Everolimus in Breast Cancer
|Target||Development Name||Generic Name||Trade Name||Status|
|MTOR||RAD001||everolimus||Afinitor||FDA approved in combination with exemestane for ER-positive breast cancera|
a Everolimus is a kinase inhibitor targeting MTOR that has been FDA approved as a combination therapy with exemestane for the treatment of postmenopausal women with HER2-negative, hormone receptor positive breast cancer after failure of treatment with letrozole or anastrozole (FDA 2012). The FDA approval of this drug combination was based on the results of the phase 3 trial BOLERO-2. In this study, 485 patients received combination therapy. The study showed an improvement in progression-free survival by 4.6 months; however, there was no change in overall survival (Baselga et al. 2012; Piccart et al. 2014; Yardley et al. 2013).
Table 1. Phase 3 Trials with Reported or Preliminary Results with Everolimus in Breast Cancer.
|Reference||Study Type / Phase||Therapeutic Setting||Treatment Agent||Mutation Status / Group||# Pts in Study||RR||PFS (months)||OS (months)|
|Hurvitz et al. 2014 (BOLERO-1)||Phase 3||First-line metastatic breast cancer||everolimus + trastuzumab + paclitaxel||HER2+||480||15|
|placebo + trastuzumab + paclitaxel||239||14.5|
|Baselga et al. 2012; Piccart et al. 2014; Yardley et al. 2013 (BOLERO-2)||Phase 3||Second-line metastatic breast cancer||everolimus + exemestane||HR+ / HER2–||485||13%||7.8||31|
|placebo + exemestane||239||2%||3.2||26.6|
|André et al. 2014 (BOLERO-3)||Phase 3||First-line or greater metastatic breast cancer||everolimus + trastuzumab + vinorelbine||HER2+||284||41%||7|
|placebo + trastuzumab + vinorelbine||285||37%||5.8|
|von Minckwitz et al. 2014 (GeparQuinto)||Phase 3||Neoadjuvant||epirubicin + cyclophosphamide; followed by docetaxel||HER2–||969||88.7% (estimated 3-year survival)|
|Epirubicin + cyclophosphamide + bevacizumab; followed by docetaxel + bevacizumab||969||90.7% (estimated 3-year survival)|
|epirubicin + cyclophosphamide +/- bevacizumab (with no response); followed by paclitaxel||198||83.4% (estimated 3-year survival)|
|epirubicin + cyclophosphamide +/- bevacizumab (with no response); followed by paclitaxel + everolimus||197||81.4% (estimated 3-year survival)|
NOTE: CR = complete response; ER = estrogen receptor; HR = hormome receptor (ER and/or PR); OS = overall survival; PFS = progression-free survival; PR = partial response; PR = progesterone receptor; Pts = patients; RR = response rate (CR + PR).
Table 2. Ongoing and Recruiting Clinical Investigation with Everolimus in Breast Cancer.
|Study Type / Phase / ID||Therapeutic Setting||Prior Therapy Requirement||Treatment Agent||Mutation Status/Group||# Patients in Study||Study Start Date|
|Phase 3 (FEVEX, NCT02404051)||2nd line||Refractory to NSAI||fulvestrant followed by everolimus + exemestane||HR+
|exemestane + everolimus followed by fulvestrant||HR+
|Phase 3 (NCT01674140)||Adjuvant||completed standard neoadjuvant or adjuvant chemotherapy||endocrine therapy + everolimus||HR+
|endocrine therapy + placebo|
|Phase 3 (NCT01805271)||Adjuvant||At least 1 year but not more than 4 years of adjuvant hormone therapy||Adjuvant hormone therapy + everolimus||HR+
|adjuvant hormone therapay + everolimus|
Inhibition of CDK4/6 is a therapeutic strategy being investigated in patients with hormone receptor positive breast cancer in the adjuvant and neoadjuvant settings, as first-line therapy, and after resistance develops to endocrine therapy.
Cyclin D1 is a transcriptional target of the estrogen receptor and is involved in regulating entry into the synthesis phase (S phase) of the cell cycle. Cyclin D1 binds to cyclin dependent kinases 4 and 6 (CDK4/6), and this complex phosphorylates the retinoblastoma (RB1) tumor suppressor protein. The RB1 protein releases the transcription factors required for S phase entry in the cell cycle. CDK4/6 inhibitors block CDK4/6 from activating RB1 to promote the cell growth cycle.
Combining ER-targeting agents such as letrozole with agents that target downstream components of the ER pathway including CDK4/6 inhibitors is a vertical targeting strategy, and improves benefit cooperatively over standard of care single-agent therapy alone in clinical studies (Finn et al. 2015; Patnaik et al. 2014a, 2014b).
Several cell cycle inhibitors have been developed which target CDK4/6. Palbociclib is a kinase inhibitor targeting CDK4/6 that is FDA approved as a combination therapy with letrozole for the treatment of postmenopausal women with HER2-negative, hormone receptor positive breast cancer (FDA 2015; Finn et al. 2015). Ribociclib (LEE011) and abemaciclib (LY2835219) are two other kinase inhibitors targeting CDK4/6.
Suggested Citation: Balko, J., I. Mayer, M. Levy, C. Arteaga. 2015. Everolimus in Breast Cancer. My Cancer Genome http://www.padiracinnovation.org/content/molecular-medicine/everolimus-breast-cancer/ (Updated June 17).
Last Updated: June 22, 2015