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JAMA Oncol. 2019 Aug 29. doi: 10.1001/jamaoncol.2019.2526. [Epub ahead of print]

Fulvestrant Plus Vistusertib vs Fulvestrant Plus Everolimus vs Fulvestrant Alone for Women With Hormone Receptor-Positive Metastatic Breast Cancer: The MANTA Phase 2 Randomized Clinical Trial.

Author information

1
Barts Cancer Institute, Centre for Experimental Cancer Medicine, Queen Mary University of London, London, United Kingdom.
2
Oncology-Clinical, Barts Health National Health Service Trust, London, United Kingdom.
3
Praxis fuer Interdisziplinaere Onkologie, Freiburg, Germany.
4
Kent Oncology Centre, Maidstone and Tunbridge Wells National Health Service Trust, Tunbridge Wells, United Kingdom.
5
Instituto Português de Oncologia do Porto Francisco Gentil, Porto, Portugal.
6
Oncology, Derriford Hospital, Plymouth Hospitals National Health System Trust, Plymouth, United Kingdom.
7
Oncology-Clinical, Nottingham University Hospitals National Health System Trust, Nottingham, United Kingdom.
8
Mount Vernon Cancer Centre, East & North Herts National Health System Trust, London, United Kingdom.
9
Institute of Clinical Oncology, Tbilisi, Republic of Georgia.
10
Cancer Centre, University Hospitals of North Midlands National Health System Trust, Stoke-on-Trent, United Kingdom.
11
Kliniken Essen-Mitte, Essen, Germany.
12
Hospital Universitario Sant Joan De Reus, Tarragona, Spain.
13
Hospital Son Espases, Palma, Spain.
14
Cancer Services, Great Western Hospitals National Health System Foundation Trust, Swindon, United Kingdom.
15
Academic Unit of Clinical Oncology, University of Sheffield, Sheffield, United Kingdom.
16
Medical Oncology, Queen Elizabeth Hospital, Woolwich, Lewisham and Greenwich National Health System Trust, London, United Kingdom.
17
Vall d'Hebron Institute of Oncology, SOLTI Breast Cancer Research Group, Vall d'Hebron University Hospital, Barcelona, Spain.
18
Institut Sainte Catherine, Avignon, France.
19
Zala County Hospital, Zalaegerszeg, Hungary.
20
Sf Nectarie Oncology Center Societate cu Raspundere Limitata, Craiova, Dolj, Romania.
21
Yonsei University Health System, Seoul, Republic of Korea.
22
National Cancer Center, Goyang-si Gyeonggi-do, Republic of Korea.
23
Oncology Translational Medicine Unit, Innovative Medicines and Early Drug Development Biotech Unit, AstraZeneca, Cambridge, United Kingdom.
24
Ramon y Cajal University Hospital, Madrid, Spain.
25
Baselga Oncology Institute, Institute of Oncology, QuironGroup, Madrid, Spain.

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.

Trial Registration:

ClinicalTrials.gov identifier: NCT02216786 and EudraCT number: 2013-002403-34.

PMID:
31465093
DOI:
10.1001/jamaoncol.2019.2526
Free PMC Article

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