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.mycancergenome.org/content/molecular-medicine/everolimus-breast-cancer/ (Updated June 17).
Last Updated: June 22, 2015