Abstract GS2-07: MANTA - A randomized phase II study of fulvestrant in combination with the dual mTOR inhibitor AZD2014 or everolimus or fulvestrant alone in estrogen receptor-positive advanced or metastatic breast cancer

Abstract

Background: Resistance to endocrine therapy remains a major clinical challenge with aberrant PI3K/ mTOR pathway activation being one of the main drivers. Randomised clinical trials have demonstrated a substantial benefit of adding everolimus to endocrine therapy. Vistusertib (AZD2014), a dual inhibitor of mTORC1 and mTORC2, has shown a broader range of activity in preclinical ER+ breast cancer models, showing superior activity to everolimus (EVE) both in hormone-sensitive and resistant models. The MANTA trial was desgined to evaluate the safety and efficacy of vistusertib (VIS) in combination with fulvestrant (FULV) relative to FULV alone or FULV + EVE. In addition to a continuous (cont) daily schedule of VIS, the study also explored an intermittent (int) schedule to assess the potential of short-term, maximum target inhibition. Methods: MANTA is an investigator-led, randomised, open-label phase II trial. Postmenopausal women with estrogen-receptor (ER)-positive breast cancer were eligible if they had disease recurrence while on or within 12 months of end of adjuvant treatment with an aromatase inhibitor (AI), or progression while on or within one month of end of AI treatment for locally advanced or metastatic breast cancer. Patients were randomly assigned (2:3:3:2) to receive either FULV (500 mg intramuscular injection on day 1, followed by 500 mg doses on days 15 and 29, and then every 28 days); FULV + daily VIS (50mg BD), FULV + intermittent VIS (2 days on, 5 days off; 125mg BD); or FULV + EVE (10mg OD). Treatment was given until disease progression (RECIST 1.1) or intolerable toxicity. Patients were stratified by disease measurability and response to prior endocrine therapy. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary objectives included objective response, clinical benefit rate, duration of response and clinical benefit, overall survival and safety. Results: Between 04/2014 and 10/2016, a total of 333 patients were randomised at 88 sites in 9 countries. 66 patients were assigned to receive FULV; 101 to FULV+VIS (cont), 95 to FULV+VIS (int); and 64 to FULV+EVE. Median PFS was 4.6 months (95% CI 3.4–6.9) in patients assigned to FULV; 7.5 months (95% CI 5.6–9.4) in those assigned to FULV+VIS (cont); 7.6 months (95% CI 5.5–9.6) in those assigned to FULV+VIS (int); and 12.2 months (95% CI 7.5–14.3) in those assigned to FULV+EVE. No significant difference was recorded between the patients assigned to FULV+VIS (cont) and FULV (hazard ratio 0.87, 95% CI 0.62-1.23; log-rank p=0.42); FULV+VIS (int) and FULV (HR 0.78, 95% CI 0.55-1.12; log-rank p=0.16); and FULV+VIS (cont) and FULV+VIS (int) (HR 1.11, 95% CI 0.81-1.52; log-rank p=0.52). PFS was significantly longer in patients assigned to FULV+EVE compared to FULV+VIS (cont) (HR 0.64, 95% CI 0.45-0.91; log-rank p=0.01) and FULV+EVE compared to FULV (HR 0.64, 95% CI 0.43-0.94; log-rank p=0.02). Conclusion: The trial failed to demonstrate a benefit of adding the TORC1/2 inhibitor vistusertib (AZD2014) to FULV. The combination FULV+EVE demonstrated significantly longer PFS compared to FULV+VIS or FULV. Citation Format: Schmid P, Zaiss M, Harper-Wynne C, Ferreira M, Dubey S, Chan S, Makris A, Nemsadze G, Brunt AM, Kuemmel S, Ruiz Cabrero I, Perelló A, Kendall A, Brown J, Kristeleit H, Conibear J, Saura C, Grenier J, Máhr K, Schenker M, Sohn JH, Lee KS, Sarker S-J, Coetzee C, Mousa K, Cortes Castan J. MANTA - A randomized phase II study of fulvestrant in combination with the dual mTOR inhibitor AZD2014 or everolimus or fulvestrant alone in estrogen receptor-positive advanced or metastatic breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS2-07.

Fulvestrant in the treatment of hormone receptor‐positive/human epidermal growth factor receptor 2‐negative advanced breast cancer: A review

“…On the contrary, results from a very recent trial, MANTA (NCT02216786), an investigator-led, randomized, open-label phase II trial failed to demonstrate any benefit of adding target of rapamycin complex 1/2 (TORC1/2) inhibitor, vistusertib (AZD2014), to fulvestrant. 83 . A total of 333 patients were randomized to receive fulvestrant (n = 66), fulvestrant + vistusertib (n = 106, continuous), fulvestrant + vistusertib (n = 95, intermittent); and fulvestrant + everolimus (n = 64).…”

Use of Novel Combination Therapies in the Treatment of Advanced HR+/HER2− Breast Cancer

“…Inhibition of mTORC1 alone with everolimus can lead to activation of a feedback mechanism via AKT signaling, possibly leading to resistance. 55 Vistusertib (AZD2014) is a novel, dual inhibitor of mTORC1 (rapamycin-sensitive) and mTORC2 (rapamycin insensitive) that has been studied with the hypothesis that this agent may be superior to everolimus by allowing for complete blockade of the signaling pathway. Additionally, preclinical models suggest a relationship between higher exposure of mTOR inhibition and increased efficacy.…”

Emerging data and future directions for CDK4/6 inhibitor treatment of patients with hormone receptor positive HER2‐non‐amplified metastatic breast cancer

“…Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, in combination with exemestane, has demonstrated prolonged median PFS compared with exemestane alone in patients who had progressed on nonsteroidal aromatase inhibitors (NSAIs) in the BOLERO‐2 trial (7.8 vs. 3.2 months; HR 0.45; 95% CI 0.38–0.54) and has been FDA and PBS approved for this indication. Similarly, everolimus extended PFS when added to fulvestrant (12.2 vs. 7.6 months; HR 0.64; 95% CI 0.45–0.91) . Preclinical studies with triplet combinations of PI3K/mTOR inhibitors, CDK4/6 inhibitors and endocrine therapies have been promising, forming the basis of a number of phase I clinical studies currently underway (Table ) .…”