Profile of abemaciclib and its potential in the treatment of breast cancer

OncoTargets and Therapy Dovepress open access to scientific and medical research Review Open Access Full Text Article OncoTargets and Therapy downloaded from https://www.dovepress.com/ by 213.32.48.132 on 21-Dec-2018 For personal use only. Profile of abemaciclib and its potential in the treatment of breast cancer This article was published in the following Dove Press journal: OncoTargets and Therapy James M Martin 1 Lori J Goldstein 2 Department of Medicine, Section of Hematology/Oncology, Temple University Hospital, Philadelphia, PA, USA; 2Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA 1 Background Correspondence: James M Martin 333 Cottman Avenue, Philadelphia, PA 19111, USA Email Breast cancer continues to be the most common malignancy among women and remains a significant cause of mortality.1,2 Hormone-receptor-positive (HR+) breast cancer is the most common subtype of both early-stage and advanced/metastatic disease, representing ~80% of all breast cancers.3 Until recently, the frontline treatment of HR+ advanced/metastatic breast cancer (AMBC) consisted of sequential courses of estrogen blockade.4,5 While most patients initially benefit from antiestrogen therapy, the need for cytotoxic chemotherapy is often inevitable. The response to chemotherapy agents is generally poor,6–9 indicating the need for additional therapeutic strategies to overcome resistance to endocrine therapy. Attempts to extend and enhance estrogen therapy have included targeting the phosphatidylinositol 3-kinase–Akt–mammalian target of rapamycin pathway, as demonstrated in the phase III BOLERO-2 study, which showed a progression-free survival (PFS) benefit with the addition of everolimus to exemestane, a steroidal aromatase inhibitor (AI), among women whose disease had progressed on a non-steroidal AI (PFS 6.9 vs 2.8 months; HR, 0.43; 95% CI, 0.35–0.54; P0.001).10 Everolimus has also been approved for combination with fulvestrant, an estrogen receptor antagonist.11 Additionally, exemestane has been combined with entinostat, a histone deacetylase inhibitor, with encouraging results.12 More recently, the promising target among women with AMBC is the inhibition of cell cycle progression by targeting cyclin-dependent kinases 4 and 6 (CDK4/6). In HR+ breast cancer, estrogen stimulates production of the protein cyclin D1, which forms an active complex with CDK4/6. This cyclin-CDK complex then phosphorylates the retinoblastoma (Rb) tumor suppressor protein, which in turn allows for progression through the G1/S transition of the cycle and subsequent cellular proliferation13–15. 5253 submit your manuscript | www.dovepress.com OncoTargets and Therapy 2018:11 5253–5259 Dovepress © 2018 Martin and Goldstein. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). http://dx.doi.org/10.2147/OTT.S149245 Powered by TCPDF (www.tcpdf.org) Abstract: Hormone-receptor-positive breast cancer is the most common subtype of breast cancer among patients with both early-stage and metastatic disease. Recent advances in the understanding of its pathophysiology have led to the discovery and utilization of targeted inhibitors to cyclin-dependent kinases 4 and 6 (CDK4/6). There are currently three available CDK4/6 inhibitors available for use in USA: palbociclib, ribociclib, and abemaciclib. Their oral administration and tolerable toxicities make this class of agents appealing to both patients and health care providers. Abemaciclib, the most recently approved CDK4/6 inhibitor, has unique pharmacologic properties and potential toxicities. This review highlights the current understanding of abemaciclib and discusses its current and future roles in the treatment of breast cancer. Keywords: abemaciclib, cyclin D1, breast cancer, CDK4/6 Dovepress OncoTargets and Therapy downloaded from https://www.dovepress.com/ by 213.32.48.132 on 21-Dec-2018 For personal use only. Martin and Goldstein Cyclin D1 and CDK4/6 overexpression has been detected in a large portion of breast cancer cases, which can lead to dysregulation of the cell cycle and uncontrolled cellular proliferation.16,17 While some studies have reported the overexpression of cyclin D1 as a poor prognostic marker, others have correlated amplification of CCND1, the gene encoding for cyclin D1, as the marker for poor prognosis.15,17,18 In preclinical studies, inhibition of CDK4/6 prevents interaction with cyclin D1 and subsequent Rb phosphorylation, leading to cell cycle arrest and restriction of cellular proliferation.19,20 There are currently three oral CDK4/6 inhibitors approved by the US Food and Drug Administration (FDA) for women with HR+ AMBC: palbociclib (Ibrance; Pfizer, New York, NY), ribociclib (Kisqali; Novartis, Basel, Switzerland), and abemaciclib (Verzenio; Lilly, Indianapolis, IN).21 Palbociclib and ribociclib Palbociclib was the first approved oral CDK4/6 inhibitor based on the results of the phase III PALOMA-2 trial, which demonstrated a significant PFS benefit with palbociclib/ letrozole (N=444) vs letrozole alone (N=222) among women with previously untreated HR+ AMBC (PFS 22.1 vs 14.5 months; HR 0.58; 95% CI, 0.46–0.72; P0.001).22 Its approval was then expanded for use in conjunction with fulvestrant, based on results of the phase III PALOMA-3 trial in which patients were randomized to receive palbociclib/fulvestrant (N=347) or fulvestrant alone (N=174) following disease progression on nonsteroidal AI (PFS 9.5 vs 4.6 months; HR 0.46; 95% CI 0.36–0.59; P0.0001).23 The most commonly reported grade 3/4 toxicities reported in these studies were neutropenia, leukopenia, and anemia. Neutropenic fever was seen in 1.8% of patients. PALLAS (NCT02513394) and PATINA (NCT02947685) are ongoing trials examining palbociclib’s potential roles in the adjuvant setting or in women with advanced human epidermal growth factor receptor 2 positive (HER2+) breast cancer.24 Ribociclib was the second oral CDK4/6 inhibitor approved for frontline AMBC treatment in conjunction with letrozole, based on the phase III MONALEESA-2 study, which similarly demonstrated a PFS benefit in the combination arm (N=334) compared with letrozole alone (N=334) in patients with previously untreated HR+ AMBC (PFS not reached vs 14.7 months; HR 0.59; 95% CI, 0.41–0.85; P=0.002).25 The most common grade 3/4 toxicities were neutropenia, leukopenia, hypertension, and elevated alanine aminotr (...truncated)