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ABEMLETR

Cancer Type: Breast  Intent: Palliative
Regimen Category: Evidence-Informed
Drugs Used:
abemaciclib (Unfunded),
Funding:
ODB Limited Use
    letrozole - Treatment of metastatic breast cancer in hormone receptor positive postmenopausal women
A - Regimen Name

ABEMLETR Regimen
Abemaciclib-Letrozole


Disease Site
Breast

Intent
Palliative

Regimen Category
Evidence-Informed :

Regimen is considered appropriate as part of the standard care of patients; meaningfully improves outcomes (survival, quality of life), tolerability or costs compared to alternatives (recommended by the Disease Site Team and national consensus body e.g. pan-Canadian Oncology Drug Review, pCODR).  Recommendation is based on an appropriately conducted phase III clinical trial relevant to the Canadian context OR (where phase III trials are not feasible) an appropriately sized phase II trial. Regimens where one or more drugs are not approved by Health Canada for any indication will be identified under Rationale and Use.


Rationale and Uses

For treatment of HR+/HER2- advanced breast cancer in patients who were previously treated with endocrine therapy.


Supplementary Public Funding

letrozole
ODB Limited Use (letrozole - Treatment of metastatic breast cancer in hormone receptor positive postmenopausal women)

 
B - Drug Regimen

abemaciclib
150 mg PO BID
(This drug is not currently publicly funded for this regimen and intent)
letrozole
2.5 mg PO Daily
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C - Cycle Frequency

CONTINUOUS TREATMENT

Until disease progression or unacceptable toxicity

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

Minimal – No routine prophylaxis; PRN recommended

 
E - Dose Modifications

Doses should be modified according to the protocol by which the patient is being treated. 

Dosage with toxicity

Dose Level Abemaciclib Dose (mg BID)
0 150
-1 100
-2 50
-3 Discontinue
-4 Not applicable

 

Toxicity

Grade

Abemaciclib Action

Letrozole Action 
Hematologic* Grade 3 Hold until ≤ grade 2; resume at same dose. No dosage adjustment required.
Grade 4 or recurrent grade 3 Hold until ≤ grade 2; resume at 1 dose level ↓.
Diarrhea** Grade 2

If no resolution to ≤ grade 1 within 24 hours, hold until resolution; resume at same dose.

Not applicable 
Grade 2 that persists/recurs after resumption at the same dose (despite maximal supportive measures) Hold until ≤ grade 1; resume at 1 dose level ↓.
≥ Grade 3 or requires hospitalization Hold until ≤ grade 1; resume at 1 dose level ↓.
Interstitial lung disease (ILD)/ Pneumonitis Persistent or recurrent grade 2 toxicity that does not resolve to baseline or grade 1 within 7 days (despite maximal supportive measures) Hold until recovery to baseline or ≤ grade 1; resume at 1 dose level ↓. Not applicable
Grade 3 or 4 Discontinue
Hepatotoxicity Persistent or recurrent grade 2 or grade 3 (ALT, AST >5 to 20 times ULN) without increase in total bilirubin >2 times ULN Hold until recovery to baseline or grade 1; resume at 1 dose level ↓. Refer to “hepatic impairment” table below
AST and/or ALT >3 times ULN with total bilirubin >2 times ULN (in the absence of cholestasis) Discontinue
Grade 4 (ALT, AST >20 times ULN) Discontinue
All other non-hematologic toxicities Persistent or recurrent grade 2 toxicity that does not resolve to baseline or grade 1 within 7 days (despite maximal supportive measures) Hold until recovery to baseline or ≤ grade 1; resume at 1 dose level ↓. Not applicable 
≥ Grade 3 Hold until recovery to baseline or ≤ grade 1; resume at 1 dose level ↓.

*If blood cell growth factors are required, hold abemaciclib for at least 48 hours after the last growth factor dose and until toxicity resolves to ≤ grade 2; resume at the next lower dose (unless already reduced due to the toxicity that required the growth factor). Growth factor use is as per current local guidelines.

**At the first sign of loose stools, begin management with antidiarrheal agents (i.e. loperamide) and increase oral fluid intake.

 

 



Hepatic Impairment

Hepatic Impairment Abemaciclib Dose Letrozole Dose
Mild or moderate impairment (Child-Pugh class A or B) No dosage adjustment necessary. No dose adjustment needed, although exposure may ↑ by 37%
Severe impairment (Child-Pugh class C) Reduce abemaciclib frequency to once daily. No data. Monitor patients closely and consider dose modification.

 


Renal Impairment

Renal Impairment Abemaciclib Dose Letrozole Dose
Mild or Moderate (CrCl ≥ 30 mL/min) No dosage adjustment necessary. No dose adjustment necessary.*
 
Severe (CrCl < 30 mL/min); ESRD Has not been studied

*There are no dosage adjustments provided in the manufacturer's labeling for letrozole for CrCl <10 mL/min.


Dosage in the Elderly

No dosage adjustment is required.  Patients ≥65 years of age on abemaciclib reported more hematologic adverse events, hypokalemia (including grade 3), hypocalcemia, grade ≥3 infections, decreased appetite, and increased blood creatinine compared to younger patients in a subgroup analysis from clinical studies.  Older patients on letrozole have an increased risk of osteoporosis and fracture.

 

Dosage based on Ethnicity 

Higher incidences of increased ALT and AST and neutropenia have been reported in East Asian patients on abemaciclib compared to Caucasian patients in clinical trials.  No dose adjustment based on race is required.

 


 
F - Adverse Effects

Refer to abemaciclib, letrozole drug monograph(s) for additional details of adverse effects


Very common (≥ 50%)

Common (25-49%)

Less common (10-24%)

Uncommon (< 10%),

but may be severe or life-threatening

  • Diarrhea
  • Estrogen deprivation symptoms
  • Fatigue
  • Myelosuppression ± infection
  • Musculoskeletal pain
  • Nausea, vomiting
  • Headache
  • Alopecia
  • Edema
  • Anorexia, weight loss
  • ↑ Cholesterol
  • Dizziness
  • Creatinine increased
  • Constipation
  • ↑ LFTs
  • Cough, dyspnea
  • Osteoporosis (May be severe)
  • Rash, pruritus
  • Fracture
  • Mucositis
  • Flu-like symptoms
  • Dry skin
  • Dysgeusia
  • Cardiotoxicity
  • Arrhythmia
  • Arterial / venous thromboembolism
  • Hypersensitivity
  • Nephrotoxicity
  • Pneumonitis
  • Osteonecrosis of jaw

 

 
G - Interactions

Refer to abemaciclib, letrozole drug monograph(s) for additional details


 

  • CYP3A4 inhibitors (i.e. ketoconazole, clarithromycin, ritonavir, fruit or juice from grapefruit, Seville oranges or starfruit); Avoid co-administration of abemaciclib with strong CYP3A4 inhibitors. Use with caution if letrozole is to be co-administrated with strong CYP3A4 inhibitors (theoretical).  Use caution when abemaciclib is co-administered with moderate or weak CYP3A inhibitors. If co-administration with a CYP3A inhibitor is unavoidable, reduce abemaciclib dose to 50 mg twice daily* (based on a 150 mg or 200 mg twice daily starting dose) when combined with strong or moderate CYP3A4 inhibitors. If a CYP3A inhibitor is discontinued, increase the abemaciclib dose (after 3-5 half-lives of the inhibitor) to the dose that was used before starting the inhibitor.
    *When combined with clarithromycin, diltiazem or verapamil, abemaciclib dose should be reduced to 100 mg twice daily. 
  • CYP3A4 inducers (i.e. phenytoin, rifampin, dexamethasone, carbamazepine, phenobarbital, St. John’s Wort, etc.); Avoid co-administration of abemaciclib with strong CYP3A4 inducers.  Use with caution if letrozole is co-administered with strong CYP3A4 inducers (theoretical).  Use with caution when abemaciclib  is co-administered with moderate or weak CYP3A4 inducers.

  • CYP2A6 inhibitors (e.g. methoxsalen, tranylcypromine); Caution with co-administration of letrozole with strong CYP2A6 inhibitors (theoretical).

  • OCT2, MATE1, MATE2 substrates (i.e. metformin); Caution with co-administration of abemaciclib with OCT2, MATE1, MATE2 substrates.

  • Tamoxifen, other anti-estrogens or estrogen-containing therapies; Avoid co-administration with letrozole.

 
H - Drug Administration and Special Precautions

Refer to abemaciclib, letrozole drug monograph(s) for additional details


Administration

Abemaciclib

  • Abemaciclib tablets should be swallowed whole (do not to chew, crush, or split tablets before swallowing). Tablets should not be ingested if they are not intact.

  • Abemaciclib doses may be taken with or without food and should be administered at approximately the same times every day.

  • Avoid fruit or juice from grapefruit, Seville oranges or starfruit.

  • If a dose is missed or vomited, the next dose should be taken at the scheduled time. The patient should not take 2 doses at the same time to make up for the missed dose.

  • Store at room temperature (15°C to 30°C).


Letrozole

  • Tablets should be taken with a glass of water, with or without food, at around the same time every day.

  • Do not crush or chew the tablets.

  • Missed doses should be taken as soon as possible, but should be skipped if within a few hours of the next planned dose.  Do not double the dose due to over-proportionality of exposure at doses above 2.5 mg daily.

  • Avoid grapefruit, starfruit, Seville oranges or their juices/products while on this treatment, since this may increase side effects.

  • Store tablets at room temperature (15-30°C)


Contraindications

  • Patients who are hypersensitive to abemaciclib or letrozole or to any ingredient in the formulation or component of the container.

  • Letrozole is also contraindicated in patients:

    • Hypersensitive to other aromatase inhibitors

    • <18 years of age

    • With premenopausal endocrine status

    • Pregnancy/breastfeeding

 

Other Warnings/Precautions

  • There are no data regarding abemaciclib safety or efficacy in patients with prior exposure to other CDK 4/6 inhibitors.

  • Letrozole usage in men with breast cancer has not been studied and is not indicated in hormone-receptor negative disease.

  •  Abemaciclib and some brands of letrozole contain lactose; carefully consider use in patients with hereditary galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption.

 

Pregnancy/Lactation

  • Abemaciclib is not recommended for use in pregnancy.  Letrozole is contraindicated in pregnancy.  Adequate contraception should be used by both sexes during treatment, and for at least 3 weeks after the last dose.
  • Breastfeeding is not recommended during abemaciclib treatment and for at least 3 weeks after the last dose. Letrozole is contraindicated with breastfeeding. 
  • Fertility Effects:

    • Abemaciclib: Unknown

      • In animal studies, no effects on female reproductive organs were observed. However, cytotoxic effects to the male reproductive tract in rats and dogs indicate that abemaciclib may impair fertility in males

    • Letrozole:  Yes

      • Observed in animal studies.

 

 

 
I - Recommended Clinical Monitoring

Recommended Clinical Monitoring

  • CBC; Baseline, every two weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated

  • Liver function tests; Baseline, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated

  • Creatinine; Baseline and as clinically indicated

  • Bone mineral density; Baseline and as clinically indicated

  • LH, FSH and/or estradiol levels in patients whose menopausal status is unclear or who become amenorrhoeic after chemotherapy; before starting letrozole and regularly during the first 6 months of treatment. Only confirmed postmenopausal patients should receive letrozole

  • Serum cholesterol and lipids evaluation; Baseline and regular

  • Clinical toxicity assessment for signs and symptoms of venous thrombosis, infections, estrogen withdrawal symptoms, musculoskeletal, cardiovascular, respiratory, dermatologic, ophthalmic, gastrointestinal and genitourinary effects and fatigue; At each visit

  • Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version

Suggested Clinical Monitoring

  • Electrolytes, including calcium; Baseline and as clinically indicated

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K - References

Abemaciclib drug monograph, Cancer Care Ontario.

Goetz MP, Toi M, Campone M, et al. MONARCH 3: abemaciclib as initial therapy for advanced breast cancer. J Clin Oncol. 2017;35:3638-3646.

Letrozole drug monograph, Cancer Care Ontario.

December 2019 Expanded to full regimen monograph


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M - Disclaimer

Regimen Abstracts
A Regimen Abstract is an abbreviated version of a Regimen Monograph and contains only top level information on usage, dosing, schedule, cycle length and special notes (if available). It is intended for healthcare providers and is to be used for informational purposes only. It is not intended to constitute or be a substitute for medical advice, and all uses of the Regimen Abstract are subject to clinical judgment. Such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability, and Cancer Care Ontario disclaims all liability for the use of this information, and for any claims, actions, demands or suits that arise from such use.
Information in regimen abstracts is accurate to the extent of the ST-QBP regimen master listings, and has not undergone the full review process of a regimen monograph.  Full regimen monographs will be published for each ST-QBP regimen as they are developed.
Regimen Monographs
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The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.
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