Abstract P5-20-06: RAD001 (Everolimus) in combination with Letrozole in the treatment of postmenopausal women with estrogen receptor positive Metastatic Breast cancer after failure of hormonal therapy – a phase II study
Authors: Safra T , Kaufman B , Ben Baruch N , Kadouri-Sonenfeld L , Nisenbaum B , Greenberg J , Ryvo L , Yerushalmi R , Evron E 
Published: August 2014

Abstract
Background and Objectives: Approximately 70% of postmenopausal women (PMW) present with hormone receptor positive Metastatic Breast cancer (MBC) and there is a need for new treatment modalities after failure of prior endocrine therapy. Activation of the mTOR pathway is a key adaptive change driving endocrine resistance. Pre-clinical and early clinical data suggest synergistic effect between RAD001 (Everolimus, a Novartis mTOR inhibitor) and Letrozole results in more profound effects on proliferation arrest and induction of tumor cell kill.
Our objectives are to assess overall response rate (ORR) as well as progression free survival (PFS), overall survival (OS) and safety profile with treatment of Letrozole and RAD001 in PMW with MBC after failure of endocrine therapies.
Methods and materials: A multi-center, Israeli phase II open label study evaluating treatment of RAD001 (10 mg daily) combined with Letrozole (2.5 mg daily) in PMW with MBC after recurrence or progression on Tamoxifen and/or Anastrozole and/or Letrozole and/or Fulvestarnt and/or Exemestane.
Sixty five patients were enrolled in 7 institutes. This abstract presents data and preliminary results of 24 patients in 2 of the study centers. Median age was 65.5 (54–80) years. Hormonal status were: 50% of the patients had ER+/PR+, 40% ER+/PR- and 10% ER−/PR+. All had MBC with 1 to 3 metastatic sites i.e. bones (90%), liver (30%), lung (12%) and skin (12%).
Patients were previously exposed to a median of 1 (1–3) therapy line for MBC, all previously treated with hormonal therapy for MBC and the majority were also exposed to adjuvant hormonal therapy.
Results: With a median follow up of 4 months (range 3–12), partial response was observed in 22%, stable disease in 28% and progressive disease in 50% of patients. Median time to progression (TTP) was 4 months (3–11) with 65% still on treatment. Median OS is too early to evaluate (all but 2 are still alive).
Grade III bone marrow toxicity was observed in about 5%. Non- hematological toxicities were: grade I fatigue in about 90%, rash and irritation(grade I-II) in about 70%, glucose level, liver function tests, blood cholesterol and triglycerides increased and/or renal function alterations (grade I-III) in about 80%, all the above disappeared after treatment delays or dose reduction, 5% developed non-inflammatory pneumonitis.
The 2 most common toxicities were mucositis; 30% grade I and 50% grade II and significant weight loss (5–10% weight reduction) in 90%.
Conclusions: Our study shows significant activity with the combination of RAD001 and Letrozole in MBC previously treated several lines of hormonal treatment with an acceptable toxicity. Combining RAD001 with Letrozolein the treatment of MBC, potentially inhibit tumor cell growth\proliferation and act as anti angiogenesis while at the same time potentially preventing the development of Letrozole resistance. Longer follow-up and further evaluation is warranted, additional data will be collected and provided towards the 2012 SABCS.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-20-06.