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+
HER2–
745 May 2015
exemestane + everolimus followed by fulvestrant HR+
HER2–
Phase 3 (NCT01674140) Adjuvant completed standard neoadjuvant or adjuvant chemotherapy endocrine therapy + everolimus HR+
HER2–
3500 April 2013
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+
HER2–
1984 March 2013
adjuvant hormone therapay + everolimus

NOTE: ER = estrogen receptor; HR = hormome receptor (ER and/or PR); NSAI = nonsteroidal aromatase inhibitor; PR = progesterone receptor.

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.

Contributors: Justin M. Balko, Pharm. D., Ph.D., Ingrid A. Mayer, M.D., M.S.C.I., Mia Levy, M.D., Ph.D., Carlos L. Arteaga, M.D.

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

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