ,HER2 ,Humans ,Chemotherapy ,HSP90 Heat-Shock Proteins ,Adverse effect ,Capecitabine ,Aged ,Dose-Response Relationship, Drug ,business.industry ,Bayes Theorem ,Isoxazoles ,Resorcinols ,medicine.disease ,Monoclonal-antibody ,Discontinuation ,Regimen ,030104 developmental biology ,business - 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/m2) 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.
- Published
- 2016