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Review Article

Editor's Choice - Free Access

Clinical Development of the CDK4/6 Inhibitors Ribociclib and Abemaciclib in Breast Cancer

Barroso-Sousa R.a · Shapiro G.I.b · Tolaney S.M.a,b

Author affiliations

a Breast Oncology Program, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; b Early Drug Development Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA

Corresponding Author

Sara M. Tolaney, MD

Department of Medical Oncology

Dana-Farber Cancer Institute

450 Brookline Avenue, Yawkey 1257, Boston, MA 02215, USA

sara_tolaney@dfci.harvard.edu

Related Articles for ""

Breast Care 2016;11:167-173

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Summary

Clinical and preclinical data support a significant role for inhibitors of the cyclin-dependent kinases (CDKs) 4 and 6 in the treatment of patients with breast cancer. Recently, based on data showing improvement in progression-free survival, the use of palbociclib (Ibrance; Pfizer, Inc.) in combination with endocrine agents was approved to treat patients with hormone receptor-positive advanced disease. Importantly, 2 other CDK4/6 inhibitors, abemaciclib (LY2835219; Lilly) and ribociclib (LEE011; Novartis), are in the late stage of clinical development. In this review, we will focus on clinical data on these 2 new drugs, highlighting their differences compared to palbociclib in terms of single-agent activity, central nervous system penetration, and common adverse events. In addition, we will present the ongoing clinical trials and discuss future directions in the field.

© 2016 S. Karger GmbH, Freiburg


References

  1. Hanahan D, Weinberg RA: The hallmarks of cancer. Cell 2000;100:57-70.
  2. Hanahan D, Weinberg RA: Hallmarks of cancer: the next generation. Cell 2011;144:646-674.
  3. Sherr CJ, Beach D, Shapiro GI: Targeting CDK4 and CDK6: from discovery to therapy. Cancer Discov 2016;6:353-367.
  4. Weinberg RA: The retinoblastoma protein and cell cycle control. Cell 1995;81:323-330.
  5. Asghar U, Witkiewicz AK, Turner NC, Knudsen ES: The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat Rev Drug Discov 2015;14:130-146.
  6. Cancer Genome Atlas Network: Comprehensive molecular portraits of human breast tumours. Nature 2012;490:61-70.
  7. Watts CK, Brady A, Sarcevic B, deFazio A, Musgrove EA, Sutherland RL: Antiestrogen inhibition of cell cycle progression in breast cancer cells is associated with inhibition of cyclin-dependent kinase activity and decreased retinoblastoma protein phosphorylation. Mol Endocrinol 1995;9:1804-1813.
  8. Thangavel C, Dean JL, Ertel A, Knudsen KE, Aldaz CM, Witkiewicz AK, et al.: Therapeutically activating RB: reestablishing cell cycle control in endocrine therapy-resistant breast cancer. Endocr Relat Cancer 2011;18:333-345.
  9. Mayer EL: Targeting breast cancer with CDK inhibitors. Curr Oncol Rep 2015;17:443.
  10. Murphy CG, Dickler MN: The role of CDK4/6 inhibition in breast cancer. Oncologist 2015;20:483-490.
  11. Beaver JA, Amiri-Kordestani L, Charlab R, Chen W, Palmby T, Tilley A, et al.: FDA approval: palbociclib for the treatment of postmenopausal patients with estrogen receptor-positive, HER2-negative metastatic breast cancer. Clin Cancer Res 2015;21:4760-4766.
  12. Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, 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.
  13. Cristofanilli M, Turner NC, Bondarenko I, Ro J, Im SA, Masuda N, 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, doi: 10.1016/S1470-2045(15)00613-0 [Epub ahead of print].
  14. Infante JR, Shapiro G, Witteveen P, Gerecitano JF, Ribrag V, Chugh R, et al.: A phase I study of the single-agent CDK4/6 inhibitor LEE011 in pts with advanced solid tumors and lymphomas. ASCO Meeting Abstracts 2014;32(15 suppl):abstr 2528.
  15. Sherr CJ: Cancer cell cycles. Science 1996;274:1672-1677.
  16. Garcia-Martinez JM, Alessi DR: mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1). Biochem J 2008;416:375-385.
  17. Vora SR, Juric D, Kim N, Mino-Kenudson M, Huynh T, Costa C, et al.: CDK 4/6 inhibitors sensitize PIK3CA mutant breast cancer to PI3K inhibitors. Cancer Cell 2014;26:136-149.
  18. Bardia A, Modi S, Oliveira M, Campone M, Ma B, Dirix L, et al.: Triplet therapy with ribociclib, everolimus, and exemestane in women with HR+/HER2- advanced breast cancer. Cancer Res 2016;76(4 suppl): abstr P6-13-01.
    External Resources
  19. Juric D, Ismail-Khan R, Campone M, García-Estévez L, Becerra C, De Boer R, et al.: Phase Ib/II study of ribociclib and alpelisib and letrozole in ER+, HER2- breast cancer: safety, preliminary efficacy and molecular analysis. Cancer Res 2016;76(4 suppl):abstr P3-14-01.
    External Resources
  20. Goel S, Wang Q, Watt AC, Tolaney SM, Dillon DA, Li W, et al.: Overcoming therapeutic resistance in HER2-positive breast cancers with CDK4/6 inhibitors. Cancer Cell 2016;29:255-269.
  21. 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; doi: 10.1158/2159-8290.CD-16-0095.
  22. Dickler MN, Tolaney SM, Rugo HS, et al.: 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 2016;34: (suppl; abstr 510).
  23. DeMichele A, Clark AS, Tan KS, Heitjan DF, Gramlich K, Gallagher M, 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;21:995-1001.
  24. Raub TJ, Wishart GN, Kulanthaivel P, Staton BA, Ajamie RT, Sawada GA, et al.: 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 2015;43:1360-1371.
  25. Lin NU, Lee EQ, Aoyama H, Barani IJ, Barboriak DP, Baumert BG, et al.: Response assessment criteria for brain metastases: proposal from the RANO group. Lancet Oncol 2015;16:e270-e278.
  26. Tolaney SM, Beeram M, Beck JT, Conlin AK, Dees EC, Dickler MN, et al.: A phase Ib study of abemaciclib with therapies for metastatic breast cancer. ASCO Meeting Abstracts 2015;33(15 suppl):abstr 522.
  27. Clark A, O'Dwyer P, Troxel A, Lal P, Feldman M, Gallagher M, et al.: Palbociclib and paclitaxel on an alternating schedule for advanced breast cancer: results of a phase Ib trial. Cancer Res 2016;76(4 suppl):abstr P6-13-08.
    External Resources
  28. Asghar U, Herrera-Abreu MT, Cutts R, Babina I, Pearson A, Turner NC: Identification of subtypes of triple negative breast cancer (TNBC) that are sensitive to CDK4/6 inhibition. ASCO Meeting Abstracts 2015;33(15 suppl):abstr 11098.
  29. Finn RS, Martin M, Rugo HS, et al.: PALOMA-2: Primary results from a phase III trial of palbociclib (P) with letrozole (L) compared with letrozole alone in postmenopausal women with ER+/HER2- advanced breast cancer (ABC). J Clin Oncol 2016;34:(suppl; abstr 507).
  30. Loibl S, Turner NC, Ro J, et al.: Palbociclib (PAL) in combination with fulvestrant (F) in pre-/peri-menopausal (PreM) women with metastatic breast cancer (MBC) and prior progression on endocrine therapy - results from Paloma-3. J Clin Oncol 2016;34:(suppl; abstr 524).

Article / Publication Details

First-Page Preview
Abstract of Review Article

Published online: June 22, 2016
Issue release date: June 2016

Number of Print Pages: 7
Number of Figures: 0
Number of Tables: 1

ISSN: 1661-3791 (Print)
eISSN: 1661-3805 (Online)

For additional information: https://www.karger.com/BRC

References

  1. Hanahan D, Weinberg RA: The hallmarks of cancer. Cell 2000;100:57-70.
  2. Hanahan D, Weinberg RA: Hallmarks of cancer: the next generation. Cell 2011;144:646-674.
  3. Sherr CJ, Beach D, Shapiro GI: Targeting CDK4 and CDK6: from discovery to therapy. Cancer Discov 2016;6:353-367.
  4. Weinberg RA: The retinoblastoma protein and cell cycle control. Cell 1995;81:323-330.
  5. Asghar U, Witkiewicz AK, Turner NC, Knudsen ES: The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat Rev Drug Discov 2015;14:130-146.
  6. Cancer Genome Atlas Network: Comprehensive molecular portraits of human breast tumours. Nature 2012;490:61-70.
  7. Watts CK, Brady A, Sarcevic B, deFazio A, Musgrove EA, Sutherland RL: Antiestrogen inhibition of cell cycle progression in breast cancer cells is associated with inhibition of cyclin-dependent kinase activity and decreased retinoblastoma protein phosphorylation. Mol Endocrinol 1995;9:1804-1813.
  8. Thangavel C, Dean JL, Ertel A, Knudsen KE, Aldaz CM, Witkiewicz AK, et al.: Therapeutically activating RB: reestablishing cell cycle control in endocrine therapy-resistant breast cancer. Endocr Relat Cancer 2011;18:333-345.
  9. Mayer EL: Targeting breast cancer with CDK inhibitors. Curr Oncol Rep 2015;17:443.
  10. Murphy CG, Dickler MN: The role of CDK4/6 inhibition in breast cancer. Oncologist 2015;20:483-490.
  11. Beaver JA, Amiri-Kordestani L, Charlab R, Chen W, Palmby T, Tilley A, et al.: FDA approval: palbociclib for the treatment of postmenopausal patients with estrogen receptor-positive, HER2-negative metastatic breast cancer. Clin Cancer Res 2015;21:4760-4766.
  12. Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, 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.
  13. Cristofanilli M, Turner NC, Bondarenko I, Ro J, Im SA, Masuda N, 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, doi: 10.1016/S1470-2045(15)00613-0 [Epub ahead of print].
  14. Infante JR, Shapiro G, Witteveen P, Gerecitano JF, Ribrag V, Chugh R, et al.: A phase I study of the single-agent CDK4/6 inhibitor LEE011 in pts with advanced solid tumors and lymphomas. ASCO Meeting Abstracts 2014;32(15 suppl):abstr 2528.
  15. Sherr CJ: Cancer cell cycles. Science 1996;274:1672-1677.
  16. Garcia-Martinez JM, Alessi DR: mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1). Biochem J 2008;416:375-385.
  17. Vora SR, Juric D, Kim N, Mino-Kenudson M, Huynh T, Costa C, et al.: CDK 4/6 inhibitors sensitize PIK3CA mutant breast cancer to PI3K inhibitors. Cancer Cell 2014;26:136-149.
  18. Bardia A, Modi S, Oliveira M, Campone M, Ma B, Dirix L, et al.: Triplet therapy with ribociclib, everolimus, and exemestane in women with HR+/HER2- advanced breast cancer. Cancer Res 2016;76(4 suppl): abstr P6-13-01.
    External Resources
  19. Juric D, Ismail-Khan R, Campone M, García-Estévez L, Becerra C, De Boer R, et al.: Phase Ib/II study of ribociclib and alpelisib and letrozole in ER+, HER2- breast cancer: safety, preliminary efficacy and molecular analysis. Cancer Res 2016;76(4 suppl):abstr P3-14-01.
    External Resources
  20. Goel S, Wang Q, Watt AC, Tolaney SM, Dillon DA, Li W, et al.: Overcoming therapeutic resistance in HER2-positive breast cancers with CDK4/6 inhibitors. Cancer Cell 2016;29:255-269.
  21. 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; doi: 10.1158/2159-8290.CD-16-0095.
  22. Dickler MN, Tolaney SM, Rugo HS, et al.: 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 2016;34: (suppl; abstr 510).
  23. DeMichele A, Clark AS, Tan KS, Heitjan DF, Gramlich K, Gallagher M, 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;21:995-1001.
  24. Raub TJ, Wishart GN, Kulanthaivel P, Staton BA, Ajamie RT, Sawada GA, et al.: 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 2015;43:1360-1371.
  25. Lin NU, Lee EQ, Aoyama H, Barani IJ, Barboriak DP, Baumert BG, et al.: Response assessment criteria for brain metastases: proposal from the RANO group. Lancet Oncol 2015;16:e270-e278.
  26. Tolaney SM, Beeram M, Beck JT, Conlin AK, Dees EC, Dickler MN, et al.: A phase Ib study of abemaciclib with therapies for metastatic breast cancer. ASCO Meeting Abstracts 2015;33(15 suppl):abstr 522.
  27. Clark A, O'Dwyer P, Troxel A, Lal P, Feldman M, Gallagher M, et al.: Palbociclib and paclitaxel on an alternating schedule for advanced breast cancer: results of a phase Ib trial. Cancer Res 2016;76(4 suppl):abstr P6-13-08.
    External Resources
  28. Asghar U, Herrera-Abreu MT, Cutts R, Babina I, Pearson A, Turner NC: Identification of subtypes of triple negative breast cancer (TNBC) that are sensitive to CDK4/6 inhibition. ASCO Meeting Abstracts 2015;33(15 suppl):abstr 11098.
  29. Finn RS, Martin M, Rugo HS, et al.: PALOMA-2: Primary results from a phase III trial of palbociclib (P) with letrozole (L) compared with letrozole alone in postmenopausal women with ER+/HER2- advanced breast cancer (ABC). J Clin Oncol 2016;34:(suppl; abstr 507).
  30. Loibl S, Turner NC, Ro J, et al.: Palbociclib (PAL) in combination with fulvestrant (F) in pre-/peri-menopausal (PreM) women with metastatic breast cancer (MBC) and prior progression on endocrine therapy - results from Paloma-3. J Clin Oncol 2016;34:(suppl; abstr 524).
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