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

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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Schmid reported grants from AstraZeneca, Roche/Genentech, Novartis, Oncogenex, Medivation, and Astellas; personal fees from AstraZeneca, Novartis, Pfizer, Boehringer, Bayer, Puma, Eisai, Celgene, Merck, and Roche; and other fees from Roche/Genentech. Dr Zaiss reported serving in a consulting or advisory role for Celgene, Janssen, Hexal, AstraZeneca, Roche, Lilly, and Takeda; and serving on the speaker’s bureau for Takeda. Dr Harper-Wynne reported receivng honoraria from Roche, Pfizer, Genomic Health, and Novartis; and serving in a consulting or advisory role at Roche, Pfizer, Genomic Health, Eisai, and Novartis. Dr Makris reported receivng honoraria from Roche, Genomic Health, and Nanostring; serving in a consulting or advisory role for Roche, Genomic Health, and Nanostring; serving on the speaker’s bureau for Roche, Genomic Health, and Nanostring; and receiving travel, accommodation, or other expenses from Roche. Dr Brunt reported serving in a consulting or advisory role for Roche, Genomic Health, Eisai, GFK Celldex, and Takeda; serving on the speaker’s bureau for Novartis and Roche; and receiving research funding from Roche, Galena Biopharma, Boerhinger Ingelheim, AstraZeneca, Bristol-Myers Squibb, AbbVie, Hoffman La Roche, and Cancer Research UK. Dr Kuemmel reported being Clinical Director of Westdeutsche Studiengruppe; serving in a consulting or advisory role for Roche, Genomic Health, Novartis, Amgen, Celgene, Daiichi Sankyo, AstraZeneca, Somatex, Puma Biotechnology, Pfizer, and Merck Sharp & Dohme; and receiving travel, accommodation, or other expenses from Roche and Daiichi Sankyo. Dr Perelló reported serving in a consulting or advisory role for Novartis and Celgene; serving on the speaker’s bureau for Roche, Novartis, and Celgene; and receving travel, accommodation, and expenses from Roche and Novartis. Dr Brown reported receiving honoraria from Amgen and Novartis; serving in a consulting or advisory role for Amgen, Novartis, Bayer, Takeda, Sandoz, Roche, and Bristol-Myers Squibb; serving on the speaker’s bureau for Amgen and Novartis; receiving research funding from Amgen and Bayer; and receiving travel, accommodation, or other expenses from Ipsen. Dr Kristeleit reported serving in a consulting or advisory role for Eisai, Roche, Amgen, Novartis, and Pfizer; serving on the speaker’s bureau for Eisai; receiving research funding from Roche; and receiving travel, accommodation, or other expenses from Pfizer. Dr Conibear reported receiving honoraria from AstraZeneca, Roche, Takeda, Pfizer, Amgen, and Merck Sharp & Dohme; serving in a consulting or advisory role for AstraZeneca, Roche, Takeda, Pfizer, Amgen, and Merck Sharp & Dohme; serving on the speaker’s bureau for AstraZeneca, Roche, Takeda, Pfizer, Amgen, and Merck Sharp & Dohme; and receiving travel, accommodation, or other expenses from AstraZeneca, Roche, Takeda, Pfizer, Amgen, and Merck Sharp & Dohme. Dr Saura reported receiving personal financial interests for serving on advisory boards for AstraZeneca, Celgene, Daiichi Sankyo, Eisai, Roche, Genomic, Novartis, Pfizer, Pierre Fabre, Puma, and Synthon; receving institutional financial interests paid directly to her institution from AstraZeneca, Roche, Genentech, Maacrogenics, Novartis, Pfizer, Piour Therapeutics, Puma, and Synthon; and receiving nonfinancial interests from SOLTI breast cancer research group. Dr Grenier reported receiving travel, accommodation, or other expenses from Roche, AstraZeneca, and Amgen. Dr Máhr reported receivng honoraria from Novartis, Roche, and Astellas; serving in a consulting or advisory role for Novartis; serving on the speaker’s bureau for Novartis, Roche, and Astellas; and receiving travel, accommodation, or other expenses from Roche. Dr Lee reported receiving research funding from Dong-A Pharm. Dr Shepherd reported being employed by AstraZeneca. Dr Oelmann reported being previously employed by AstraZeneca and owning shares in the company. Dr Cortés reported having stock or ownership in MedSIR; receiving honoraria from Roche, Novartis, Celgene, Eisai, Pfizer, and Samsung; serving in a consulting or advisory role for Roche, Celgene, Cellestia, AstraZeneca, Biothera Pharmaceutical, Merus, Seattle Genetics, Daiichi Sankyo, and Erytech; receiving research funding from Roche; holding patent or intellectual property with MedSIR; and receiving travel, accommodation, or other expenses from Roche, Pfizer, Eisai, and Novartis. No other disclosures were reported.

Figures

Figure 1.. CONSORT Diagram

LVEF indicates left ventricular ejection fraction.

Figure 2.. Kaplan-Meier Plot of Progression-Free Survival (PFS)

A, Fulvestrant plus daily vistusertib vs fulvestrant (median PFS: fulvestrant plus daily vistusertib, 7.6 months; fulvestrant, 5.4 months; hazard ratio, 0.88 [95% CI, 0.63-1.24]; log-rank P = .46). B, Fulvestrant plus everolimus vs fulvestrant plus daily vistusertib (median PFS: fulvestrant plus everolimus, 12.3 months; fulvestrant plus daily vistusertib, 7.6 months; hazard ratio, 0.63 [95% CI, 0.45-0.90]; log-rank P = .01). C, Fulvestrant plus everolimus vs fulvestrant (median PFS: fulvestrant plus everolimus, 12.3 months; fulvestrant, 5.4 months; hazard ratio, 0.63 [95% CI, 0.42-0.92]; log-rank P = .01). D, Fulvestrant plus daily vistusertib vs fulvestrant plus intermittent vistusertib (median PFS: fulvestrant plus daily vistusertib, 7.6 months; fulvestrant plus intermittent vistusertib, 8.0 months; hazard ratio, 1.11 [95% CI, 0.81-1.52]; log-rank P = .52).