A Pharmacist’s Perspective on CDK4/6 Inhibitors

Breast cancer is the most common cancer in women and remains a leading cause of cancer-related morbidity, mortality, and resource utilization. For patients with advanced breast cancer, prognosis remains especially suboptimal, primarily because of acquired pharmacologic resistance.

Fortunately, several new drugs and drug combinations have recently become available. Specifically, the class of drugs that utilize cyclin-dependent kinase (CDK)4/6 inhibitors is frequently incorporated into first-line treatment of patients with postmenopausal, hormone receptor–positive (HR+)/HER2− advanced breast cancer.

Abemaciclib is the newest CDK4/6 inhibitor approved by the US Food and Drug Administration. Mechanistically, abemaciclib more potently inhibits CDK4/cyclin D1 and CDK6/cyclin D3 than either palbociclib or ribociclib¹ and is more selective for CDK4 than for CDK6.² The clinical implications of these mechanistic differences remain to be determined regarding their impact on efficacy, but these differences appear to explain the differing adverse effect (AE) profiles of these 3 drugs. In addition, abemaciclib has been shown to cross the blood–brain barrier, whereas palbociclib and ribociclib do not.³ Whether abemaciclib may be helpful in treating patients with brain metastases or in reducing the likelihood of developing brain metastases is an important question being evaluated in clinical studies.

Palbociclib and ribociclib have been studied in thousands of patients throughout the PALOMA^4,5 and MONALEESA^6,7 series of clinical trials, with predominantly consistent results. Abemaciclib has demonstrated clinical efficacy with a generally tolerable safety profile in the MONARCH 1, 2, and 3 clinical trials.^1,8,9 An exploratory analysis of the MONARCH 2 and MONARCH 3 data sets was recently performed to determine whether patient and disease characteristics may be defined to assist in optimizing treatment strategies with abemaciclib.¹⁰ The findings showing substantial benefit from treatment with abemaciclib in a group with poor prognosis, including those with hepatic metastases, progesterone receptor–negative tumors, or high-grade tumors, are intriguing but should be viewed as hypothesis-generating at this time.

In the absence of head-to-head comparisons, differentiating factors may include cross-study evaluation of efficacy as well as of AE profiles; dosing and administration considerations; drug interactions; and cost. All 3 CDK4/6 inhibitors are indicated as combination therapy with an aromatase inhibitor as initial therapy.^11-13 Both palbociclib and abemaciclib are indicated as combination therapy with fulvestrant following progression on endocrine therapy in postmenopausal HR+/HER2− advanced or metastatic breast cancer.^11,13 However, abemaciclib is the only CDK4/6 inhibitor currently indicated as monotherapy following progression on endocrine therapy and chemotherapy,¹³ with a response rate of approximately 20%.¹⁴

The most common dose-limiting AE of palbociclib and ribociclib is neutropenia, whereas diarrhea is most predominant with abemaciclib.¹⁴ Neutropenia or thrombocytopenia may occur with any of the CDK4/6 inhibitors and requires monitoring. Ribociclib, as well as abemaciclib, may cause elevation in liver function tests, also warranting monitoring. QTc prolongation is possible with ribociclib, and electrocardiograms and serum electrolyte monitoring are therefore recommended to reduce the risk for complications. Fatigue is another noteworthy AE of CDK4/6 inhibitors, including abem­aciclib.¹⁴ Whereas management of the AEs related to the use of CDK4/6 inhibitors generally includes withholding or reducing doses or providing symptom management, between 5% and nearly 20% discontinuation rates have been reported across clinical trials.

All of the CDK4/6 inhibitors are hepatically metabolized, primarily by the CYP3A enzymes.¹⁴ Patients receiving strong CYP3A inhibitors or inducers, as well as sensitive CYP3A substrates, must be evaluated closely. Specific risk mitigation strategies may include dose modification or avoidance of concomitant use, depending on the particular medications involved.¹⁴

Another distinguishing feature of CDK4/6 inhibitors is their dosing schedule. Whereas palbociclib and ribociclib are administered once daily for 21 consecutive days of a 28-day cycle,^11,12 abemaciclib is administered twice daily continuously.¹³ Palbociclib is dosed as a single capsule taken with food.¹¹ Depending on tolerability, concomitant medications, and hepatic function, the dose of ribociclib may be 1 to 3 tablets without regard to food intake.¹² Finally, abemaciclib is dosed as a single tablet most frequently given twice daily without regard to food, with the exception being in patients with severe hepatic impairment, who receive the dose once daily.¹³

Currently, CDK4/6 inhibitors have an established role in the management of postmenopausal women with HR+/HER2− advanced or metastatic breast cancer. Ongoing studies in other breast cancer settings continue. Abemaciclib is the most recent entry into the CDK4/6 inhibitor class, with established efficacy and a unique toxicity profile. The question of whether there is a preferred CDK4/6 inhibitor for select subsets of patients remains to be answered. Future studies will better define the unique role and best overall value of palbociclib, ribociclib, and abemaciclib.

References

1. Dickler MN, Tolaney SM, Rugo HS, et al. MONARCH 1, a phase II study of abemaciclib, a CDK4 and CDK6 inhibitor, as a single agent, in patients with refractory HR+/HER2− metastatic breast cancer. Clin Cancer Res. 2017;23:5218-5224.
2. Patnaik A, Rosen LS, Tolaney SM, et al. Efficacy and safety of abemaciclib, an inhibitor of CDK4 and CDK6, for patients with breast cancer, non–small cell lung cancer, and other solid tumors. Cancer Discov. 2016;6:740-753.
3. Polk A, Kolmos IL, Kümler I, Nielsen DL. Specific CDK4/6 inhibition in breast cancer: a systematic review of current clinical evidence. ESMO Open. 2017;1:e000093.
4. Finn RS, Crown JP, Lang I, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol. 2015;16:25-35.
5. Crown J, Finn RS, Ettl J, et al. Efficacy and safety of first-line palbociclib plus letrozole compared with letrozole alone in patients aged ≥ 65 years with estrogen receptor-positive, HER2-negative advanced breast cancer: a subgroup analysis by age of the PALOMA-1/TRIO-18 trial. J Clin Oncol. 2015;33(15 suppl). Abstract 571.
6. Hortobagyi GN, Stemmer SM, Burris HA, et al. Updated results from MONALEESA-2, a phase 3 trial of first-line ribociclib + letrozole in hormone receptor-positive (HR+), HER2-negative (HER2–), advanced breast cancer (ABC). J Clin Oncol. 2017;35(suppl 15). Abstract 1038.
7. NCT02422615: Study of efficacy and safety of LEE011 in men and postmenopausal women with advanced breast cancer (MONALEESA-3). https://www.clinicaltrials.gov/ct2/show/NCT02422615?term=NCT02422615&rank=1. Accessed January 9, 2018.
8. Sledge GW Jr, Toi M, Neven P, et al. MONARCH 2: abemaciclib in combination with fulvestrant in women with HR+/HER2− advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol. 2017;35:2875-2884.
9. Goetz MP, Toi M, Campone M, et al. MONARCH 3: abemaciclib as initial therapy for advanced breast cancer. J Clin Oncol. 2017;35:3638-3646.
10. Goetz MP, O’Shaughnessy J, Sledge GW Jr, et al. The benefit of abemaciclib in prognostic subgroups: an exploratory analysis of combined data from the MONARCH 2 and 3 studies. Presented at: San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, TX. Abstract GS6-02.
11. Ibrance^® (palbociclib) [prescribing information]. New York, NY: Pfizer, Inc; 2017.
12. Kisqali^® (ribociclib) [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2017.
13. Verzenio™ (abemaciclib) [prescribing information]. Indianapolis, IN: Eli Lilly and Co; 2018.
14. Spring LM, Zangardi ML, Moy B, Bardia A. Clinical management of potential toxicities and drug interactions related to cyclin-dependent kinase 4/6 inhibitors in breast cancer: practical considerations and recommendations. Oncologist. 2017;22:1039-1048.