CDK4/6 Inhibitors in HR+/HER2- Advanced Breast Cancer

Written by: Ann Schwemm, PharmD, MPH, BCOP, University of Minnesota Health
Download Here

Cyclin-dependent kinase (CDK) 4/6 inhibitors have demonstrated significant advances in the treatment of hormone receptor (HR) positive and human epidermal growth factor receptor (HER2) negative advanced breast cancer. While current available data do not support the preferential use of one agent over the other, the dosing and safety monitoring differ and may help in treatment decision making with patients. Multi-disciplinary care teams have key roles in education and supportive care management to optimize the use of these agents and disease response^1,2.

Background:

Patients with HR+/HER2- advanced breast cancer should be considered candidates for CDK inhibitors (CDKi) therapy (palbociclib, ribociclib, and abemaciclib) due to the progression free survival (PFS) advantages demonstrated in the PALOMA, MONALEESA, and MONARCH trials, summarized in Table 2 of Supplemental Information within this PQI. A recent meta-analysis of the trials evaluating CDKi in HR+/HER2- advanced breast cancer demonstrated a 50% reduction in the rate of disease progression when CDKis were used in the first or second line setting irrespective of age, site of metastasis, and disease free interval⁵. In addition, a recent publication of long term follow up of PALOMA-2 reported the safety profile remained favorable and with no differences in patient reported quality of life with the addition of palbociclib to endocrine therapy over time¹¹. CDKis work at CDK 4/6 resulting in the blockade of phosphorylation of the retinoblastoma (Rb) protein which hinders the activation of transcription factors involved in S-phase entry, arresting the cell cycle progression at G1 phase.³

PQI Process:

Upon receipt of an order for a CDK inhibitor:

• Ensure the patient has HR+/HER2- advanced breast cancer.
• If patient had recently been on endocrine only therapy and experienced disease recurrence or progression, ensure endocrine therapy was changed along with prescribing of CDKi. New hormonal therapy can be started while access to new CDKi is in process.
• There is no data to support continued CDKi use following disease progression; although switching from one to another due to tolerability is appropriate.
• Assessment of drug interaction should be reviewed at baseline and throughout therapy as new medication are prescribed.
  • CDKi are cytochrome P450 3A4 substrates. Medication lists should be reviewed and alternatives discussed for strong inhibitors/inducers. The use of moderate CYP3A4 inducers/inhibitors should be reviewed and adjustments in dose and/or monitoring discussed with patients and providers.
• Due to the high rate of dose interruptions, care coordination is critical to ensure laboratory monitoring and assessments are occurring at appropriate times in order to avoid unnecessary holds while ensuring the safe monitoring. If a cycle is delayed, future labs should be adjusted from the true start of the current cycle.
• A one week assessment should be conducted for all CDKis, especially to support abemaciclib diarrhea management.
• Midcycle CBC is recommended for ribociclib and palbociclib
• EKG is recommended every 2 weeks for ribociclib for the first 2 cycles.

Patient Centered Activities:

• Provided Oncology Chemotherapy Education Sheet for their CDKi and hormonal therapy to patient.
• Ensure patients are aware their hormonal therapy does not stop when dose interruptions of CDKi therapy occur.
• Provide patient expectations of therapeutic assessment and laboratory monitoring when starting therapy, especially during first 8 weeks. Review more than half of patients will require dose interruption or reduction, although ADRs generally resolve rapidly.

• Review with patients as they require dose reductions there is no dose response established with CDKi. Regardless of dose, patients can continue to experience efficacy.
• Refer to Table 1 of Supplemental Information within this PQI for drug-specific dosing, monitoring, and counseling.
• Provided instructions for use of loperamide and potentially provide a prescription for diphenoxylate/atropine for patients prescribed abemaciclib.
  • Provide antidiarrheal management guidance per Abemaciclib Diarrhea Management PQI.
• All medications should be stored in a cool dry place at room temperature. If dispensed in blister packaging, CDKis should stay in original packaging.
• Take medication at approximately the same time each day, do not double doses if one is forgotten.

Patient assistance:

• Copay cards: abemaciclib: https://www.verzenio.com/savings-support/savings-card

palbociclib: https://www.ibrance.com/financial-support-resources

ribociclib: https://www.copay.novartisoncology.com/?name=kisqali

Supplemental Information:

Table 1: Dosing and Monitoring Guideline Summary

*grade 3 anemia can occur late, therefore continued periodic monitoring is recommended

**dose reductions are not warranted if baseline liver function tests are grade 2 at baseline; grade 2 AST/ALT with Tbili elevation (in absence of cholestasis) therapy should be discontinued

Table 2: Clinical Trial Summary

*not statistically significant, potentially due to small population

**Progression during neo-adjuvant/adjuvant ET, <12months from end of adjuvant ET or during 1st line ET for advanced breast cancer treatment. 

References:

1. Thill M, Schmidt M. Management of adverse events during cyclin-dependent kinase 4/6 (CDK4/6) inhibitor-based treatment in breast cancer. Therapeutic Advances in Medical Oncology. 2018. Vol10:1-12.
2. Jenkins, K. Which patients should get CDK4/6 inhibitors? — Some, however, are asking instead: who should not get them? Clinical challenges>SABCS: Breast Cancer MedPage Today. Dec 10, 2018. Accessed on Dec 11, 2018 at: https://www.medpagetoday.com/clinical-challenges/sabcs-breast-cancer/76827
3. Sammons S, Topping D, Blackwell K. HR+, HER2- advanced breast cancer and CDK4/6 inhibitors: mode of action, clinical activity, and safety profiles. Current Cancer Drug Targets. 2017.17, 637-649.
4. Shah M, Nunes MR, Stearns V. CDK4/6 inhibitors: game changers in the management of hormone receptor-positive advanced breast cancer?
5. Gennari A, Saggia C, Rossi V, et al. Efficacy of CDK 4/6 inhibitors in ER positive metastatic breast cancer: Systematic review and meta-analysis of randomized clinical trials. Journal of Clinical Oncology 2018 36:15_suppl, e13040-e13040
6. 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 estrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol. 2015;16:25-35
7. Finn RS, Crown J, Lang I, et al. Overall survival results from the randomized phase II study of palbociclib (P) in combination with letrozole (L) vs letrozole alone for frontline treatment of ER+/HER2- advanced breast cancer (PALOMA-1; TRIO-18). J Clin Oncol. 2017;34(suppl; abstr 1001)
8. Hu W, Sung T, Jessen BA et al. Mechanistic investigation of bone marrow suppression associated with palbociclib and its differentiation from cytotoxic chemotherapies. Clin Cancer Res 2016;22:2000-2008.
9. Goetz MP, Martin M, Di Leo A, et al. MONARCH 3: Abemaciclib as initial therapy for patients with HR+, HER2- advanced breast cancer – Results from the preplanned final PFS analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT040.
10. Finn RS, Martin M, Rugo H, et al. Palbociclib and letrozole in advanced breast cancer. N Engl J Med 2016; 375:1925-1936.
11. Rugo HS, Finn RS, Dieras V, et al. Palbociclib plus letrozole as first-line therapy in estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer with extended follow up.
12. The US Food and Drug Administration. Palbociclib (IBRANCE). http:// https://www.fda.gov/drugs/informationondrugs/ approveddrugs/ucm549978.htm. Accessed Jan 5 2018.
13. Verma S, Barlet CH, Schnell P, et al. Palbociclib in combination with fulvestrant in women with hormone receptor-positive/HER2-negative advanced metastatic breast cancer: detailed safety analysis from a multicenter randomized, placebo-controlled, phase III study (PALOMA-3). Oncologist. 2016 Oct;21(10):1165-1175.
14. Hortobgyi GN, Stemmer SM, Burris HA, 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 Jul 1;29(7): 1541-1547.
15. Kisqali (ribociclib) tablets prescribing information, Novartis Pharmaceuticals Corporation, July 2018. Available at: https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm546438.htm Accessed Jan 5 2019.
16. Cristofanilli M, Turner NC, Bondarenko I, 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;17:425.
17. Turner NC, Slamon D, Jungsil R, et al. Overall survival with palbociclib and fulvestrant in advanced breast cancer. N Engl J Med 2018; 379: 1926-1936.
18. Goetz. J, Toi M, Compone M, et al. MONARCH 3: abemaciclib as initial therapy for advanced breast cancer. Clin Oncol. 2017;35(32): 3638-3634.
19. Slamon J, Neven P, Chia S, 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 Aug 20; 36(24):2465-2472.
20. Dickler MN, Tolney SM, Rugo H, et al. MONARCH 1, a phase II study of abemciclib, 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
21. Sledge GW Jr., Toi M, Neven P, et al. MONARCH2: Abemaciclib in combination with fulvestratnt in women with HR+/HER2- advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol 2017 35:25, 2875-2884
22. Tripathy D, Im SA, Colleoni M, et al. Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomized phase 3 trial. Lancet Oncol. 2018;19:904-915.

Important notice: National Community Oncology Dispensing Association, Inc. (NCODA), has developed this Positive Quality Intervention platform. This platform represents a brief summary of medication uses and therapy options derived from information provided by the drug manufacturer and other resources. This platform is intended as an educational aid and does not provide individual medical advice and does not substitute for the advice of a qualified healthcare professional. This platform does not cover all existing information related to the possible uses, directions, doses, precautions, warning, interactions, adverse effects, or risks associated with the medication discussed in the platform and is not intended as a substitute for the advice of a qualified healthcare professional. The materials contained in this platform are for informational purposes only and do not constitute or imply endorsement, recommendation, or favoring of this medication by NCODA, which assumes no liability for and does not ensure the accuracy of the information presented. NCODA does not make any representations with respect to the medications whatsoever, and any and all decisions, with respect to such medications, are at the sole risk of the individual consuming the medication. All decisions related to taking this medication should be made with the guidance and under the direction of a qualified healthcare professional.