CDK4/6 inhibitors for the treatment of advanced hormone receptor positive breast cancer and beyond: 2016 update

ABSTRACT

Introduction: Breast cancer remains a major cause of morbidity and mortality worldwide. Given the central role of cyclin-dependent kinases in regulating cell division, there has been a longstanding interest in developing compounds which target the cyclin D1: CDK4/6 axis in breast cancer. The recent discovery of potent and selective CDK4/6 inhibitors (CDK4/6i) was an important breakthrough.

Areas covered: There are three CDK4/6i in clinical development (palbociclib, ribociclib and abemaciclib). Phase II and III studies using palbociclib in combination with endocrine therapy demonstrated remarkable clinical activity in women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer, resulting in two separate FDA approvals in 2015 and 2016. In this article, we review the preclinical and clinical development of these compounds as well as discussing the role for novel applications of these agents outside the arena of HR-positive, HER2-negative advanced breast cancer.

Expert opinion: In combination with endocrine therapy, CDK4/6i have shown promising efficacy in patients with advanced HR-positive, HER2-negative advanced breast cancer. Numerous trials in a variety of clinical settings and in different tumor types are ongoing or planned.

KEYWORDS:

• Abemaciclib
• CDK4/6 inhibitors
• endocrine resistance
• palbociclib
• ribociclib

Article highlights

• CDK4/6 inhibitors are a promising new class of agents which have potential utility in the treatment of solid and liquid malignancies apart from HR-positive advanced breast cancer

• The combination of the CDK4/6 inhibitor,palbociclib, and the non-steroidal aromatase inhibitor, letrozole, was granted FDA approval for the first line treatment of postmenopausal women with HR-positive, HER2-negative advanced breast cancer in 2015 (PFS was doubled in women who received combination therapy vs. endocrine therapy alone)

• The combination of palbociclib and the estrogen antagonist, fulvestrant,was granted FDA approval for the second-line treatment of pre and postmenopausal women with HR-positive, HER2-negative advanced breast cancer in 2016

• The toxicity profile of CDK4/6 inhibitors in combination with endocrine therapy is largely favorable (uncomplicated neutropenia with palbociclib; diarrhea with abemaciclib)

• A large number of clinical trials are underway in several different settings in HR-positive breast cancer (adjuvant, neoadjuvant, post-neoadjuvant and advanced) and also in other solid and liquid malignancies (e.g. glioblastoma, non-small cell lung carcinoma, acute leukemias, endometrial and ovarian carcinomas)

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Declaration of interest

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.