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Fulvestrant Plus Vistusertib vs Fulvestrant Plus Everolimus vs Fulvestrant Alone for Women With Hormone Receptor–Positive Metastatic Breast Cancer

Schmid, Peter; Zaiss, Matthias; Harper-Wynne, Catherine; Ferreira, Marta; Dubey, Sidharth; Chan, Stephen; Makris, Andreas; Nemsadze, Gia; Brunt, Adrian M.; Kuemmel, Sherko; Ruiz, Isabel; Perelló, Antonia; Brown, Anne Kendall; Brown, Janet; Kristeleit, Hartmut; Conibear, John; Saura, Cristina; Grenier, Julien; Máhr, Károly; Schenker, Michael; Sohn, Joohyuk; Lee, Keun Seok; Shepherd, Christopher J.; Oelmann, Elisabeth; Sarker, Shah-Jalal; Prendergast, Aaron; Marosics, Patricia; Moosa, Atiyyah; Lawrence, Cheryl; Coetzee, Carike; Mousa, Kelly; Cortés, Javier

Fulvestrant Plus Vistusertib vs Fulvestrant Plus Everolimus vs Fulvestrant Alone for Women With Hormone Receptor–Positive Metastatic Breast Cancer Thumbnail


Authors

Peter Schmid

Matthias Zaiss

Catherine Harper-Wynne

Marta Ferreira

Sidharth Dubey

Stephen Chan

Andreas Makris

Gia Nemsadze

Sherko Kuemmel

Isabel Ruiz

Antonia Perelló

Anne Kendall Brown

Janet Brown

Hartmut Kristeleit

John Conibear

Cristina Saura

Julien Grenier

Károly Máhr

Michael Schenker

Joohyuk Sohn

Keun Seok Lee

Christopher J. Shepherd

Elisabeth Oelmann

Shah-Jalal Sarker

Aaron Prendergast

Patricia Marosics

Atiyyah Moosa

Cheryl Lawrence

Carike Coetzee

Kelly Mousa

Javier Cortés



Abstract

IMPORTANCE: Randomized clinical trials have demonstrated a substantial benefit of adding everolimus to endocrine therapy. Everolimus inhibits the mammalian target of rapamycin complex 1 (mTORC1) complex but not mTORC2, which can set off an activating feedback loop via mTORC2. Vistusertib, a dual inhibitor of mTORC1 and mTORC2, has demonstrated broad activity in preclinical breast cancer models, showing superior activity to everolimus.

OBJECTIVE: To evaluate the safety and efficacy of vistusertib in combination with fulvestrant compared with fulvestrant alone or fulvestrant plus everolimus in postmenopausal women with estrogen receptor–positive advanced or metastatic breast cancer.

DESIGN, SETTING, AND PARTICIPANTS: The MANTA trial is an open-label, phase 2 randomized clinical trial in which 333 patients with estrogen receptor–positive breast cancer progressing after prior aromatase inhibitor treatment underwent randomization (2:3:3:2) between April 1, 2014, and October 24, 2016, at 88 sites in 9 countries: 67 patients were assigned to receive fulvestrant, 103 fulvestrant plus vistusertib daily, 98 fulvestrant plus vistusertib intermittently, and 65 fulvestrant plus everolimus. Treatment was continued until disease progression, development of unacceptable toxic effects, or withdrawal of consent. Analysis was performed on an intention-to-treat basis.

INTERVENTIONS: Fulvestrant alone or in combination with vistusertib (continuous or intermittent dosing schedules) or everolimus.

MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival (PFS).

RESULTS Among the 333 women in the study (median age, 63 years [range, 56-70 years]), median PFS was 5.4 months (95% CI, 3.5-9.2 months) with fulvestrant, 7.6 months (95% CI, 5.9-9.4 months) with fulvestrant plus daily vistusertib, 8.0 months (95% CI, 5.6-9.9 months) with fulvestrant plus intermittent vistusertib, and 12.3 months (95% CI, 7.7-15.7 months) with fulvestrant plus everolimus. There was no significant difference in PFS between those receiving fulvestrant plus daily or intermittent vistusertib and fulvestrant alone (hazard ratio, 0.88 [95% CI, 0.63-1.24]; P = .46; and hazard ratio, 0.79 [95% CI, 0.55-1.12]; P = .16).

CONCLUSIONS AND RELEVANCE: The combination of fulvestrant plus everolimus demonstrated significantly longer PFS compared with fulvestrant plus vistusertib or fulvestrant alone. The trial failed to demonstrate a benefit of adding the dual mTORC1 and mTORC2 inhibitor vistusertib to fulvestrant.

Journal Article Type Article
Acceptance Date Apr 17, 2019
Publication Date Aug 29, 2019
Journal JAMA Oncology
Print ISSN 2374-2437
Publisher American Medical Association
Peer Reviewed Peer Reviewed
Volume 5
Issue 11
Pages 1556 - 1556
DOI https://doi.org/10.1001/jamaoncol.2019.2526
Publisher URL https://jamanetwork.com/journals/jamaoncology/fullarticle/2749178

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