Cdk4/6 Clinical Comparison Essay

1447 WordsMay 21, 20156 Pages
Michael Ritchie The Clinical Activity and Tolerability of CKD4/6 Inhibitors March 30, 2015 Introduction The development of novel therapeutics for the treatment of breast cancer remains an important medical need. Approximately 232,000 new cases of invasive breast cancer are diagnosed in the US every year, with 40,000 deaths. Roughly 70% of all diagnosed breast cancer cases are positive for hormone receptors (HR+), which include the Human Epidermal Growth Factor Receptor 2 (HER2), the Progesterone Receptor (PR), and the Estrogen Receptor (ER). For the breast tumors that are HR+/HER2-, endocrine therapy has been the traditional therapeutic mainstay for disease treatment. However, de novo or acquired resistance to endocrine therapy is common, and remains an important clinical hurdle to overcome in new therapeutic development. Many HR+ metastatic breast cancers (MBCs) present in the clinic with an enhanced expression of the protein cyclin D1. Cyclin D1 interacts with cyclin dependent kinases (CDK) 4 and 6 to initiate cell cycle progression through the G1 restriction point via the inactivation of the 2 retinoblastoma (Rb) tumor suppressor protein. The increased expression of Cyclin D1 and the resultant augmented interaction with CDK4/6 contributes to the uncontrolled cell proliferation causing tumors to grow. Thus, inhibiting CDK 4/6 can help prevent cell cycle progression, and thus arrest tumor growth. Recently, the CDK4/6 inhibitor Palbocilcib (Ibrance, Pfizer) received accelerated approval by the FDA for the treatment of advanced ER+/HER2- breast cancer in combination with Lexetrole; while two others, LY2835219 (abemaciclib, Eli Lilly) and LEE011 (Novartis), remain in clinical development. Clinical Activity of the CDK4/6 Agents Results from a randomized phase 2 study of first line Letrozole alone or in combination with Palbociclib for metastatic

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