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Cyclin-Dependent Kinase 4/6 Inhibitors in the Management of Breast Cancer

Rodney J. Hunter, PharmD BCOP
Clinical Pharmacy Specialist, Oncology
University of Texas Health/Memorial Hermann Cancer Center–Texas Medical Center
Assistant Professor
Texas Southern University, College of Pharmacy and Health Sciences
Houston, TX


Cyclin-dependent kinases (CDKs) are a family of proteins involved in the regulation of the cell cycle. Cyclins regulate the cell cycle by activating CDKs to phosphorylate other molecules. This activation then signals the cell that it is ready to pass into the mitotic phase of the cell cycle where cell division occurs. In many cancers, either CDKs are overactive or CDK-inhibiting proteins are not functional, causing overproliferation of cancer cells.1,2 CDKs act on different parts of the cell cycle. Specifically, CDK 4/6 is a key component of cell growth and proliferation for both normal and cancerous cells. A major target of CDK 4/6 during cell cycle progression is the retinoblastoma protein (Rb). Rb is a tumor-suppressor protein that prevents excessive cell growth by inhibiting the cell-cycle progression between the G1 checkpoint and the S phase until a cell is ready to divide. Hyperphosphorylation of Rb by CDK 4/6 inactivates its growth-suppressive properties, leading to overproduction of cancer cells.2,3 Therefore, it is rational to target CDKs, particularly CDK 4/6, to prevent unregulated proliferation of cancer cells. Recently, advances have been made in using highly selective CDK 4/6 inhibitors in the treatment of breast cancer. The CDK 4/6 inhibitors that are currently available commercially include palbociclib, ribociclib, and abemaciclib (Table 1 - see PDF).

Currently Approved CDK 4/6 Inhibitors

Palbociclib
Palbociclib (Ibrance), in combination with letrozole in the PALOMA-2 trial, was granted accelerated approval by the U.S. Food and Drug Administration (FDA) in February 2015 for the treatment of hormone receptor (HR)–positive/human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer.3 In this double-blind phase 3 study, patients were randomly assigned, in a 2:1 ratio, to receive 125 mg of palbociclib by mouth (PO) daily for 21 consecutive days followed by 7 days off or the placebo; all patients received 2.5 mg of letrozole PO daily. A total of 666 postmenopausal women with HR-positive/HER2-negative breast cancer who had not received prior treatment for advanced disease were enrolled in this study. Median progression-free survival (PFS) was 24.8 months (95% confidence interval [CI], 22.1 to "not estimable") in the palbociclib-letrozole group compared with 14.5 months (95% CI, 12.9–17.1) in the placebo-letrozole group (hazard ratio [HR] for disease progression or death, .58; 95% CI, .46–.72; two-sided p < .001). Most common adverse events of grade 3 or 4 in the palbociclib-letrozole group were neutropenia (66.4%) and leukopenia (24.8%).4

Palbociclib was studied further in the PALOMA-3 trial to assess the safety and efficacy of the combination of palbociclib and fulvestrant in premenopausal or postmenopausal women with HR-positive advanced breast cancer that progressed during prior endocrine therapy. This double-blind phase 3 study included 521 women with advanced HR-positive/HER2-negative breast cancer that had relapsed or progressed during prior endocrine therapy. Patients were randomly assigned, in a 2:1 ratio, to receive palbociclib 125 mg per day (for 3 weeks followed by 1 week off) and fulvestrant 500 mg intramuscularly (day 1, day 15, day 29, and then every 4 weeks) or matching placebo and fulvestrant. Median PFS was 9.5 months (95% CI, 9.2–11) for the palbociclib-fulvestrant group and 4.6 months (95% CI, 3.5–5.6) for the placebo-fulvestrant group (HR .46; 95% CI .36–.59; p < .0001). The most common grade 3 or greater adverse event was neutropenia (65%).4 The PALOMA-2 and PALOMA-3 trials yielded FDA approvals in the first-line and endocrine refractory settings, respectively.5

Ribociclib
Ribociclib (Kisqali) was approved by the FDA on March 13, 2017, in combination with letrozole for treatment of postmenopausal women with HR-positive/HER2-negative advanced or metastatic breast cancer.6 Approval was based on a randomized double-blind placebo-controlled international clinical trial, MONALEESA-2. A total of 668 postmenopausal women with HR-positive/HER2-negative advanced or metastatic breast cancer were randomized to receive either oral ribociclib 600 mg or placebo once a day for 21 consecutive days, followed by 7 days off, with letrozole 2.5 mg for a total of 28 days. Treatment continued until the disease progressed or unacceptable levels of toxicity were reached. After 18 months, the PFS rate was 63% (95% CI, 54.6–70.3) in the ribociclib-letrozole group versus 42.2% (95% CI, 34.8–49.5) in the placebo-letrozole group (HR .56; 95% CI, .43–.72; p = 3.29 ×10−6 for superiority). The objective response rate in patients with measurable disease was 52.7% in the ribociclib-letrozole group versus 37.1% in the placebo-letrozole group. Overall survival (OS) data are immature. The most common grade 3 or 4 adverse events observed in patients taking ribociclib were neutropenia (59.3%), leukopenia (21.0%), hypertension (9.9%), abnormal liver function tests (increased alanine aminotransferase 9.3%, increased aspartate aminotransferase 5.7%), and lymphopenia (6.9%).7

The MONALEESA-7 trial is a phase 3 randomized double-blind placebo-controlled trial investigating the efficacy and safety of ribociclib in combination with oral hormonal therapies and goserelin versus endocrine therapy (ET) alone in premenopausal or perimenopausal women with HR-positive/HER2-negative advanced breast cancer who had not previously received ET for advanced disease. The primary end point for the study was PFS, with secondary end points of OS, overall response rate, and clinical benefit rate. In the study, in the ribociclib plus tamoxifen/nonsteroidal aromatase inhibitor arm the median PFS was 23.8 months (95% CI, 19.2 to "not reached") compared to 13 months in the placebo arm (95% CI, 11–16.4). The primary end point was met in reference to PFS (HR = .553; 95% CI, .441–.694; p = 9.83 × 10–8). The adverse events reported were consistent with those in other randomized clinical trials involving ribociclib and ET: all grades— neutropenia {76%), hot flashes (34%), nausea (32%), leukopenia (31%), and arthralgia (30%).8

Abemaciclib
Abemaciclib (Verzenio) was granted FDA approval for stand-alone use on September 28, 2017, for the treatment of HR-positive/HER2-negative advanced or metastatic breast cancer with disease progression following ET based on the MONARCH 1 trial.9 It was designed to evaluate the single-agent activity and adverse-event profile of abemaciclib. In this phase 2 single-arm open-label study, 132 women with HR-positive/HER2-negative metastatic breast cancer whose disease had progressed on or after prior ET and had received one or two chemotherapy regimens in the metastatic setting were enrolled. Patients were given abemaciclib 200 mg PO every 12 hours until the disease progressed or an unacceptable level of toxicity was reached. The primary objective of the MONARCH 1 trial was investigator-assessed objective response rate. The objective response rate in MONARCH 1 was 19.7% (95% CI, 13.3–27.5; 15% not excluded). Secondary end points of clinical benefit rate (CBR), PFS, and OS were also analyzed. The CBR was 42.4%, the median PFS was 6 months, and the median OS was 17.7 months. The most common treatment-emergent adverse events of any grade were increased creatinine (98.5%), diarrhea (90.2%; managed with loperamide and fluids), decreased neutrophil count (87.7%), anemia (68.5%), fatigue (65.2%), and nausea (64.4%). Discontinuations due to adverse events were infrequent (7.6%).10

The approval for the drug in combination with fulvestrant was based on results of the MONARCH 2 trial.11 The MONARCH 2 trial compared the efficacy and safety of abemaciclib-fulvestrant versus fulvestrant alone in patients with advanced breast cancer. This double-blind phase 3 study included 670 women with HR-positive/HER2-negative advanced breast cancer whose disease had progressed while they were receiving neoadjuvant or adjuvant ET, less than 12 months from the end of adjuvant ET, or while they were receiving first-line ET for metastatic disease. Patients were randomly assigned in a 2:1 ratio to receive abemaciclib 150 mg twice a day on a continuous schedule and fulvestrant 500 mg per label or matching placebo and fulvestrant. Women in the abemaciclib-fulvestrant group had a median PFS of 16.4 months compared with 9.3 months in the placebo-fulvestrant group (HR .553; 95% CI, .449–.681; p < .001). The most common adverse events seen in the abemaciclib-fulvestrant group were diarrhea (86.4%), neutropenia (46.0%), nausea (45.1%), and fatigue (39.9%).11

Future Direction of CDK 4/6 Inhibitors

Palbociclib, ribociclib, and abemaciclib have shown activity in a variety of treatment settings in breast cancer patients. Palbociclib has been incorporated into the adjuvant endocrine treatment setting in HR-positive/HER2-negative early-stage breast cancer in the PALLAS trial. The PALLAS trial is a prospective two-arm international multicenter randomized open-label phase 3 trial evaluating the benefit of 2 years of palbociclib 125 mg (3 weeks on and 1 week off) with the standard 5 years of ET compared to 5 years of ET alone. The primary outcome measure of the PALLAS trial will be invasive disease–free survival.12

Ribociclib is also being evaluated in the adjuvant setting of HR-positive/HER2-negative patients in the EarLEE-1 and EarLEE-2 trials. Both studies are multicenter randomized double-blind phase 3 clinical trials that will evaluate the safety and efficacy of ribociclib with ET as adjuvant therapy in pre- and postmenopausal women. EarLEE-1 will assess ribociclib plus adjuvant ET compared to adjuvant ET alone in women with HR-positive/HER2-negative high-risk early breast cancer, and EarLEE-2 will enroll women with HR-positive/HER2-negative intermediate-risk early breast cancer. In both trials the primary outcome measure is invasive disease–free survival.13

Abemaciclib is also being investigated outside the metastatic setting of breast cancer. The NeoMONARCH study is analyzing the benefits of abemaciclib for 14 weeks in combination with letrozole (14 weeks of abemaciclib 150 mg PO twice daily only vs. 14 weeks of abemaciclib 150 mg PO twice daily plus anastrazole 1 mg PO daily vs. anastrazole 1 mg PO daily alone). End points in the trial include change in Ki-67, pathological complete responses, complete responses, and radiological responses.14 CDK 4/6 inhibitors are being investigated in the adjuvant, neoadjuvant, and metastatic setting in combination with the mammalian target of rapamycin inhibitors and other novel targeted agents as well.

Conclusion

Palbociclib, ribociclib, and abemaciclib are CDK 4/6 inhibitors currently approved by the FDA for the treatment of HR-positive/HER2-negative advanced breast cancer. The CDK 4/6 inhibitors are an important addition to the treatment options available for the management of breast cancers and are also being evaluated for treatment of other malignancies. CDK 4/6 inhibitors are being studied clinically in other tumor types, specifically non-small-cell lung cancer, especially the KRAS-mutant subset. Additionally, the drugs are being looked at preclinically and clinically in a variety of other tumor types, including melanoma, glioblastoma, pancreatic cancer, and colorectal cancer. 

References

  1. O’Connor CM, Adams JU. Cyclin-Dependent Kinases Regulate Progression through the Cell Cycle. In Essentials of Cell Biology. Cambridge, MA: NPG Education, 2010.
  2. Kwapisz D. Cyclin-dependent kinase 4/6 inhibitors in breast cancer: palbociclib, ribociclib, and abemaciclib. Breast Cancer Res Treat. 2017;166(1):41-54.
  3. U.S. Food and Drug Administration. Palbociclib (Ibrance). https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm549978.htm. Accessed December 20, 2017.
  4. Finn RS, Martin M, Rugo HS, et al. Palbociclib and letrozole in advanced breast cancer. New Engl J Med. 2016;375(23):1925-1936.
  5. Cristofanilli M, Turner NC, Bondarenko I, et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol. 2016;17(4):425-439.
  6. U.S. Food and Drug Administration. Ribociclib (Kisqali). https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm546438.htm. Accessed December 12, 2017.
  7. Hortobagyi GN, Stemmer SM, Burris HA, et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. New Engl J Med. 2016;375(18):1738-1748.
  8. Tripathy D, Sohn J, Im S-A, et al. First-line ribociclib or placebo combined with goserelin and tamoxifen or a non-steroidal aromatase inhibitor in premenopausal women with hormone receptor positive, HER2 negative advanced breast cancer: results from the randomized phase III MONALEESA-7 trial. Oral presentation at San Antonio Breast Cancer Symposium, December 5-9, 2017; San Antonio, TX. Presentation GS2-05. http://www.abstracts2view.com/sabcs/view.php?nu=SABCS17L_828&terms=
  9. U.S. Food and Drug Administration. Abemaciclib (Verzenio). https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm578081.htm. Accessed December 17, 2017.
  10. 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(17):5218-5224.
  11. 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(25):2875-2884.
  12. ClinicalTrials.gov. Palbociclib. Bethesda, MD: U.S. National Institutes of Health. https://clinicaltrials.gov/ct2/ results?cond=palbociclib&term= &cntry=&state=&city=&dist=&Search=Search. Accessed December 7, 2017.
  13. ClinicalTrials.gov. Ribociclib. Bethesda, MD: U.S. National Institutes of Health. https://clinicaltrials.gov/ct2/results?cond=Ribociclib&term=&cntry= &state=&city=&dist=&Search=Search. Accessed December 7, 2017.
  14. ClinicalTrials.gov. Abemaciclib. Bethesda, MD: U.S. National Institutes of Health. https://clinicaltrials.gov/ct2/results?cond=Abemaciclib&term=&cntry =&state=&city=&dist=&Search=Search. Accessed December 7, 2017.
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