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

Noah Kornblum, Fengmin Zhao, Judith Manola, Paula Klein, Bhuvaneswari Ramaswamy, Adam Brufsky, Phillip J. Stella, Brian Burnette, Melinda Telli, Della F. Makower, Puneet Cheema, Cristina I. Truica, Antonio C. Wolff, Gamini S. Soori, Barbara Haley, Timothy R. Wassenaar, Lori J. Goldstein, Kathy Miller, Joseph A. Sparano

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1556-1563
Number of pages8
JournalJournal of Clinical Oncology
Volume36
Issue number16
DOIs
StatePublished - Jun 1 2018

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Aromatase Inhibitors
Placebos
Hormones
Breast Neoplasms
Estrogen Receptors
Sirolimus
Therapeutics
Disease-Free Survival
Arm
Stomatitis
Hypertriglyceridemia
Everolimus
fulvestrant
human ERBB2 protein
Exanthema
Phosphatidylinositol 3-Kinases
Hyperglycemia
Fatigue
Mouth
Anemia

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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. / Kornblum, Noah; Zhao, Fengmin; Manola, Judith; Klein, Paula; Ramaswamy, Bhuvaneswari; Brufsky, Adam; Stella, Phillip J.; Burnette, Brian; Telli, Melinda; Makower, Della F.; Cheema, Puneet; Truica, Cristina I.; Wolff, Antonio C.; Soori, Gamini S.; Haley, Barbara; Wassenaar, Timothy R.; Goldstein, Lori J.; Miller, Kathy; Sparano, Joseph A.

In: Journal of Clinical Oncology, Vol. 36, No. 16, 01.06.2018, p. 1556-1563.

Research output: Contribution to journalArticle

Kornblum, N, Zhao, F, Manola, J, Klein, P, Ramaswamy, B, Brufsky, A, Stella, PJ, Burnette, B, Telli, M, Makower, DF, Cheema, P, Truica, CI, Wolff, AC, Soori, GS, Haley, B, Wassenaar, TR, Goldstein, LJ, Miller, K & Sparano, JA 2018, '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', Journal of Clinical Oncology, vol. 36, no. 16, pp. 1556-1563. https://doi.org/10.1200/JCO.2017.76.9331
Kornblum, Noah ; Zhao, Fengmin ; Manola, Judith ; Klein, Paula ; Ramaswamy, Bhuvaneswari ; Brufsky, Adam ; Stella, Phillip J. ; Burnette, Brian ; Telli, Melinda ; Makower, Della F. ; Cheema, Puneet ; Truica, Cristina I. ; Wolff, Antonio C. ; Soori, Gamini S. ; Haley, Barbara ; Wassenaar, Timothy R. ; Goldstein, Lori J. ; Miller, Kathy ; Sparano, Joseph A. / 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. In: Journal of Clinical Oncology. 2018 ; Vol. 36, No. 16. pp. 1556-1563.
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title = "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",
abstract = "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.",
author = "Noah Kornblum and Fengmin Zhao and Judith Manola and Paula Klein and Bhuvaneswari Ramaswamy and Adam Brufsky and Stella, {Phillip J.} and Brian Burnette and Melinda Telli and Makower, {Della F.} and Puneet Cheema and Truica, {Cristina I.} and Wolff, {Antonio C.} and Soori, {Gamini S.} and Barbara Haley and Wassenaar, {Timothy R.} and Goldstein, {Lori J.} and Kathy Miller and Sparano, {Joseph A.}",
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TY - JOUR

T1 - 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

T2 - Results of PrE0102

AU - Kornblum, Noah

AU - Zhao, Fengmin

AU - Manola, Judith

AU - Klein, Paula

AU - Ramaswamy, Bhuvaneswari

AU - Brufsky, Adam

AU - Stella, Phillip J.

AU - Burnette, Brian

AU - Telli, Melinda

AU - Makower, Della F.

AU - Cheema, Puneet

AU - Truica, Cristina I.

AU - Wolff, Antonio C.

AU - Soori, Gamini S.

AU - Haley, Barbara

AU - Wassenaar, Timothy R.

AU - Goldstein, Lori J.

AU - Miller, Kathy

AU - Sparano, Joseph A.

PY - 2018/6/1

Y1 - 2018/6/1

N2 - 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.

AB - 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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