Written by: Ann Schwemm, PharmD, MPH, BCOP, University of Minnesota Health
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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 response1,2.

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.
  • 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:

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

PalbociclibRibociclibAbemaciclib
FDA IndicationHR+/HER2- advanced or metastatic breast cancer in combination with

·       Letrozole as initial endocrine-based therapy in postmenopausal women

·       Fulvestrant in women with disease progression following endocrine therapy

HR+/HER2- advanced or metastatic breast cancer in combination with

·       An AI as initial endocrine-based therapy for pre/peri or postmenopausal women

·       Fulvestrant as initial endocrine-based therapy or following disease progression on endocrine therapy for postmenopausal women

HR+/HER2- advanced or metastatic breast cancer in combination with
Dosing125 mg daily with food 3 wk on/1 wk off w/ continuous ET600 mg daily qam without regards to meals 3 wk on/1 wk off w/ continuous ET200mg daily monotherapy OR

150mg daily without regards to meals w/ continuous ET

Monitoring
CBC w/diff:D1&15 cycles 1&2,then Qcycle x 4, then Q3 mos* if no gr 3/4 neutropenia within first 6mosD1&15 cycles 1&2,then Qcycle x 2
LFTs/Tbili:NAQ2wk x 4, then

Qmos x 4, then Q3mos or as clinically indicated

Q2wk x 4, then Qmos x 2 (same as CBC), then Q3mos or as clinically indicted
Electrolytes (BMP)NAQmos x 6NA
EKG:NAQ2wk x 3; <450msec to initiate, refer to PI for management after initiation.NA
Neutropenia ManagementDay 1 of each cycle must have ANC ≥1.0 to start

D15 first 2 cycles: ANC 0.5-1.0 continue and recheck day 22; if <0.5 at day 22: start next cycle at reduced dose once improves to grade 2.

At any time: ANC<1.0 w fever or <0.5: hold, initiate at reduced dose once returns to gr ≥2

Day 1 of each cycle: ANC ≥1.0 to start. Interrupt therapy until patient meets criteria at same dose if grade 3 ANC was experienced on Day 1 or at reduced dose if grade 4 or recurrent grade 3
Hepatobiliary Management (onset: 2-6 months)

 

 

N/A

LFTs>3-5xULN AND Tbili<2xULN: interrupt until returns to baseline, restart at same dose; If recurrence: resume at dose reduction**

LFTs>5-20xULN AND Tbili<2xULN: interrupt therapy until return to baseline, restart at dose reduction; Gr 3 recurrence, discontinue.

LFTs>20xULN: Discontinue

LFTs >3-5xULN AND Tbili<2xULN: no interruption; if recurrence: consider interruption and dose reduction**

LFTs>5-20xULN AND Tbili<2xULN: interrupt therapy until resolution to baseline or grade 1, restart at dose reduction

LFTs>20xULN: Discontinue

Dose Reductions125mg→100mg→75mg daily 3 wk on/1 wk off

75mg 2 wk on/2 wk off has been reported

600mg→400mg→200mg daily 3 wk on/1 wk off200mg→150mg→100mg→50mg twice daily continuously

(200mg if monotherapy)

Adjustments at treatment initiationHepatic: Child Pugh Class C: reduce to 75mg daily 3 wk on/1 wk offHepatic: Child Pugh Class B or C: reduce to 400mg daily 3 wk on/1 wk offHepatic: Child Pugh Class C: reduce to once daily dosing

 

Renal: Not studied <15ml/min, not anticipated to impact metabolismRenal: eGFR 15-30ml/min reduce to 200mg; not studied <15ml/min

 

 

Renal: Not studied <30ml/min, not anticipated to impact metabolism.

SCr increases anticipated after initiation, not anticipated to reflect change in renal function1. Assess along with severity of diarrhea.

DDIxn: Strong CYP3A4 inhibitors and inducers should be avoided, including grapefruit.

Moderate CYP3A4 inhibitors and inducers should be discussed with prescribers.

Assessment to review:Fevers, chills, dizziness; SOB, weakness; Unusual bruising or bleeding; chest pain, tachypnea, tachycardia; adherence; laboratory values
At week 1: adherence and ensuring day 15 labs to be completeAt week 1: N/V, diarrhea, utilization of antidiarrheals

*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

Patient PopulationDescriptionOutcome
Paloma-1/

Trio-186,7

Phase II 1st line Post-menopausal HR+/HER2-Letrozole vs

Letrozole + Palbociclib

ORR: 39% vs 55%

PFS: 10.2 vs 20.2 months

OS: 33.3 vs 37.5 months*

Paloma-210,11Phase III 1st line Post-menopausal HR+/HER2-Letrozole + Placebo vs

Letrozole + Palbociclib

ORR: 44% vs 55%

PFS 14.5 vs 27.6 months

Paloma-316,17Phase III 2nd line or later Post-menopausal HR+/HER2-Fulvestrant + placebo vs

Fulvestrant + Palbociclib

PFS 4.6 vs 9.5 months

OS: 28.0 vs 34.9 months

OS: 29.7 vs 39.7 months (in those w/prior sensitivity to endocrine therapy)

Monaleesa-214Phase III 1st line

Post-menopausal HR+/HER2-

Letrozole + Placebo vs

Letrozole + Ribociclib

ORR: 39% vs 55%

PFS: 16 vs 25.3 months

Monaleesa-722Phase III 1st line

Pre- and peri-menopausal HR+/HER2-

OFS/AI or Tamoxifen + Ribociclib vs OFS/AI or Tamoxifen + PlaceboORR: 36% vs 51%

PFS 13.0 vs 23.8 months

Monalessa-319Phase III 1st line or 2nd line

HR+/HER2-

Fulvestrant + Placebo vs

Fulvestrant + Ribociclib

ORR: 36% vs 51%

PFS: 18.3 vs NR*1st line

ORR: 19 vs 41%

PFS: 12.8 vs 20.5 months

MONARCH-120Phase II 3rd line or later HR+/HER2-Abemaciclib monotherapyORR: 20%

PFS: 6.0 months

OS: 22 months

MONARCH-221Phase III 2nd line**

Pre-/Peri-/Post-menopausal HR+/HER2-

Fulvestrant + Placebo vs

Fulvestrant + abemaciclib

ORR: 21 vs 48%

PFS: 9.3 vs 16.4months

MONARCH-318Phase III First Line

Post-menopausal

HR+/HER2-

NSAI + Placebo vs

NSAI + Abemaciclib

ORR: 44 vs 59%

PFS: 14.7 vs 28.18 months

*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.
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