Schmid, P;
Mathias, Z;
Harper-Wynne, C;
Ferreira, M;
Dubey, S;
Chan, S;
Makris, A;
... Cortes, J; + view all
(2019)
Randomised trial of fulvestrant plus vistusertib versus fulvestrant plus everolimus versus fulvestrant alone in hormone-receptor-positive metastatic breast cancer (MANTA).
JAMA Oncology
(In press).
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Abstract
Importance: Randomised clinical trials have demonstrated a substantial benefit of adding everolimus to endocrine therapy. Everolimus inhibits the mTORC1 complex but not mTORC2, which can set off a 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 to fulvestrant alone or fulvestrant plus everolimus. Design: MANTA is an open-label, randomised phase 2 trial. Between April 2014 and October 2016, 333 patients underwent randomisation (2:3:3:2) 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 toxicity or withdrawal of consent. Setting: Investigator led, international, multicentre clinical trial. Participants: 333 postmenopausal women with ER-positive breast cancer progressing after prior aromatase inhibitor treatment. Interventions: Fulvestrant alone or in combination with vistusertib (continuous or intermittent dosing schedules) or everolimus. Main Outcome and Measure: The primary endpoint was progression-free survival (PFS). Results: Median PFS was 5·4 months (95% CI 3·5–9·2) with fulvestrant; 7·6 months (95%CI 5·9–9·4) with fulvestrant plus daily vistusertib; 8·0 months (95%CI 5·6–9·9) with fulvestrant plus intermittent vistusertib; and 12·3 months (95%CI 7·7–15·7) with fulvestrant plus everolimus. There was no difference in PFS between fulvestrant plus daily or intermittent vistusertib and fulvestrant [HR 0·88 (95%CI 0·63-1·24; p=0·46) and HR 0·79 (95%CI 0·55-1·12; p=0·16), respectively]. PFS was longer in patients assigned to fulvestrant plus everolimus compared to fulvestrant plus vistusertib (HR 0·63, 95%CI 0·45-0·90; p=0·01) or fulvestrant (HR 0·63, 95%CI 0·42-0·92; p=0·01). Conclusions and Relevance: The combination of fulvestrant plus everolimus demonstrated significantly longer PFS compared to fulvestrant plus vistusertib or fulvestrant alone. The trial failed to demonstrate a benefit of adding the TORC1/2 inhibitor vistusertib to fulvestrant.
| Type: | Article |
|---|---|
| Title: | Randomised trial of fulvestrant plus vistusertib versus fulvestrant plus everolimus versus fulvestrant alone in hormone-receptor-positive metastatic breast cancer (MANTA) |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | Breast cancer, MTORC1, MTORC2, aromatase inhibitor |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10075621 |
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