Kelly Mousa

Abstract OT1-03-12: 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

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, Perello A, Kendall A, Brown J, Kristeleit H, Conibear J, Saura C, Grenier J, Mahr 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.

Abstract OT1-03-13: A phase II, double blind, randomised, placebo-controlled study of the AKT Inhibitor AZD5363 in combination with paclitaxel in triple-negative advanced or metastatic breast cancer (TNBC)(NCT02423603)

Management of metastatic TNBC remains a challenge. Chemotherapy is the mainstay of treatment but benefits are frequently short-lived with rapid development of resistance. The PI3K/AKT/mTOR pathway has been implicated in many ways in TNBC, making inhibition of AKT an attractive therapeutic target. Based on downstream pathway activation signatures, PI3K pathway activation appears higher in TNBC compared to other molecular subtypes, despite a relatively low percentage of activating PI3K mutations. Alternative means of activating the PI3K pathway have been identified in TNBC, including loss or mutation of PTEN (up to 35%) and INPP4B (up to 30%) and/or amplification of PIK3CA, AKT2 or AKT3, resulting in increased activation of AKT. Induction of AKT by chemotherapy can be an early compensatory mechanism that can be exploited therapeutically to increase the efficacy of chemotherapy. Preclinical TNBC models with activated AKT signalling have been shown to be highly sensitive to AKT inhibitors. AZD5363 is a potent pan-AKT inhibitor with good oral bioavailability. Multiple lines of investigation have demonstrated strong synergistic effects between AKT inhibition and taxane chemotherapy in models of TNBC both in vitro and in vivo, providing rationale for the combination of AZD5363 and paclitaxel in TNBC. PAKT is designed to test the hypothesis that inhibition of AKT will increase the anti-tumour activity of paclitaxel chemotherapy in TNBC. The study will try to characterize those patients who may benefit from this treatment to identify potential predictors of sensitivity. PAKT is an international investigator led and sponsored, double-blind, placebo controlled, randomised phase II trial. Patients are randomised 1:1 to receive paclitaxel weekly (90mg/m2) on days 1,8, and 15 plus AZD5363 (400mgBD) or placebo (400mgBD) on days 2-5, 9-12, 15-19 (28 day treatment cycles). Patients are stratified by the number of metastatic sites and the interval from the end of adjuvant chemotherapy. Treatment is given until disease progression (RECIST 1.1), intolerable toxicity or elective withdrawal. Tumour assessments are carried out every 8 weeks. PAKT enrols patients with histologically documented locally advanced/metastatic TNBC (ER≤Allred2, PR≤Allred2, HER2=0,1+or2+), no prior systemic therapy for advanced TNBC, ECOG PS 0-2 and measurable disease per RECIST v1.1. Patients with brain metastases, significant cardiovascular disease, motor polyneuropathy are excluded. The primary endpoint is progression-free survival. Secondary endpoints are objective response rate, change in tumour size, clinical benefit rate, overall survival, duration of response, and patient reported outcomes. Archival tumour tissue must be available to evaluate potential biomarkers associated with therapeutic response and resistance. PFS will be compared between treatment arms by the stratified log-rank test. HR for disease progression/death will be estimated using a stratified Cox proportional hazards model. Kaplan-Meier methodology will be used to estimate the median PFS for each arm. Approximately 140 patients will be enrolled at ≈65 sites in the UK, France, Hungary, Romania, Georgia & South Korea. Citation Format: Schmid P, Wheatley D, Baird R, Chan S, Abraham J, Tutt A, Kristeleit H, Patel G, Bathakur U, Bishop J, Harper-Wynne C, Sims E, Copson E, Perren T, Stein R, Poole C, Cartwright H, Sarker S-J, Mousa K, Turner N. A phase II, double blind, randomised, placebo-controlled study of the AKT Inhibitor AZD5363 in combination with paclitaxel in triple-negative advanced or metastatic breast cancer (TNBC)(NCT02423603). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT1-03-13.