Peter Schmid
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
Authors
Matthias Zaiss
Catherine Harper-Wynne
Marta Ferreira
Sidharth Dubey
Stephen Chan
Andreas Makris
Gia Nemsadze
Professor Adrian Brunt m.brunt@keele.ac.uk
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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