Breast Cancer Research and Treatment

, Volume 166, Issue 1, pp 41–54 | Cite as

Cyclin-dependent kinase 4/6 inhibitors in breast cancer: palbociclib, ribociclib, and abemaciclib

Review

Abstract

Purpose

The cyclin D-cyclin dependent kinase (CDK) 4/6-inhibitor of CDK4 (INK4)-retinoblastoma (Rb) pathway plays a crucial role in cell cycle progression and its dysregulation is an important contributor to endocrine therapy resistance. CDK4/6 inhibitors trigger cell cycle arrest in Rb protein (pRb)-competent cells. Recent years have seen the development of selective CDK4/6 inhibitors, which have delivered promising results of efficacy and manageable safety profiles. The main objective of this review is to discuss preclinical and clinical data to date, and ongoing clinical trials with palbociclib, ribociclib, and abemaciclib in breast cancer.

Methods

A literature search of above topics was carried out using PubMed and data reported at international oncology meetings and clinicaltrials.gov were included.

Results

The highly selective oral CDK4/6 inhibitors have been tested in combination with endocrine therapy in Phase III studies in metastatic breast cancer. Results led to the US Food and Drug Administration approval of palbociclib (PD0332991) and ribociclib (LEE011), and abemaciclib (LY2835219) is in development. Studies of these agents, in combination with endocrine therapy, are also underway in ER-positive early breast cancer in the neoadjuvant and adjuvant settings. Moreover, they are also being investigated with other agents in the advanced setting and in triple negative breast cancer.

Conclusions

After having demonstrated impressive activity in ER-positive, HER2-negative metastatic breast cancer, currently CDK4/6 inhibitors are in further development. It is obvious that this class of agents with their efficacy, low and easily manageable toxicity, and oral dosage is a very important treatment option for breast cancer patients.

Keywords

CDK4/6 inhibitors Breast cancer Palbociclib Ribociclib Abemaciclib 

References

  1. 1.
    Arnold A, Papanikolaou A (2005) Cyclin D1 in breast cancer pathogenesis. J Clin Oncol 23:4215–4224CrossRefPubMedGoogle Scholar
  2. 2.
    Cancer Genome Atlas Network (2012) Comprehensive molecular portraits of human breast tumours. Nature 490:61–70CrossRefGoogle Scholar
  3. 3.
    Witkiewicz AK, Knudsen ES (2014) Retinoblastoma tumor suppressor pathway in breast cancer: prognosis, precision medicine, and therapeutic interventions. Breast Cancer Res 16:207CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Weinberg RA (1995) The retinoblastoma protein and cell cycle control. Cell 81:323–330CrossRefPubMedGoogle Scholar
  5. 5.
    Chen P, Lee NV, Hu W et al (2016) Spectrum and degree of CDK drug interactions predicts clinical performance. Mol Cancer Ther 15:2273–2281CrossRefPubMedGoogle Scholar
  6. 6.
    Schwartz GK, Shah MA (2005) Targeting the cell cycle: a new approach to cancer therapy. J Clin Oncol 23:9408–9421CrossRefPubMedGoogle Scholar
  7. 7.
    Hosford SR, Miller TW (2014) Clinical potential of novel therapeutic targets in breast cancer: CDK4/6, Src, JAK/STAT, PARP, HDAC, and PI3K/AKT/mTOR pathways. Pharmgenomics Pers Med 7:203–215PubMedPubMedCentralGoogle Scholar
  8. 8.
  9. 9.
  10. 10.
  11. 11.
    DiPippo AJ, Patel NK, Barnett CM (2016) Cyclin-dependent kinase inhibitors for the treatment of breast cancer: past, present, and future. Pharmacotherapy 36:652–667CrossRefPubMedGoogle Scholar
  12. 12.
    Raub TJ, Wishart GN, Kulanthaivel P, Staton BA, Ajamie RT, Sawada GA et al (2015) Brain exposure of two selective dual CDK4 and CDK6 inhibitors and the antitumor activity of CDK4 and CDK6 inhibition in combination with temozolomide in an intracranial glioblastoma xenograft. Drug Metab Dispos 43:1360–1371CrossRefPubMedGoogle Scholar
  13. 13.
    Shapiro G, Rosen LS, Tolcher AW et al (2013) A first-in-human phase I study of the CDK4/6 inhibitor, LY2835219, for patients with advanced cancer. J Clin Oncol 31:2500CrossRefGoogle Scholar
  14. 14.
    Flaherty KT, Lorusso PM, Demichele A et al (2012) Phase I, dose escalation trial of the oral cyclin-dependent kinase 4/6 inhibitor PD 0332991, administered using a 21-day schedule in patients with advanced cancer. Clin Cancer Res 18:568–576CrossRefPubMedGoogle Scholar
  15. 15.
    O’Leary B, Finn RS, Turner NC (2016) Treating cancer with selective CDK4/6 inhibitors. Nat Rev 13:417–430Google Scholar
  16. 16.
    Infante JR, Cassier PA, Gerecitano JF et al (2016) A phase I study of the cyclin-dependent kinase 4/6 inhibitor ribociclib (LEE011) in patients with advanced solid tumors and lymphomas. Clin Cancer Res. doi: 10.1158/1078-0432.CCR-16-1248 PubMedCentralGoogle Scholar
  17. 17.
    Patnaik A, Rosen LS, Tolaney SM et al (2016) 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 6:1–14CrossRefGoogle Scholar
  18. 18.
    https://clinicaltrials.gov. Accessed 1 July 2017
  19. 19.
    www.fda.gov. Accessed 10 May 2017
  20. 20.
    Walker AJ, Wedam S, Amiri-Kordestani L et al (2016) FDA approval of palbociclib in combination with fulvestrant for the treatment of hormone receptor-positive, HER2-negative metastatic breast cancer. Clin Cancer Res 22:4968–4972CrossRefPubMedGoogle Scholar
  21. 21.
    Fry DW, Harvey PJ, Keller PR et al (2004) Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol Cancer Ther 3:1427–1438PubMedGoogle Scholar
  22. 22.
    Tamura K, Mukai H, Naito Y et al (2016) Phase I study of palbociclib, a cyclin-dependent kinase 4/6 inhibitor, in Japanese patients. Cancer Sci 107:755–763CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Schwartz GK, LoRusso PM, Dickson MA et al (2011) Phase I study of PD 0332991, a cyclin-dependent kinase inhibitor, administered in 3-week cycles (schedule 2/1). Br J Cancer 104:1862–1868CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Clark AS, O’Dwyer PJ, Heitjan D et al (2014) A phase I trial of palbociclib and paclitaxel in metastatic breast cancer. J Clin Oncol 32(5):527Google Scholar
  25. 25.
    DeMichele A, Clark AS, Tan KS, Heitjan DF, Gramlich K, Gallagher M et al (2015) CDK 4/6 inhibitor palbociclib (PD0332991) in Rb+ advanced breast cancer: phase II activity, safety, and predictive biomarker assessment. Clin Cancer Res 21:995–1001CrossRefPubMedGoogle Scholar
  26. 26.
    Finn RS, Crown JP, Lang I et al (2015) The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole vs. 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 16:25–35CrossRefPubMedGoogle Scholar
  27. 27.
    Vidula N, Rugo HS (2016) Cyclin-dependent kinase 4/6 inhibitors for the treatment of breast cancer: a review of preclinical and clinical data. Clin Breast Cancer 16:8–17CrossRefPubMedGoogle Scholar
  28. 28.
    Beaver JA, Amiri-Kordestani L, Charlab R et al (2015) FDA approval: palbociclib for the treatment of postmenopausal patients with estrogen receptor-positive, HER2-negative metastatic breast cancer. Clin Cancer Res 21:4760–4766CrossRefPubMedGoogle Scholar
  29. 29.
    Bell T, Crown JP, Lang I et al (2016) Impact of palbociclib plus letrozole on pain severity and pain interference with daily activities in patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer as first-line treatment. Curr Med Res Opin 32:959–965. doi: 10.1185/03007995.2016.1157060 CrossRefPubMedGoogle Scholar
  30. 30.
    Finn RS, Martin M, Rugo HS et al (2016) Palbociclib and Letrozole in advanced breast cancer. N Engl J Med 375:1925–1936CrossRefPubMedGoogle Scholar
  31. 31.
    Turner NC, Ro J, André F et al (2015) Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med 373:209–219CrossRefPubMedGoogle Scholar
  32. 32.
    Cristofanilli M, Turner NC, Bondarenko I et al (2016) Fulvestrant plus palbociclib vs. 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 17:425–439CrossRefPubMedGoogle Scholar
  33. 33.
    Iwata H, Im S-A, Masuda N et al (2017) PALOMA-3: phase III trial of fulvestrant with or without palbociclib in premenopausal and postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer that progressed on prior endocrine therapy—safety and efficacy in Asian patients. J Glob Oncol. doi: 10.1200/JGO.2016.008318 PubMedPubMedCentralGoogle Scholar
  34. 34.
    Harbeck N, Iyer S, Turner N et al (2016) Quality of life with palbociclib plus fulvestrant in previously treated hormone receptor-positive, HER2 negative metastatic breast cancer: patient-reported outcomes from the PALOMA-3trial. Ann Oncol 27:1047–1054CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Ma CX, Gao F, Luo J et al (2017) NeoPalAna neoadjuvant palbociclib, a cyclin-dependent kinase 4/6 inhibitor, and anastrozole for clinical stage 2 or 3 estrogen receptor positive breast cancer. Clin Cancer Res. doi: 10.1158/1078-0432.CCR-16-3206 Google Scholar
  36. 36.
    Witkiewicz AK, Cox D, Knudsen ES (2014) CDK4/6 inhibition provides a potent adjunct to Her2-targeted therapies in preclinical breast cancer models. Genes Cancer 5:261–272PubMedPubMedCentralGoogle Scholar
  37. 37.
    Asghar US, Barr AR, Cutts R et al (2017) Single-cell dynamics determines response to CDK4/6 inhibition in triple negative breast cancer. Clin Cancer Res. doi: 10.1158/1078-0432.CCR-17-0369 PubMedGoogle Scholar
  38. 38.
    Lehmann BD, Bauer JA, Chen X et al (2011) Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest 121:2750–2767. doi: 10.1172/JCI45014 CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Traina TA, Miller K, Yardley DA et al (2015) Results from a phase 2 study of enzalutamide (ENZA), an androgen receptor (AR) inhibitor, in advanced AR+ triple-negative breast cancer (TNBC). J Clin Oncol 33:1003Google Scholar
  40. 40.
    Bonnefoi H, Grellety T, Tredan O et al (2016) A phase II trial of abiraterone acetate plus prednisone in patients with triple-negative androgen receptor positive locally advanced or metastatic breast cancer (UCBG 12-1). Ann Oncol 27:812–818CrossRefPubMedGoogle Scholar
  41. 41.
    Rader J, Russell MR, Hart LS et al (2013) Dual CDK4/CDK6 inhibition induces cell-cycle arrest and senescence in neuroblastoma. Clin Cancer Res 19:6173–6182CrossRefPubMedGoogle Scholar
  42. 42.
    PedsODAC (2015) Pediatric Oncology Subcommittee of the Oncologic Drugs Advisory Committee briefing document: LEE011. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisory.Committee/UCM373175.pdf. Accessed 7 Oct 2015
  43. 43.
    Infante JR, Shapiro G, Witteveen P et al (2014) A phase I study of the single-agent CDK4/6 inhibitor LEE011 in pts with advanced solid tumors and lymphomas. J Clin Oncol 32:2528CrossRefGoogle Scholar
  44. 44.
    Infante JR, Shapiro GI, Witteveen PO et al (2013) Abstract 276: phase 1 multicenter, open-label, dose-escalation study of LEE011, an oral inhibitor of cyclin dependent kinase 4/6, in patients with advanced solid tumors or lymphomas. Mol Cancer Ther 12:A276CrossRefGoogle Scholar
  45. 45.
    Bardia A, Chavez-MacGregor C, Modi S et al (2014) Triple blockade with LEE011, everolimus, and exemestane in women with ER+/HER2− advanced/metastatic breast cancer: results from a phase Ib clinical trial. Eur J Cancer 50(S6):163CrossRefGoogle Scholar
  46. 46.
    Bardia A, Modi S, Gregor MCM et al (2014) Phase Ib/II study of LEE011, everolimus, and exemestane in postmenopausal women with ER+/HER2− metastatic breast cancer. J Clin Oncol 32(5):535Google Scholar
  47. 47.
    Herrera-Abreu MT, Asghar US, Elliot R et al (2015) PI3kinase/mTOR inhibition increases sensitivity of ER positive breast cancers to CDK4/6 inhibition by blocking cell cycle re-entry driven by cyclin D1 and inducing apoptosis. Ann Oncol 26:29–30CrossRefGoogle Scholar
  48. 48.
    Garcia-Martinez JM, Alessi DR (2008) mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1). Biochem J 416:375–385CrossRefPubMedGoogle Scholar
  49. 49.
    Vora SR, Juric D, Kim N, Mino-Kenudson M, Huynh T, Costa C et al (2014) CDK 4/6 inhibitors sensitize PIK3CA mutant breast cancer to PI3K inhibitors. Cancer Cell 26:136–149CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Hortobagyi GN, Stemmer SM, Burris HA et al (2016) First-line ribociclib + letrozole for postmenopausal women with hormone receptor-positive (HR+), HER2-negative (HER2–), advanced breast cancer (ABC). European Society for Medical Oncology (ESMO) Congress, Copenhagen. LBA1_PRGoogle Scholar
  51. 51.
    Hortobagyi GN, Stemmer SM, Burris HA et al (2016) Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med 375:1738–1748CrossRefPubMedGoogle Scholar
  52. 52.
    Bardia A, Modi S, Oliveira M, Campone M, Ma B, Dirix L et al (2016) Triplet therapy with ribociclib, everolimus, and exemestane in women with HR+/HER2– advanced breast cancer. Cancer Res 76:P6-13-01CrossRefGoogle Scholar
  53. 53.
    Munster PN, Hamilton EP, Estevez LG et al (2014) Phase Ib study of LEE011 and BYL719 in combination with letrozole in ER+, HER2− breast cancer. J Clin Oncol 32:143CrossRefGoogle Scholar
  54. 54.
    Juric D, Hamilton E, Estevez LG et al (2015) Phase Ib/II study of LEE011 and BYL719 and letrozole in ER+, HER2− breast cancer: safety, preliminary efficacy and molecular analysis. Cancer Res 75:P5-19-24CrossRefGoogle Scholar
  55. 55.
    Munster PN, Hamilton EP, Franklin C et al (2014) Phase lb study of LEE011 and BYL719 in combination with letrozole in estrogen receptor-positive, HER2-negative breast cancer (ER+, HER2− BC). J Clin Oncol 32:533CrossRefGoogle Scholar
  56. 56.
    Curigliano G, Gómes Pardo P, Meric-Bernstam F et al (2016) Ribociclib plus letrozole in early breast cancer: a presurgical, window-of-opportunity study. The Breast 28:191–198CrossRefPubMedGoogle Scholar
  57. 57.
    Tate SC, Cai S, Ajamie RT et al (2014) Semi-mechanistic pharmacokinetic/pharmacodynamic modeling of the antitumor activity of LY2835219, a new cyclin-dependent kinase 4/6 inhibitor, in mice bearing human tumor xenografts. Clin Cancer Res 14:3763–3774CrossRefGoogle Scholar
  58. 58.
    Gelbert LM, Cai S, Lin X et al (2014) Preclinical characterization of the CDK4/6 inhibitor LY2835219: in vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine. Invest New Drugs 32:825–837CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Barroso-Sousa R, Shapiro GI, Tolaney SM (2016) Clinical development of the CDK4/6 inhibitors ribociclib and abemaciclib in breast cancer. Breast Care 11:167–173CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Fujiwara Y, Tamura K, Kondo S et al (2016) Phase 1 study of abemaciclib, an inhibitor of CDK 4 and 6, as a single agent for Japanese patients with advanced cancer. Cancer Chemother Pharmacol 78:281–288CrossRefPubMedGoogle Scholar
  61. 61.
    Tolaney SM, Beeram M, Beck JT, Conlin AK, Dees EC, Dickler MN, et al (2015) A phase Ib study of abemaciclib with therapies for metastatic breast cancer. ASCO Meeting Abstracts 522Google Scholar
  62. 62.
    Dickler MN, Tolaney SM, Rugo HS et al (2016) MONARCH1: results from a phase II study of abemaciclib, a CDK4 and CDK6 inhibitor, as monotherapy, in patients with HR+/HER2− breast cancer, after chemotherapy for advanced disease. J Clin Oncol 34:510CrossRefGoogle Scholar
  63. 63.
    Sledge GW Jr, Toi M, Neven P et al (2017) MONARCH 2: abemaciclib in combination with fulvestrant in women with HR+/HER– advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol. doi: 10.1200/JCO.2017.73.7585 Google Scholar
  64. 64.
    Hurvitz S, Abad MF, Rostorfer R et al (2016) Interim results from neoMONARCH: a neoadjuvant phase II study of abemaciclib in postmenopausal women with HR+/HER2− breast cancer (BC). Ann Oncol 27:1–36CrossRefGoogle Scholar
  65. 65.
    Hurvitz S, Martin M, Abad MF, et al. Biological and clinical effects of abemaciclib in a phase 2 neoadjuvant study for premenopausal patients with HR+, HER2− breast cancer. In: Presented at 2016 San Antonio Breast Cancer Symposium, San Antonio, TX, December 6–10 (Abstract S4–06)Google Scholar
  66. 66.
    Goel S, Wang Q, Watt AC, Tolaney SM, Dillon DA, Li W et al (2016) Overcoming therapeutic resistance in HER2 positive breast cancers with CDK4/6 inhibitors. Cancer Cell 29:255–269CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Patel JM, Torous V, Hacker MR et al (2017) Retinoblastoma (Rb) protein expression in triple-negative breast cancer. J Clin Oncol 35:1097. doi: 10.1200/JCO.2017.35.15_suppl.1097 Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  1. 1.Specialist Outpatient ClinicWarsawPoland

Personalised recommendations