Cyclin-dependent kinase 4/6 inhibitors in breast cancer: palbociclib, ribociclib, and abemaciclib
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.
A literature search of above topics was carried out using PubMed and data reported at international oncology meetings and clinicaltrials.gov were included.
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.
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.
KeywordsCDK4/6 inhibitors Breast cancer Palbociclib Ribociclib Abemaciclib
- 8.https://pubchem.ncbi.nlm.nih.gov/compound/pd0332991#section=Top. Accessed 10 May 2017
- 9.https://pubchem.ncbi.nlm.nih.gov/compound/44631912. Accessed 10 May 2017
- 10.https://pubchem.ncbi.nlm.nih.gov/compound/46220502. Accessed 10 May 2017
- 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
- 15.O’Leary B, Finn RS, Turner NC (2016) Treating cancer with selective CDK4/6 inhibitors. Nat Rev 13:417–430Google Scholar
- 18.https://clinicaltrials.gov. Accessed 1 July 2017
- 19.www.fda.gov. Accessed 10 May 2017
- 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
- 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
- 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
- 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.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
- 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
- 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
- 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
- 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
- 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
- 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