Targeting Cell Cycle Progression: CDK4/6 Inhibition in Breast Cancer

Sneha Phadke, DO; Alexandra Thomas, MD
Published: Friday, Oct 03, 2014
div style="width:100%;margin:20px 0px;font-size:12px;line-height:13px;border-top:3px solid #000;">

Table 2. Phase 3 Trials of CDK 4/6 Inhibitors in Breast Cancer

CDK 4/6 Inhibitor Participants Arms Primary Outcome Measure
Palbociclib

Trial Name: PENELOPE-B
Women with ER+, HER-2 negative breast cancer with residual disease after neoadjuvant chemotherapy and surgery Palbociclib + endocrine treatment vs placebo + endocrine treatment Invasive disease-free survival
Palbociclib

Trial Name: PALOMA-2
Postmenopausal women with ER+ HER-2 negative advanced breast cancer, no prior systemic therapy Palbociclib + letrozole vs letrozole + placebo Progression-free survival
Palbociclib

Trial Name: PALOMA-3
Women with ER+ HER-2 negative metastatic breast cancer with progression after prior endocrine therapy Palbociclib + fulvestrant vs fulvestrant + placebo Progression-free survival
Palbociclib

Trial Name: PEARL
Postmenopausal women with ER+ HER-2 negative metastatic breast cancer with resistance to nonsteroidal aromatase inhibitors Palbociclib + exemestane vs chemotherapy (capecitabine) Progression-free survival
LEE011

Trial Name: MONALEESA-2
Postmenopausal women with ER+ HER-2 negative advanced breast cancer, no prior systemic therapy LEE011 + letrozole vs letrozole + placebo Progression-free survival
LY2835219 Postmenopausal women with ER+ HER-2 negative advanced breast cancer Fulvestrant + LY2835219 vs fulvestrant + placebo Progression-free survival


One study is evaluating the impact of adding a novel cyclin inhibitor to carboplatin and gemcitabine in metastatic triple-negative breast cancer.32 Finally, since radiation therapy requires cells to be moving through the cell cycle to exert its effect, these agents could play a role in limiting toxicity from radiation exposure in tumors that have lost an intact Rb protein by preventing noncancerous bystander cells from progressing through the cell cycle until radiation treatment is complete. The CDK4/6 inhibitor can then be stopped, allowing the cell cycle to return to normal.

As many human cancers harbor cell cycle activating mutations, it is thought that selective CDK4/6 inhibitors will have antitumor activity against a wide range of cancers with a relatively tolerable side effect profile. Trials targeting vulnerabilities in cell cycle proliferation are ongoing in a variety of malignancies including hematologic malignancies, glioblastoma multiforme, and advanced melanoma.5,33-36

Conclusion

Inhibition of the CDK4/6 pathway has demonstrated initial promise in advanced hormone receptor–positive breast cancer. Additionally, emerging evidence suggests that novel combinations may expand the use of these agents to other breast cancer subtypes and to other roles in anti-neoplastic therapy. Notably, these small molecules appear to be relatively well tolerated. Studies looking at resistance mechanisms will be important to furthering the use of CDK4/6 inhibitors, particularly in those tumors that have an intact Rb protein but are not vulnerable to therapy. Defining gene expression patterns in tumors that confer sensitivity to these drugs will also help determine which patients will have the greatest benefit as we increasingly move toward an era of more precise, personalized medicine.


References
  1. Roberts PJ, Bisi JE, Strum JC, et al. Multiple roles of cyclin-dependent kinase 4/6 inhibitors in cancer therapy. J Natl Cancer Inst. 2012;104(6):476-487.
  2. Arnold A, Papanikolaou A. Cyclin D1 in breast cancer pathogenesis. J Clin Onc. 2005;23(18):4215-4224.
  3. Dickson C, Fantl V, Gillett C, et al. Amplification of chromosome band 11q13 and a role for cyclin D1 in human breast cancer. Cancer Lett. 1995;90(1):43-50.
  4. Lundgren K, Brown M, Pineda S, et al. Effects of cyclin D1 gene amplification and protein expression on time to recurrence in postmenopausal breast cancer patients treated with anastrozole or tamoxifen: a TransATAC study. Breast Cancer Res. 2012;14(2):R57.
  5. Sheppard KE, McArthur GA. The cell-cycle regulator CDK4: an emerging therapeutic target in melanoma. Clin Cancer Res. 2013;19(19):5320-5328.
  6. Shapiro GI. Cyclin-dependent kinase pathways as targets for cancer treatment. J Clin Oncol. 2006;24(11):1770-1783.
  7. Blagden S, de Bono J. Drugging cell cycle kinases in cancer therapy. Curr Drug Targets. May 2005;6(3):325-335.
  8. Kobayashi M, Takahashi-Suzuki I, Shimomura T, Iwasawa Y, Hirai H. Cell death induction in resting lymphocytes by pan-Cdk inhibitor, but not by Cdk4/6 selective inhibitor. Invest New Drugs. 2011;29(5):921-931.
  9. Massard C, Soria JC, Anthoney DA, et al. A first in man, phase I dose-escalation study of PHA-793887, an inhibitor of multiple cyclin-dependent kinases (CDK2, 1 and 4) reveals unexpected hepatotoxicity in patients with solid tumors. Cell Cycle. 2011;10(6):963-970.
  10. Finn RS, Dering J, Conklin D, Kalous O, et al. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res. 2009;11(5):R77.
  11. Cancer Genome Atlas N. Comprehensive molecular portraits of human breast tumours. Nature. October 4, 2012;490(7418):61-70.
  12. Lange CA, Yee D. Killing the second messenger: targeting loss of cell cycle control in endocrine-resistant breast cancer. Endocr Relat Cancer. 2011;18(4):C19-C24.
  13. Zwijsen RM, Wientjens E, Klompmaker R, van der Sman J, Bernards R, Michalides RJ. CDK-independent activation of estrogen receptor by cyclin D1. Cell. 1997;88(3):405-415.
  14. Schwartz GK, LoRusso PM, Dickson MA, et al. Phase I study of PD 0332991, a cyclin-dependent kinase inhibitor, administered in 3-week cycles (Schedule 2/1). Br J Cancer. 2011;104(12):1862-1868. 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. J Clin Onc. 2014;32;5s:Abstract 2528.
  15. Shapiro G, Rosen LS, Tolcher AW, et al. A first-in-human phase I study of the CDK4/6 inhibitor, LY2835219, for patients with advanced cancer. J Clin Oncol. 2013(suppl):Abstract 2500.
  16. Finn RS, Crown JP, Lang I, et al. Results of a randomized phase 2 study of PD 0332991, a cyclin-dependent kinase (CDK) 4/6 inhibitor, in combination with letrozole vs letrozole alone for first-line treatment of ER+/HER2- advanced breast cancer (BC). Cancer Research. 2012;72:S1-S6. doi:10.1158/0008-5472.SABCS12-S1-6.
  17. Finn RS, Crown JP, Lang I, et al. Final results of a randomized Phase II study of PD 0332991, a cyclin-dependent kinase (CDK)-4/6 inhibitor, in combination with letrozole vs letrozole alone for first-line treatment of ER+/HER2- advanced breast cancer (PALOMA-1; TRIO-18). Paper presented at: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research. 2014; San Diego, CA.
  18. Infante JR, Shapiro GI, Witteveen PO, et al. 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. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; October 19-23, 2013; Boston, MA. Philadelphia, PA: AACR; Mol Cancer Ther. 2013;12(11 suppl):Abstract A276.
  19. Kim S, Loo A, Chopra R, Caponigro G, et al. LEE011: An orally bioavailable, selective small molecule inhibitor of CDK4/6– Reactivating Rb in cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; October 19-23, 2013; Boston, MA. Philadelphia, PA: AACR; Mol Cancer Ther. 2013;12(11 suppl):Abstract nr PR02.
  20. O'Brien NA, Di Tomaso E, Ayala R, et al. In vivo efficacy of combined targeting of CDK4/6, ER and PI3K signaling in ER+ breast cancer [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; April 5-9, 2014; San Diego, CA. Philadelphia, PA: AACR; 2014. Abstract 4756.
  21. Gelbert LM, Cai S, Lin X, 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. June 13, 2014.
  22. Patnaik A, Rosen LS, Tolaney SM, et al. Clinical activity of LY2835219, a novel cell cycle inhibitor selective for CDK4 and CDK6, in patients with metastatic breast cancer [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; April 5-9, 2014; San Diego, CA. Philadelphia, PA: AACR; 2014:Abstract CT232.
  23. A Study of Palbociclib (PD-0332991) + Letrozole vs. Letrozole For 1st Line Treatment Of Postmenopausal Women With ER+/HER2- Advanced Breast Cancer (PALOMA-2). http://clinicaltrials.gov/show/NCT01740427.
  24. Palbociclib (PD-0332991) Combined With Fulvestrant In Hormone Receptor+ HER2-Negative Metastatic Breast Cancer After Endocrine Failure (PALOMA-3). http://clinicaltrials.gov/ct2/show/NCT01942135.
  25. A Study of Palbociclib in Addition to Standard Endocrine Treatment in Hormone Receptor Positive Her2 Normal Patients With Residual Disease After Neoadjuvant Chemotherapy and Surgery (PENELOPE-B). http://clinicaltrials.gov/ct2/show/NCT01864746.
  26. Study of Efficacy and Safety of LEE011 in Postmenopausal Women With Advanced Breast Cancer.(MONALEESA-2). http://clinicaltrials.gov/ct2/show/NCT01958021.
  27. A Study of LY2835219 Combined With Fulvestrant in Women With Hormone Receptor Positive HER2 Negative Breast Cancer (MONARCH 2). http://clinicaltrials.gov/ct2/show/NCT02107703.
  28. Study of LEE011 With Fulvestrant and BYL719 or BKM120 in Advanced Breast Cancer. http://clinicaltrials.gov/ct2/show/NCT02088684.
  29. Phase Ib/II Trial of LEE011 With Everolimus (RAD001) and Exemestane in the Treatment of ER+ Her2- Advanced Breast Cancer. http://clinicaltrials.gov/ct2/show/NCT01857193.
  30. Dickson MA, Schwartz GK. Development of cell-cycle inhibitors for cancer therapy. Curr Oncology. 2009;16(2):36-43.
  31. A Clinical Trial Comparing Gemcitabine and Carboplatin With and Without P276-00 in Subjects With Metastatic Triple Negative Breast Cancer, With a Run-in of Escalating Dose of P276-00 Added to Gemcitabine and Carboplatin. http://clinicaltrials.gov/ct2/show/NCT01333137?term=NCT01333137&rank=1
  32. Dickson MA, Tap WD, Keohan ML, et al. Phase II trial of the CDK4 inhibitor PD0332991 in patients with advanced CDK4-amplified well-differentiated or dedifferentiated liposarcoma. J Clin Oncol. 2013;31(16):2024-2028.
  33. Luke JJ, D’Adamo DR, Dickson MA, et al. The cyclin-dependent kinase inhibitor flavopiridol potentiates doxorubicin efficacy in advanced sarcomas: preclinical investigations and results of a phase I dose-escalation clinical trial. Clin Cancer Res. 2012;18(9):2638-2647.
  34. Leonard JP, LaCasce AS, Smith MR, et al. Selective CDK4/6 inhibition with tumor responses by PD0332991 in patients with mantle cell lymphoma. Blood. 2012;119(20):4597-4607.
  35. Wiedemeyer WR, Dunn IF, Quayle SN, et al. Pattern of retinoblastoma pathway inactivation dictates response to CDK4/6 inhibition in GBM. Proc Natl Acad Sci USA. 2010;107(25):11501-11506.



View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Miami Breast Cancer Conference®: Attendee Tumor Board OnlineNov 30, 20181.5
Community Practice Connections™: 1st Annual Paris Breast Cancer Conference™Dec 31, 20181.5
Publication Bottom Border
Border Publication
x