The Role of CDK4/6 Inhibitors in Breast Cancer
- 66 Downloads
Oral inhibitors of CDK4/6 have been shown to increase response rates and prolong disease control when combined with endocrine therapy in hormone-responsive (HR+) HER2-negative advanced breast cancer. Palbociclib, ribociclib and abemaciclib are all approved in combination with non-steroidal aromatase inhibitors in first-line therapy for post-menopausal women, with a 40–45% improvement in progression-free survival seen with the addition of any of these CDK4/6 inhibitors. Additional approved indications, including first- and second-line combination therapy for pre-menopausal women, combination with fulvestrant and use as monotherapy, vary with each agent and are reviewed fully in the subsequent texts. These agents also differ in their toxicity profiles and monitoring requirements, and prescribers should be aware of the individual requirements for each agent. Current clinical trials are investigating the expanded use of these agents in other breast cancer subtypes, such as HER2-positive and triple-negative breast cancer, as well as in the adjuvant and neoadjuvant treatments of early breast cancer. Resistance to CDK4/6 inhibition can occur through multiple mechanisms. Rational combinations with other therapies, such as PI3K inhibitors, HER2-directed therapies and immunotherapy, are being explored.
KeywordsBreast cancer Clinical trials CDK4/6 inhibitors Endocrine therapy Palbociclib Ribociclib Abemaciclib Endocrine resistance Triple-negative breast neoplasms HER2-positive breast cancer
Compliance with Ethical Standards
Conflict of Interest
Conleth G. Murphy declares that he has no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by the author.
References and Recommended Reading
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 7.Finn RS, Crown JP, Lang I, 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(1):25–35.CrossRefGoogle Scholar
- 8.•• Finn RS, Martin M, Rugo HS, Jones S, Im SA, Gelmon K, et al. Palbociclib and Letrozole in advanced breast cancer. N Engl J Med. 2016;375(20):1925–36 This phase 3 study provided the basis for the approval of palbociclib with an aromatase inhibitor as initial endocrine therapy of advanced HR+, HER2-negative breast cancer in post-menopausal women.CrossRefGoogle Scholar
- 9.•• 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;17(4):425–39 This phase 3 study provided the basis for the approval of palbociclib in combination with fulvestrant in pre- and post-menopausal women with disease progression following endocrine therapy.CrossRefGoogle Scholar
- 13.Kim S, Loo A, Chopra R, Caponigro G, Huang A, Vora S, et al. Abstract PR02: LEE011: an orally bioavailable, selective small molecule inhibitor of CDK4/6-reactivating Rb in cancer. Mol Cancer Ther. 2013;12(11 Suppl):PR02.Google Scholar
- 15.•• Hortobagyi GN, Stemmer SM, Burris HA, Yap YS, Sonke GS, Paluch-Shimon S, et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med. 2016;375(18):1738–48 This phase 3 study provided the basis for the approval of ribociclib in combination with an aromatase inhibitor as initial endocrine therapy for the treatment of HR+, HER2-negative advanced breast cancer in postmenopausal women.CrossRefGoogle Scholar
- 16.Hortobagyi GN, Stemmer SM, Burris HA, Yap YS, Sonke GS, Paluch-Shimon S, et al. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. Ann Oncol. 2018;29(7):1541–7.PubMedGoogle Scholar
- 17.• Tripathy D, Im SA, Colleoni M, Franke F, Bardia A, Harbeck N, et al. Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial. Lancet Oncol. 2018;19(7):904–15 This study provided the basis for the approval of ribociclib with an aromatase inhibitor and ovarian function suppression for premenopausal women with HR+, HER2-negative advanced breast cancer.CrossRefGoogle Scholar
- 18.•• Slamon DJ, Neven P, Chia S, Fasching PA, De Laurentiis M, Im SA, et al. Phase III randomized study of Ribociclib and Fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: MONALEESA-3. J Clin Oncol. 2018;36(24):2465–72 This phase 3 study provided the basis for the approval of ribociclib in combination with fulvestrant for the treatment of postmenopausal women with HR+, HER2-negative advanced breast cancer, as initial endocrine based therapy or following disease progression on endocrine therapy.CrossRefGoogle Scholar
- 19.US Food and Drug Administration. Prescribing information for ribociclib. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209092s001lbl.pdf. Accessed online 15 January 2019.
- 20.US Food and Drug Administration. FDA approves new treatment for certain advanced or metastatic breast cancers. Press release, September 28 2017. Available at www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm578071.htm. Accessed online 15 January 2019.
- 21.US Food and Drug Administration. Prescribing information for abemaciclib. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208855s000lbl.pdf. Accessed online 15 January 2019.
- 22.•• Sledge GW Jr, Toi M, Neven P, Sohn J, Inoue K, Pivot X, 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 This phase 3 study provided the basis for the approval of abemaciclib in combination with fulvestrant in the treatment of post-menopausal women with HR+, HER2-negative advanced breast cancer with disease progression following endocrine therapy.CrossRefGoogle Scholar
- 23.• Dickler MN, Tolaney SM, Rugo HS, Cortés J, Diéras V, Patt D, 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 This phase 2 study provided the basis for the approval of abemaciclib as monotherapy in patients with HR+, HER2-negative advanced breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting.CrossRefGoogle Scholar
- 24.•• Goetz MP, Toi M, Campone M, Sohn J, Paluch-Shimon S, Huober J, et al. MONARCH 3: Abemaciclib as initial therapy for advanced breast cancer. J Clin Oncol. 2017;35(32):3638–46 This phase 3 study provided the basis for the approval of abemaciclib with an aromatase inhibitor as initial endocrine therapy of advanced HR+, HER2-negative breast cancer in post-menopausal women.CrossRefGoogle Scholar
- 27.Malorni L, Piazza S, Ciani Y, Guarducci C, Bonechi M, Biagioni C, et al. A gene expression signature of retinoblastoma loss-of-function is a predictive biomarker of resistance to palbociclib in breast cancer cell lines and is prognostic in patients with ER positive early breast cancer. Oncotarget. 2016;7(42):68012–22.CrossRefGoogle Scholar
- 36.Parrish KE, Pokorny J, Mittapalli RK, Bakken K, Sarkaria JN, Elmquist WF. Efflux transporters at the blood-brain barrier limit delivery and efficacy of cyclin-dependent kinase 4/6 inhibitor palbociclib (PD-0332991) in an orthotopic brain tumor model. J Pharmacol Exp Ther. 2015;355(2):264–71.CrossRefGoogle Scholar
- 38.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(9):1360–71.CrossRefGoogle Scholar
- 40.Bardia A, Yardley DA, Hurvitz S, Wright G, Moroose R, Ma C, et al. Abstract PD5-11: Ribociclib in combination with everolimus and exemestane in men and postmenopausal women with HR+/HER2− advanced breast cancer following progression on a CDK4/6 inhibitor: efficacy and updated safety and pharmacokinetic results from phase 1 of the TRINITI-1 study. Cancer Res. 2018;78(4 Suppl):PD5–11.Google Scholar
- 41.Beeram M, Tolaney SM, Beck JT, Dickler MN, Conlin AK, Dees C, et al. Abstract LBA-18: a phase 1 study of Abemaciclib, an inhibitor of CDK4 and CDK6 in combination with endocrine and HER2 targeted therapies for patients with metastatic breast cancer. Ann Oncol. 2016;27((suppl_6)):LBA–18.Google Scholar
- 42.• Goel S, DeCristo MJ, Watt AC, BrinJones H, Sceneay J, Li BB, et al. CDK4/6 inhibition triggers anti-tumour immunity. Nature. 2017;548(7668):471–5 This landmark study provides a preclinical rationale for the combination of CDK4/6 inhibitors with immune checkpoint blockade in breast cancer.CrossRefGoogle Scholar
- 44.Pembrolizumab, Letrozole, and Palbociclib in treating postmenopausal patients with newly diagnosed metastatic stage IV estrogen receptor positive breast cancer. Available at https://clinicaltrials.gov/ct2/show/NCT02778685. Accessed online 15 January 2019.
- 50.Ribociclib and Bicalutamide in AR+ TNBC. Available at https://clinicaltrials.gov/ct2/show/NCT03090165. Accessed online 15 January 2019.
- 54.Gianni L, Bisagni G, Colleoni M, Del Mastro L, Zamagni C, Mansutti M, et al. Neoadjuvant treatment with trastuzumab and pertuzumab plus palbociclib and fulvestrant in HER2-positive, ER-positive breast cancer (NA-PHER2): an exploratory, open-label, phase 2 study. Lancet Oncol. 2018;19(2):249–56.CrossRefGoogle Scholar
- 58.Johnston S, Puhalla S, Wheatley D, Ring A, Barry P, Holcombe C, et al. Randomized phase II study evaluating Palbociclib in addition to Letrozole as neoadjuvant therapy in estrogen receptor-positive early breast cancer: PALLET trial. J Clin Oncol. 2018;JCO1801624. https://doi.org/10.1200/JCO.18.01624.CrossRefGoogle Scholar
- 60.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). Available at https://clinicaltrials.gov/ct2/show/NCT01864746. Accessed online 15 January 2019.
- 61.PALbociclib CoLlaborative adjuvant study: a randomized phase III trial of Palbociclib with standard adjuvant endocrine therapy versus standard adjuvant endocrine therapy alone for hormone receptor positive (HR+)/human epidermal growth factor receptor 2 (HER2)-negative early breast cancer (PALLAS). Available at https://clinicaltrials.gov/ct2/show/NCT02513394. Accessed online 15 January 2019.