Looking for a Therapeutic Edge Among CDK Inhibitors

George W. Sledge Jr, MD

Biologic Background

The 3 CDK 4/6 Inhibitors: Current FDA Approvals

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.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.

Toxicity

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.

Gastrointestinal toxicity, in the form of diarrhea, is more common with abemaciclib. This diarrhea is dose dependent and in the MONARCH 2 trial led to a decrease of the dose of abemaciclib from 200 mg to 150 mg. This diarrhea occurs early on (typically in the first or second cycle), is readily manageable with conventional antidiarrheal agents, and in the MONARCH 2 trial rarely led to drug discontinuation (1.6% of the time).

All 3 agents are metabolized via the cyclooxygenase CYP3A enzyme, so strong inhibitors of this enzyme should be avoided if possible.

Logistical Considerations

Overall, the toxicities of ribociclib (QT prolongation) and abemaciclib (diarrhea) give a slight edge to palbociclib for ease of use, although these differences are modest and the toxicities are readily manageable.Both palbociclib and ribociclib are administered on a 3-week-on, 1-week-off schedule, a schedule necessitated by the greater neutropenia seen with these agents compared with abemaciclib. Abemaciclib, in contrast, is administered as a continuous oral agent. In preclinical models, continuous inhibition of CDK 4 and 6 leads to sustained rather than intermittent cell cycle arrest with rebound, which is a theoretical advantage for abemaciclib compared with the other 2 agents. Whether this theoretical advantage translates to a difference in clinical efficacy is unknown and, indeed, unknowable in the absence of a head-to-head comparison trial.

Future Directions

Because Novartis produces both ribociclib and its partner, letrozole, the FDA has approved copackaging of these oral medications, wherein patients may receive both medicines in 1 package with 1 prescription and 1 copay. It’s not clear whether this will translate in real life to any major benefit; aromatase inhibitors are available off patent, and payers, pharmacies, and hospitals frequently bargain over price with companies, directing patients to particular agents based on financial arrangements specific to those organizations.There are many remaining questions regarding the use of CDK 4/6 inhibitors, and some of these may ultimately result in preferences for one or another agent. While all 3 agents offer impressive improvements in PFS, we lack any strong evidence that any of these agents improves overall survival (OS)—a high bar that none may meet in a disease with multiple therapeutic options after frontline therapy. The few data we do have (from the PALOMA-1 palbociclib randomized phase II trial) do not hint at an OS advantage, although this trial is a weak reed to bear such a heavy load from a statistical standpoint.

While all 3 agents are entering the adjuvant setting, we obviously have no current data regarding adjuvant benefits. In addition to efficacy questions, a crucial concern in the adjuvant setting is patient compliance. Compliance is multifactorial, but ease of use and perceived and actual toxicities are clearly important factors. If studies were to demonstrate, early in their course, that there were real differences in patient compliance in an adjuvant setting, this would certainly affect our enthusiasm for 1 or more of these agents. A patient is unlikely to benefit from a drug she will not take. This may be particularly important if prolonged administration of a CDK 4/6 inhibitor is required for ultimate benefit.

Preclinical data suggest that CDK 4/6 inhibitors may have a role to play in HER2-positive disease. While all 3 of these agents are currently being studied in HER2-positive disease, we currently lack any data that would suggest an advantage for one drug over another.

Finally, we do not know whether these agents differ in patterns of resistance. Evaluation of drug resistance in the CDK 4/6 field is in its infancy, with few preclinical studies and no studies attached to large clinical trials. If the agents differ significantly in terms of mechanisms of resistance, then it is possible that means of overcoming resistance may differ, to the benefit of one or another of the drugs.

Nevertheless, the advent of 3 agents with notable clinical activity represents a significant opportunity for patients with breast cancer. Recent data demonstrating the long-term risk of recurrence in the adjuvant setting for estrogen-driven breast cancer emphasize the need for new approaches that will bring us closer to a cure for all patients.