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J Clin Oncol. 2018 Jun 1;36(16):1556-1563. doi: 10.1200/JCO.2017.76.9331. Epub 2018 Apr 17.

Randomized Phase II Trial of Fulvestrant Plus Everolimus or Placebo in Postmenopausal Women With Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer Resistant to Aromatase Inhibitor Therapy: Results of PrE0102.

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Noah Kornblum, Della F. Makower, and Joseph A. Sparano, Albert Einstein College of Medicine, Bronx; Paula Klein, Mount Sinai Beth Israel Comprehensive Cancer Center, New York, NY; Fengmin Zhao and Judith Manola, Dana-Farber Cancer Institute, Boston, MA; Bhuvaneswari Ramaswamy, The Ohio State University Comprehensive Cancer Center, Columbus, OH; Adam Brufsky, University of Pittsburgh, Pittsburgh; Cristina I. Truica, Penn State Cancer Institute, Hershey; Lori J. Goldstein, Fox Chase Cancer Center, Philadelphia, PA; Phillip J. Stella, Saint Joseph Mercy (Michigan Cancer Consortium), Ann Arbor, MI; Brian Burnette, Saint Vincent Hospital, Green Bay; Timothy R. Wassenaar, Pro Health Care, Waukesha, WI; Melinda Telli, Stanford University School of Medicine, Stanford, CA; Puneet Cheema, Metro-Minnesota Community Oncology Research Consortium, Saint Louis Park, MN; Antonio C. Wolff, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD; Gamini S. Soori, Missouri Valley Cancer Consortium, Omaha, NE; Barbara Haley, UT Southwestern Medical Center, Dallas, TX; and Kathy D. Miller, Indiana University School of Medicine, Indianapolis, IN.


Purpose The mammalian target of rapamycin inhibitor everolimus targets aberrant signaling through the PI3K/AKT/mammalian target of rapamycin pathway, a mechanism of resistance to anti-estrogen therapy in estrogen receptor (ER)-positive breast cancer. We hypothesized that everolimus plus the selective ER downregulator fulvestrant would be more efficacious than fulvestrant alone in ER-positive metastatic breast cancer resistant to aromatase inhibitor (AI) therapy. Patients and Methods This randomized, double-blind, placebo-controlled, phase II study included 131 postmenopausal women with ER-positive, human epidermal growth factor receptor 2-negative, AI-resistant metastatic breast cancer randomly assigned to fulvestrant (500 mg days 1 and 15 of cycle 1, then day 1 of cycles 2 and beyond) plus everolimus or placebo. The study was designed to have 90% power to detect a 70% improvement in median progression-free survival from 5.4 months to 9.2 months. Secondary end points included objective response and clinical benefit rate (response or stable disease for at least 24 weeks). Prophylactic corticosteroid mouth rinses were not used. Results The addition of everolimus to fulvestrant improved the median progression-free survival from 5.1 to 10.3 months (hazard ratio, 0.61 [95% CI, 0.40 to 0.92]; stratified log-rank P = .02), indicating that the primary trial end point was met. Objective response rates were similar (18.2% v 12.3%; P = .47), but the clinical benefit rate was significantly higher in the everolimus arm (63.6% v 41.5%; P = .01). Adverse events of all grades occurred more often in the everolimus arm, including oral mucositis (53% v 12%), fatigue (42% v 22%), rash (38% v 5%), anemia (31% v. 6%), diarrhea (23% v 8%), hyperglycemia (19% v 5%), hypertriglyceridemia (17% v 3%), and pneumonitis (17% v 0%), although grade 3 to 4 events were uncommon. Conclusion Everolimus enhances the efficacy of fulvestrant in AI-resistant, ER-positive metastatic breast cancer.


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