Schmid, P, Zaiss, M, Harper-Wynne, C, Ferreira, M, Dubey, S, Chan, S, Makris, A, Nemsadze, G, Brunt, AM, Kuemmel, S, Ruiz, I, Perelló, A, Kendall, A, Brown, J, Kristeleit, H, Conibear, J, Saura, C, Grenier, J, Máhr, K, Schenker, M, Sohn, J, Lee, KS, Shepherd, CJ, Oelmann, E, Sarker, S-J, Prendergast, A, Marosics, P, Moosa, A, Lawrence, C, Coetzee, C, Mousa, K and Cortés, J (2019) Fulvestrant Plus Vistusertib vs Fulvestrant Plus Everolimus vs Fulvestrant Alone for Women With Hormone Receptor–Positive Metastatic Breast Cancer. JAMA Oncology, 5 (11). 1556 - 1556. ISSN 2374-2437

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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.

Item Type: Article
Additional Information: This is an open access article distributed under the terms of the CC-BY-NC-ND License. © 2019 Schmid P et al. JAMA Oncology.
Subjects: R Medicine > R Medicine (General)
Divisions: Faculty of Medicine and Health Sciences > Institute for Science and Technology in Medicine
Depositing User: Symplectic
Date Deposited: 25 Nov 2019 15:13
Last Modified: 08 Mar 2021 12:00
URI: https://eprints.keele.ac.uk/id/eprint/7295

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