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Looking for a Therapeutic Edge Among CDK Inhibitors

George W. Sledge Jr, MD
Published: Tuesday, Mar 13, 2018

George W. Sledge Jr, MD

George W. Sledge Jr, MD
The cyclin-dependent kinases (CDKs) 4 and 6 are now well-established therapeutic targets in estrogen receptor (ER)- positive breast cancer, with 3 separate agents having received FDA approval in recent years. These agents are rapidly moving to occupy multiple environmental niches in the metastatic disease setting and are being studied in the adjuvant and neoadjuvant settings. Whenever 3 agents joining the therapeutic armamentarium do so for similar indications with essentially identical mechanisms of action, it is reasonable to ask whether these agents have specific differences that might help decide which to use. This article offers a first stab at such comparisons, realizing that in a rapidly moving field, such comparisons may soon become dated as new data emerge.

Biologic Background

CDKs 4 and 6 are members of a family of kinases integrally involved in cell division and several other cellular metabolic processes. In patients with ER-positive breast cancer, CDKs are part of a chain of effector molecules linking the estrogen receptor with the cell cycle. Estrogen stimulates expression of cyclin D1, facilitating activation of CDK 4 and 6, retinoblastoma phosphorylation, subsequent release of E2F, and cell proliferation. Inhibition of CDK 4 and 6 leads to cell cycle arrest, which in turn can lead to initiation of apoptosis or cell senescence.

The 3 CDK 4/6 Inhibitors: Current FDA Approvals

There are 3 CDK 4/6 inhibitors approved for use in patients with metastatic ER-positive breast cancer: palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio). Palbociclib and ribociclib are approved as initial therapy for treatment of hormone receptor–positive, HER2-negative advanced or metastatic breast cancer in combination with an aromatase inhibitor. Similarly, both palbociclib and abemaciclib are approved, in combination with the selective ER degrader fulvestrant (Faslodex), for patients whose tumors have progressed on frontline endocrine therapy. Ribociclib currently does not have a second-line approval, though there is no particular reason to believe that it would function any differently from the other 2 agents in this setting.

Ribociclib has, unlike its competitors, been specifically studied in premenopausal women in the frontline setting (in the MONALEESA-7 trial), and as in postmenopausal women, the results suggest an impressive improvement in PFS, with similar toxicity to that seen in the postmenopausal setting. Again, it is likely that all 3 agents would offer similar benefits in premenopausal women, but there are no data yet presented or published for the other 2 agents in this setting.

Toxicity

The 3 approved CDK 4/6 inhibitors have overlapping yet somewhat distinct toxicity profiles. All 3 agents induce dose-related neutropenia, with rare neutropenic fevers. Abemaciclib is somewhat less potent as an inducer of grade 3 or 4 neutropenia than the other 2 agents, although this does not obviate the requirement for neutropenia monitoring and potential dose adjustment. Ribociclib has been associated with QT prolongation, leading to a requirement for electrocardiogram monitoring.
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