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.
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.
In late February, abemaciclib received FDA approval for frontline treatment of postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer, based on results from the phase III MONARCH 3 trial, in which the addition of abemaciclib to anastrozole or letrozole reduced the risk of progression or death by 46% compared with a nonsteroidal aromatase inhibitor alone.
Given what we know regarding these agents, it is likely that all 3 have roughly similar efficacy profiles. While the trials vary somewhat regarding entry criteria, and hence with likelihood of benefit reported in the trials (a higher response rate in the MONARCH 2 fulvestrant trial than in its sister PALOMA 3 trial), the hazard ratios for benefit are statistically similar in both the front- and secondline disease settings. All 3 agents provide clinically significant improvements in progression-free survival (PFS). Barring evidence from a not-yet-existing head-to-head comparison, we cannot decide among these agents based on efficacy alone.
Abemaciclib has previously received FDA approval as monotherapy, based on the MONARCH 1 trial, which demonstrated an objective response rate of 19.7%, with a median duration of response of 8.6 months. This trial is important because it suggests benefit independent of hormonal therapy, although with the ready adoption of CDK 4/6 inhibitors in the frontline setting, this may not prove clinically relevant.
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.
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.