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A phase 2 study of everolimus combined with trastuzumab and paclitaxel in patients with HER2-overexpressing advanced breast cancer that progressed during prior trastuzumab and taxane therapy |
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| Authors: | Sara A. Hurvitz Florence Dalenc Mario Campone Ruth M. O’Regan Vivianne C. Tjan-Heijnen Joseph Gligorov Antonio Llombart Haresh Jhangiani Hamid R. Mirshahidi Elizabeth Tan-Chiu Sara Miao Mona El-Hashimy Jeremie Lincy Tetiana Taran Jean-Charles Soria Tarek Sahmoud Fabrice André |
| Affiliation: | 1. Department of Medicine, Hematology/Oncology, UCLA Jonsson Comprehensive Cancer Center, 10945 Le Conte Avenue, PVUB Suite 3360, Los Angeles, CA, 90095, USA 2. Institut Claudius Regaud, Toulouse, France 3. Centre René Gauducheau, Nantes-Saint-Herblain, France 4. Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, USA 5. Department of Medical Oncology, Maastricht University Medical Centre, Maastricht, The Netherlands 6. Medical Oncology Department, APHP-IUC, APREC, Paris, France 7. Oncology Service, Hospital Universitario Arnau de Vilanova, Lleida, Spain 8. Compassionate Cancer Care Medical Group Inc., Corona, CA, USA 9. Division of Medical Oncology and Hematology, Loma Linda University Cancer Center, Loma Linda, CA, USA 10. Florida Cancer Care, Plantation, FL, USA 11. Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA 12. Novartis Pharma AG, Basel, Switzerland 13. Early Clinical Trials Unit (SITEP), Institut Gustave Roussy, Villejuif, France 14. Institut Gustave Roussy, Villejuif, France |
| Abstract: | Increased activation of the PI3K/Akt/mTOR pathway is a common factor in putative mechanisms of trastuzumab resistance, resulting in dysregulation of cell migration, growth, proliferation, and survival. Data from preclinical and phase 1/2 clinical studies suggest that adding everolimus (an oral mTOR inhibitor) to trastuzumab plus chemotherapy may enhance the efficacy of, and restore sensitivity to, trastuzumab-based therapy. In this phase 2 multicenter study, adult patients with HER2-positive advanced breast cancer resistant to trastuzumab and pretreated with a taxane received everolimus 10 mg/day in combination with paclitaxel (80 mg/m2 days 1, 8, and 15 every 4 weeks) and trastuzumab (4 mg/kg loading dose followed by 2 mg/kg weekly), administered in 28-day cycles. Endpoints included overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Fifty-five patients were enrolled; one remained on study treatment at the time of data cutoff. The median number of prior chemotherapy lines for advanced disease was 3.5 (range 1–11). The ORR was 21.8 %, the clinical benefit rate was 36.4 %, the median PFS estimate was 5.5 months (95 % confidence interval [CI]: 4.99–7.69 months), and the median OS estimate was 18.1 months (95 % CI: 12.85–24.11 months). Hematologic grade 3/4 adverse events (AEs) included neutropenia (25.5 % grade 3, 3.6 % grade 4), anemia (7.3 % grade 3), and thrombocytopenia (5.5 % grade 3, 1.8 % grade 4). Nonhematologic grade 3/4 AEs included stomatitis (20.0 %), diarrhea (5.5 %), vomiting (5.5 %), fatigue (5.5 %), and pneumonia (5.5 %), all grade 3. These findings suggest that the combination of everolimus plus trastuzumab and paclitaxel is feasible, with promising activity in patients with highly resistant HER2-positive advanced breast cancer. This combination is currently under investigation in the BOLERO-1 phase 3 trial. |
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