Abemacyclib is a unique representative of the class of CDK4/6 inhibitors in the treatment of HR+/HER2- metastatic breast cancer


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Abstract

Abemacyclib is the last registered member of the class of cyclin-dependent kinase 4 and 6 inhibitors (iCDK4/6), which has unique pharmacokinetic properties making it highly effective in the treatment of patients with HR+/HER2- metastatic breast cancer (mBC). The MONARCH cycle, which evaluates the effectiveness of therapy with abemacyclib in mono-regimen, in combination with fulvestrant (in the 2nd line) and aromatase inhibitors (in the 1st line treatment), has become a registration study. The potential efficacy of abemacyclib therapy in patients with intracranial metastatic lesions has been demonstrated. The spectrum, frequency and severity of adverse events (AEs) during therapy with abemocyclib differ somewhat from those characteristic of palbociclib and ribociclib; however, these AEs are amenable to correction and are rarely the reason for discontinuation of therapy. This article reviews the clinical data on the efficacy and safety of abemacyclib.

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About the authors

K. S Grechukhina

A.S. Loginov Moscow Clinical Research Center; Lomonosov Moscow State University

Email: dr.grechukhina@gmail.com
Moscow, Russia

K. A Vorontsova

A.S. Loginov Moscow Clinical Research Center

Moscow, Russia

T. M Kuko

A.S. Loginov Moscow Clinical Research Center

Moscow, Russia

A. A Prosvirnov

A.S. Loginov Moscow Clinical Research Center

Moscow, Russia

I. P Ganshina

N.N. Blokhin National Medical Research Center of Oncology

Moscow, Russia

E. V Lubennikova

N.N. Blokhin National Medical Research Center of Oncology

Moscow, Russia

I. V Kolyadina

National Medical Research Center for Obstetrics, Gynecology and Perinatology n.a. Acad. V.I. Kulakov; Russian Medical Academy of Continuous Professional Education

Moscow, Russia

L. G Zhukova

A.S. Loginov Moscow Clinical Research Center

Moscow, Russia

References

  1. Fry D.W., Bedford D.C., Harvey P.H., et al. Cell cycle and biochemical effects of PD 0183812. A potent inhibitor of the cyclin D-dependent kinases CDK4 and CDK6. J boil Chem. 2001;276(20):16617- 23. doi: 10.1074/jbc.M008867200
  2. Lallemand L., Duhoux F.P. CDK4/6 inhibitors in the treatment of advanced breast cancer. Belg J Med Oncol. 2017;11(5):234-41
  3. Prall O.W., Sarcevic B., Musgrove E.A., et al. Estrogen-induced activation of Cdk4 and Cdk2 during G1-S phase progression is accompanied by increased cyclin D1 expression and decreased cyclin-dependent kinase inhibitor association with cyclinE-Cdk2.JBoilChem.1997;272(16):10882- 94. doi: 10.1074/jbc.272.16.10882
  4. Finn R.S.,Dering J., Conklin D., et al. PD0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptorpositive human breast cancer cell lines in vitro. Breast Cancer res. 2009;11(5):R77. doi: 10.1186/bcr2419
  5. Vidula N., Rugo H.S. Cyclin-Dependent Kinase 4/6 Inhibitors for the Treatment of Breast Cancer: A Review of Preclinical and Clinical Data. Clin Breast Cancer. 2016;16(1):8-17. Doi: 10.1016/j. clbc.2015.07.005
  6. Giuliano M., Schettini F., RognoniC., et al. Endocrine treatment versus chemotherapy in postmenopausal women with hormone receptor-positive, HER2- negative, metastatic breast cancer: a systematic review and network meta-analysis. Lancet. Oncol. 2019;20(10):1360-69. doi: 10.1016/S1470- 2045(19)30420-6
  7. Gebbia V., Valerio M.R., Firenze A., et al. Abemaciclib: safety and effectiveness of a unique cyclin-dependent kinase inhibitor. Expert Opin Drug Saf. 2020;19(8):945-54. doi: 10.1080/14740338.2020.1781814
  8. Lallena M.J., Boehnke K., Torres R., et al. Abstract 3101: In-vitro characterization of Abemaciclib pharmacology in ER+ breast cancer cell lines. Cancer Res. 2015;75(Suppl. 15):3101. doi: 10.1158/1538-7445.AM2015-3101
  9. Robert M., Frenel J.S., Bourbouloux E., et al. Pharmacokinetic drug evaluation of abemaciclib for advanced breast cancer. Expert Opin Drug Metab Toxicol. 2019;15(2):85-91. doi: 10.1080/17425255.2019.1559816
  10. Goel S., DeCristo M.J., Watt A.C., et al. CDK4/6 inhibition triggers anti-tumour immunity. Nature. 2017;548(7668):471-75. Doi: 10.1038/ nature23465
  11. DeMichele A., Clark A.S., Tan K.S., et al. CDK 4/6 inhibitor palbociclib (PD0332991) in Rb+ advanced breast cancer: phase II activity, safety, and predictive biomarker assessment. Clin Cancer Res. 2015;21(5):995-1001. doi: 10.1158/1078- 0432.CCR-14-2258
  12. Infante J.R., Cassier P.A., Gerecitano J.F., et al. 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. 2016;22(23):5696-705. doi: 10.1158/1078-0432.CCR-16-1248
  13. Yamada Y., Ishikawa N., Kakizume T., et al. Abstract B31: a phase I study of single-agent ribociclib in Japanese patients with advanced solid tumors. Mol Cancer Ther. 2015;14(12 suppl 2):B31. doi: 10.1111/cas.13428
  14. Dickler M.N., Tolaney S.M., Rugo H.S., 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):5218-24. doi: 10.1158/1078- 0432.CCR-17-0754
  15. Rugo H.S., Tolaney M., Cortes J., et al. Abstract CT044: MONARCH 1: Final overall survival analysis of a phase 2 study of abemaciclib, a CDK4 and CDK6 inhibitor, as monotherapy, in patients with HR+/HER2- breast cancer, after chemotherapy for advanced disease. Cancer Res. 2017;77(Suppl.13) CT044. doi: 10.1158/1538-7445.AM2017- CT044
  16. Hamilton E., Cortes J., Ozyilkan O., et al. nextMONARCH: Abemaciclib Monotherapy or Combined With Tamoxifen for Metastatic Breast Cancer. Clin Breast Cancer. 2020: doi: 10.1016/j. clbc.2020.09.011
  17. Palumbo A., Lau G., Saraceni M. Abemaciclib: The NewestCDK4/6InhibitorfortheTreatmentofBreast Cancer. Ann Pharmacother. 2019;53(2):178-85. doi: 10.1177/1060028018795146
  18. Gelbert L.M., Cai S., Lin X., et al. 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. 2014;32(5):825-37. doi: 10.1007/s10637- 014-0120-7
  19. Corona S.P., Generali D. Abemaciclib: a CDK4/6 inhibitor for the treatment of HR+/HER2- advanced breast cancer. Drug Des Devel Ther. 2018;12:321-30. doi: 10.2147/DDDT. S137783
  20. Sledge G.W. 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):2875-84. doi: 10.1200/JCO.2017.73.7585
  21. Sledge G.W., Toi M., Neven P., et al. The Effect of Abemaciclib Plus Fulvestrant on Overall Survival in Hormone Receptor-Positive, ERBB2-Negative Breast Cancer That Progressed on Endocrine Therapy-MONARCH 2: A Randomized Clinical Trial. JAMA Oncol. 2019;6(1):116-24. doi: 10.1001/ jamaoncol.2019.4782
  22. Goetz M.P., Toi M., Campone M., et al. MONARCH 3: Abemaciclib As Initial Therapy for Advanced Breast Cancer. J Clin Oncol. 2017;35(32):3638- 46. doi: 10.1200/JCO.2017.75.6155
  23. Johnston S., Martin M., Di Leo A., et al. MONARCH 3 final PFS: a randomized study of abemaciclib as initial therapy for advanced breast cancer. NPJ. Breast Cancer. 2019;5:5. doi: 10.1038/s41523- 018-0097-z
  24. Di Leo A., Toi M., Campone M., et al. Ann. Oncol. 2017;28(Suppl. 5):v605-v649. Doi: 10.1093/ annonc/mdx440
  25. Sanchez-Martinez C., Gelbert L.M., Shannon H., et al. Abstract B234: LY2835219, a potent oral inhibitor of the cyclin-dependent kinases 4 and 6 (CDK4/6) that crosses the blood-brain barrier and demonstrates in vivo activity against intracranial human brain tumor xenografts. Mol Cancer Ther. 2011;10(Suppl. 11):B234. doi: 10.1158/1535- 7163.TARG-11-B234
  26. Patnaik A., Rosen L.S., Tolaney S.M., 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(7):740-53. doi: 10.1158/2159- 8290.CD-16-0095
  27. Tolaney S.M., Lin N.U., Thornton D., et al. Abemaciclib for the treatment of brain metastases (BM) secondary to hormone receptor positive (HR+), HER2 negative breast cancer. J Clin Oncol. 2017;35(Suppl. 15):1019. Doi: 10.1200/ JCO.2017.35.15_suppl.1019
  28. Kotake T., Toi M. Abemaciclib for the treatment of breast cancer. Expert Opin Pharmacother. 2018;19(5):517-24. doi: 10.1080/14656566.2018.1448787
  29. Tolaney S.M., Sahebjam S., Le Rhun E., et al. A Phase II Study of Abemaciclib in Patients with Brain Metastases Secondary to Hormone Receptor-Positive Breast Cancer. Clin Cancer Res. 2020;26(20):5310-19. doi: 10.1158/1078- 0432.CCR-20-1764
  30. Howlett S., Harvey-Jones E., Smith D., et al. Does Concurrent Use of CDK4/6 Inhibitors During Palliative Radiotherapy Increase Toxicity in Patients With Metastatic Breast Cancer? Clin Oncol. (R Coll Radiol). 2021;33(1):e99. Doi: 10.1016/j. clon.2020.10.005
  31. Petrelli F., Ghidini A., Pedersini R., et al. Comparative efficacy of palbociclib, ribociclib and abemaciclib for ER+ metastatic breast cancer: an adjusted indirect analysis of randomized controlled trials. Breast Cancer Res Treat. 2019;174(3):597-604. doi: 10.1007/s10549-019-05133-y
  32. Messina C., Messina M., Zanardi E. Risks and benefits from CDK inhibitors for advanced HR+ Her 2- breast cancer. Ann Oncol. 2017;28(12):3099- 100. doi: 10.1093/annonc/mdx530
  33. Ramos-Esquivel A., Hernández-Steller H., Savard M.F., et al. Cyclin-dependent kinase 4/6 inhibitors as first-line treatment for post-menopausal metastatic hormone receptor-positive breast cancer patients: a systematic review and meta-analysis of phase III randomized clinical trials. Breast Cancer. 2018;25(4):479-88. doi: 10.1007/s12282- 018-0848-6
  34. Ribnikar D., Volovat S.R., Cardoso F. Targeting CDK4/6 pathways and beyond in breast cancer. Breast. 2019;43:8-17. doi: 10.1016/j. breast.2018.10.001
  35. Scheicher R., Hoelbl-Kovacic A., Bellutti F., et al. CDK6 as a key regulator of hematopoietic and leukemic stem cell activation. Blood. 2015;125(1):90-101. doi: 10.1182/blood2014-06-584417
  36. Desnoyers A., Nadler M.B., Kumar V., et al. Comparison of treatment-related adverse events of different Cyclin-dependent kinase 4/6 inhibitors in metastatic breast cancer: A network metaanalysis. Cancer Treat Rev. 2020;90:102086. doi: 10.1016/j.ctrv.2020.102086
  37. Tamura K. Differences of cyclin-dependent kinase 4/6 inhibitor, palbociclib and abemaciclib, in breast cancer. Jpn J Clin Oncol. 2019;49(11):993-98. doi: 10.1093/jjco/hyz151
  38. Sledge G.W. Abemaciclib Plus Fulvestrant Delays Breast Cancer Progression in MONARCH 2. ASCO Ann Meeting. 2017;Abstract 1000. Doi: 10.199/ Abst_199_180696
  39. Goetz M.P., Martin M., Tokunaga E., et al. Health-Related Quality of Life in MONARCH 3: Abemaciclib plus an Aromatase Inhibitor as Initial Therapy in HR+, HER2- Advanced Breast Cancer. Оncol. 2020;25(9):e1346-54. Doi: 10.1634/ theoncologist.2020-0084
  40. Omori Y., Enatsu S., Cai Z., et al. Patients’ preferences forpostmenopausalhormone receptorpositive, human epidermal growth factor receptor 2-negative advanced breast cancer treatments in Japan. Breast Cancer. 2019;26(5):652-62. doi: 10.1007/s12282-019-00965-4
  41. Bossi P., Antonuzzo A., Cherny N.I., et al. ESMO Guidelines Committee. Diarrhoea in adult cancer patients: ESMO Clinical Practice Guidelines. Ann Oncol. 2018;29(Suppl. 4):iv126-42. doi: 10.1093/annonc/mdy145
  42. Hurvitz S.A., Martin M., Press M.F., et al. Potent Cell-Cycle Inhibition and Upregulation of Immune Response with Abemaciclib and Anastrozole in neoMONARCH, Phase II Neoadjuvant Study in HR+/HER2- Breast Cancer. Clin Cancer Res. 2020;26(3):566-80. doi: 10.1158/1078-0432. CCR-19-1425
  43. Johnston S.R., Harbeck N., Hegg R., et al. monarchE Committee Members and Investigators. Abemaciclib Combined With Endocrine Therapy for the Adjuvant Treatment of HR+, HER2-, Node-Positive, High-Risk, Early Breast Cancer (monarchE). J Clin Oncol. 2020;38(34):3987- 98. doi: 10.1200/JCO.20.02514
  44. Tolaney S.M., Wardley A.M., Zambelli S., et al. Abemaciclib plus trastuzumab with or without fulvestrant versus trastuzumab plus standardof-care chemotherapy in women with hormone receptor-positive, HER2-positive advanced breast cancer (monarcHER): a randomised, openlabel, phase 2 trial. Lancet. Oncol. 2020;21(6): 763-75. doi: 10.1016/S1470-2045(20) 30112-1

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