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LENV

Cancer Type: Endocrine, Thyroid  Intent: Palliative
Regimen Category: Evidence-Informed
Funding:
Exceptional Access Program
    For the treatment of patients with locally recurrent or metastatic, progressive, radioactive-iodine-refractory differentiated thyroid cancer (DTC) according to criteria
A - Regimen Name

LENV Regimen
lenvatinib


Disease Site
Endocrine - Thyroid

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 the treatment of patients with locally recurrent or metastatic, progressive, radioactive-iodine refractory differentiated thyroid cancer (DTC).


Supplementary Public Funding

lenvatinib
Exceptional Access Program (For the treatment of patients with locally recurrent or metastatic, progressive, radioactive-iodine-refractory differentiated thyroid cancer (DTC) according to criteria) (EAP Website)

 
B - Drug Regimen

lenvatinib
24 mg PO Daily

(outpatient prescription available in 10 mg and 4 mg capsules)

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C - Cycle Frequency

CONTINUOUS TREATMENT

Until disease progression or unacceptable toxicity.

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

Moderate

Other Supportive Care:

Also refer to CCO Antiemetic Summary

 
E - Dose Modifications

Doses should be modified according to the protocol by which the patient is being treated. The following recommendations have been adapted from clinical trials or product monographs and could be considered.

Blood pressure should be well controlled and electrolyte abnormalities should be corrected prior to starting treatment. Washout periods of 4 weeks after prior therapy such as sorafenib were used in the clinical trials. Carefully consider risk vs. benefit when tumour invasion of major blood vessels is present prior to treatment.

 

 

 

Dosage with toxicity

Dose level Lenvatinib dose (mg)
0 24
-1 20
-2 14
-3 10
-4 Discontinue

 

Lenvatinib may be delayed and/or dose reduced for toxicity as suggested below. Reduced doses should not be increased.

Toxicity Severity Action
Hypertension ≥ 140/90 Treat with anti-hypertensives
  Grade 3 that persists despite optimal antihypertensive therapy Hold until recovery to ≤ grade 2, resume at one dose level reduction*
  Grade 4, life-threatening Discontinue
Cardiotoxicity or hemorrhage Grade 3 Hold until recovery to ≤ grade 1 or baseline, resume at one dose level reduction* or discontinue depending on severity and persistence.
  Grade 4 Discontinue
Arterial thromboembolism   Discontinue
Nephrotoxicity or hepatotoxicity Grade 3 Hold until recovery to ≤ grade 1 or baseline, resume at one dose level reduction* or discontinue depending on severity and persistence.
  Hepatic failure Discontinue
Proteinuria ≥ 2 g proteinuria / 24 h (≥ 2+ on urine dipstick) Hold until proteinuria < 2 g / 24 h, resume at one dose level reduction*
  Nephrotic syndrome Discontinue
GI perforation or fistula   Discontinue
Nausea, vomiting, diarrhea** Grade 3 Hold until recovery to ≤ grade 1 or baseline. Resume at one dose level reduction*
  Grade 4 despite medical management Discontinue
QT prolongation Grade 3 or 4 Hold until recovery to ≤ grade 1 or baseline, resume at one dose level reduction*
PRES   Hold until fully resolved. Resume at a reduced dose or discontinue depending on the severity and persistence of neurologic symptoms.
Other treatment-related toxicity Persistent and intolerable grade 2 or grade 3 Medically manage nausea/vomiting/diarrhea. Hold until recovery to ≤ grade 1 or baseline, resume at one dose level reduction*
  Grade 4 Discontinue
Major surgery   Hold temporarily. Resume after adequate wound healing.

*For each occurrence of toxicity, reduce dose in succession based on the previous dose level (see dose levels table). 

**Initiate prompt medical management



Hepatic Impairment

Lenvatinib exposure increases in severe hepatic impairment. 

 

 

Childs classification of hepatic impairment

Starting Dose (mg daily) 

A

24

B

24

C

14

 


Renal Impairment

Lenvatinib exposure increases with severe renal impairment. 

Creatinine clearance (ml/min)

Starting Dose (mg daily)

50-80

24

30-49

24

< 30

14

End stage renal failure

No data: not recommended for use


 

 

Body weight

Patients with body weight less than 60 kg had a higher incidence of hand-foot syndrome, proteinuria, severe electrolyte abnormalities and a trend towards severe anorexia.


 
Dosage based on gender

Females had a higher incidence of hypertension, including severe hypertension, proteinuria and hand-foot syndrome, while males had a higher incidence of cardiotoxicity, GI perforation and fistulas.


 
Dosage based on ethnicity

Asian patients had a higher incidence of peripheral edema, hypertension, fatigue, hand-foot syndrome, proteinuria, thrombocytopenia and elevated TSH levels compared to Caucasian patients.


Dosage in the Elderly

Patients aged 65 and older had more toxicity, including fatal adverse events compared to younger patients. Hypertension, proteinuria, anorexia and dehydration were more common. No dosage adjustment is recommended. Use with caution and monitor patients closely. 

 


 
F - Adverse Effects

Refer to lenvatinib 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

  • Hypertension (may be severe)
  • Diarrhea (may be severe)
  • Anorexia, weight loss
  • Hyperglycemia
  • Increased LFTs (may be severe)
  • Increased TSH
  • Increased creatinine (may be severe)

 

  • Hypoalbuminemia
  • Nausea, vomiting
  • Fatigue
  • Mucositis
  • Abnormal electrolytes
  • Headache
  • Proteinuria (may be severe)
  • Hand-foot syndrome
  • Abdominal pain
  • Dysphonia
  • Constipation
  • Musculoskeletal pain
  • Hemorrhage (may be severe)
  • Cough, dyspnea (may be severe)
  • Peripheral edema
  • Dysgeusia
  • Rash
  • Dry mouth
  • Increased triglycerides
  • Dizziness
  • Dyspepsia
  • Increased amylase/lipase
  • Alopecia
  • Infection
  • Insomnia
  • Bradycardia
  • Prolonged QT interval
  • Arterial / venous  thromboembolism
  • Cardiotoxicity
  • Arrhythmia
  • Fracture
  • GI obstruction, perforation, fistula
  • Hypersensitivity
  • Retinal vein thrombosis
  • Rhabdomyolysis
  • PRES, seizure
  • Wound dehiscence
  • Cholecystitis
  • Secondary malignancy
  • Pneumonitis 
 
G - Interactions

Refer to lenvatinib drug monograph(s) for additional details


  • Lenvatinib is extensively metabolized by CYP3A4, but may be co-administered with CYP3A4 inhibitors and inducers, PGP inducers and inhibitors, BRCP inhibitors and drugs that effect gastric pH without dosage adjustment.
  • The drug may be an inducer of CYP3A4 and PgP in the GI tract that could lead to decreased exposure to oral CYP3A4/PgP substrates. Use with caution with substrates that have a narrow therapeutic index.
  • Drugs that decrease heart rate, prolong the PR or QT interval, or disrupt electrolyte levels may increase the risk of arrhythmias. Avoid if possible; monitor closely if used together.
 
H - Drug Administration and Special Precautions

Refer to lenvatinib drug monograph(s) for additional details


Administration:

  • Lenvatinib should be taken at the same time daily, with or without food
  • Capsules should be swallowed whole with water
  • If a dose is missed and it cannot be taken within 12 hours, then that dose should be skipped and the next dose should be taken at the usual time
  • Lenvatinib should be stored between 15-30oC

Contraindications:

  • Patients who have a hypersensitivity to this drug or any of its components
  • The degree of tumour invasion of major blood vessels should be considered prior to treatment given the potential risk of hemorrhage associated with tumour shrinkage.

Other Warnings/Precautions:

  • Lenvatinib is not recommended in patients with congenital long QT syndrome or those who are taking medications known to prolong the QT interval
  • Use with caution in patients at risk of prolonged QT, including females, aged ≥ 65 years, family history of sudden cardiac death at < 50 years of age, pre-existing cardiac disease, history of arrhythmias, electrolyte disturbances or conditions leading to electrolyte disturbances, bradycardia, acute neurological events, diabetes mellitus and autonomic neuropathy.
  • Lenvatinib has not been studied in patients with end stage renal disease or severe hepatic impairment
  • Use lenvatinib with caution in patients who are at risk for, or have a history of cardiac events. The drug has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months.
  • Patients with prior surgery or radiotherapy are at increased risk of GI perforation or fistulas

Pregnancy and lactation:

  • Lenvatinib is not recommended for use in pregnancy.  Highly effective contraception (including barrier method) should be used by both sexes during treatment, and for at least 1 month after the last dose.
  • Breastfeeding is not recommended
  • Reduced male and female fertility is likely
 
I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Recommended Clinical Monitoring

  • Blood pressure; Baseline, after 1 week, then every 2 weeks for the first 2 months, monthly therafter
  • CBC; Baseline and at each visit
  • ECG and electrolytes; Baseline and at each visit
  • Liver function tests; Baseline, every 2 weeks for the first 2 months, then monthly during treatment
  • TSH levels; Baseline and monthly during treatment
  • Urine protein; Baseline and at each visit
  • Clinical toxicity assessment for GI effects, infection, bleeding, hypertension, cardiac and neurologic effects; At each visit
  • Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version


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J - Administrative Information

Outpatient prescription for home administration


 
K - References

Lenvatinib drug monograph, Cancer Care Ontario.

Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med. 2015 Feb 12;372(7):621-30.


October 2017 updated rationale & use, dosage with toxicity based on product monograph update


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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
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
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.
The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.
Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.
While care has been taken in the preparation of the information contained in the Formulary, 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.
CCO and the Formulary’s content providers shall have no liability, whether direct, indirect, consequential, contingent, special, or incidental, related to or arising from the information in the Formulary or its use thereof, whether based on breach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using the information in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCO and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and expenses) arising from such person’s use of the information in the Formulary.