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Hepatic advanced or metastatic leNVAtinib

 This document is currently under review:

For queries relating to this document please contact feedback@eviq.org.au.

Check for clinical trials in this patient group. Link to Australian Clinical Trials opens in a new tab or window website

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Drug Dose Route
leNVAtinib 12 mg ONCE a day PO

Continuous until disease progression or unacceptable toxicity

Notes:

If bodyweight is < 60 kg, 8 mg ONCE a day (see dose modifications) 

Overall management should be in consultation with a multidisciplinary liver cancer team.

Drug status:

Lenvatinib is PBS authority opens in a new tab or window

Lenvatinib is available as 4 mg capsules. 

Cost:
~ $5,750 per month "How this cost is calculated"

The cost displayed on the protocol is intended as rudimentary guide only for the Australian context.

The cost includes anti-cancer drugs only (not antiemetics, supportive medications or consumables), unless otherwise indicated.

Drug unit costs are taken directly from the Pharmaceutical Benefits Scheme (PBS) website (www.pbs.gov.au). These costs are reviewed and updated on eviQ at 6 monthly intervals. Anti-cancer drugs that are not included on the PBS do not have a cost included in eviQ protocols.

Where there are differing unit costs based on vial sizes and tablet strengths, the mean unit cost is used. The cost of oral continuous therapy is based on a 28 day month.

Where oral drugs are available on the PBS for both 30- and 60-day prescriptions, the unit cost for the 30-day supply is used.

The protocol cost is derived from drug dose calculations based upon a default body surface area (BSA) of 1.8 m2; weight of 75 kg; and creatinine clearance of 75 mL/min.

One off loading doses and ongoing maintenance doses are not included in protocol cost calculations.

The cost displayed is the actual drug cost and does not necessarily reflect the cost incurred by the patient as many anti-cancer drugs are reimbursed on the PBS.

The supportive therapies (e.g. antiemetics, premedications, growth factor support etc.), infusion times, diluents, volumes and routes of administration, if included, are listed as defaults. They may vary between institutions and can be substituted to reflect individual institutional policy.

Antiemetics if included in the treatment schedule are based upon recommendations from national and international guidelines. These are defaults only and may be substituted to reflect individual institutional policy. Select here for recommended doses of alternative antiemetics.

Continuous treatment
leNVAtinib 12 mg (PO) ONCE a day (3 x 4 mg capsules) with or without food

If bodyweight is < 60 kg, 8 mg ONCE a day (see dose modifications) 

Continuous until disease progression or unacceptable toxicity

Drug Dose Route
leNVAtinib 12 mg ONCE a day PO

Continuous until disease progression or unacceptable toxicity

Notes:

If bodyweight is < 60 kg, 8 mg ONCE a day (see dose modifications) 

Overall management should be in consultation with a multidisciplinary liver cancer team.

Drug status:

Lenvatinib is PBS authority opens in a new tab or window

Lenvatinib is available as 4 mg capsules. 

Cost:
~ $5,750 per month "How this cost is calculated"

The cost displayed on the protocol is intended as rudimentary guide only for the Australian context.

The cost includes anti-cancer drugs only (not antiemetics, supportive medications or consumables), unless otherwise indicated.

Drug unit costs are taken directly from the Pharmaceutical Benefits Scheme (PBS) website (www.pbs.gov.au). These costs are reviewed and updated on eviQ at 6 monthly intervals. Anti-cancer drugs that are not included on the PBS do not have a cost included in eviQ protocols.

Where there are differing unit costs based on vial sizes and tablet strengths, the mean unit cost is used. The cost of oral continuous therapy is based on a 28 day month.

Where oral drugs are available on the PBS for both 30- and 60-day prescriptions, the unit cost for the 30-day supply is used.

The protocol cost is derived from drug dose calculations based upon a default body surface area (BSA) of 1.8 m2; weight of 75 kg; and creatinine clearance of 75 mL/min.

One off loading doses and ongoing maintenance doses are not included in protocol cost calculations.

The cost displayed is the actual drug cost and does not necessarily reflect the cost incurred by the patient as many anti-cancer drugs are reimbursed on the PBS.

The supportive therapies (e.g. antiemetics, premedications, growth factor support etc.), infusion times, diluents, volumes and routes of administration, if included, are listed as defaults. They may vary between institutions and can be substituted to reflect individual institutional policy.

Antiemetics if included in the treatment schedule are based upon recommendations from national and international guidelines. These are defaults only and may be substituted to reflect individual institutional policy. Select here for recommended doses of alternative antiemetics.

Continuous treatment
leNVAtinib 12 mg (PO) ONCE a day (3 x 4 mg capsules) with or without food

If bodyweight is < 60 kg, 8 mg ONCE a day (see dose modifications) 

Continuous until disease progression or unacceptable toxicity

Indications:

  • monotherapy for advanced (unresectable) hepatocellular carcinoma Child-Pugh class A
  • patients must not have previously received a vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) for hepatocellular carcinoma, or must have developed intolerance to a previous VEGF TKI
  • ECOG performance status 0 to 2.

Precautions:

  • The pivotal trial only included patients who were Barcelona Clinic Liver Cancer stage B or C, and Child-Pugh class A. 
  • The pivotal trial excluded patients with Child-Pugh class B or C, ≥ 50% liver occupation, clear invasion of the bile duct or invasion of the main portal vein. Patients with significant cardiovascular disease were also excluded (see evidence). 
Caution with oral anti-cancer drugs

Select links for information on the safe prescribing, dispensing and administration of orally administered anti-cancer drugs. 

Read more about at COSA guidelines for the safe prescribing, dispensing and administration of systemic cancer therapy opens in a new tab or window and oral anti-cancer therapy opens in a new tab or window
Emetogenicity minimal or low

No routine prophylaxis required. If patients experience nausea and/or vomiting, consider using the low emetogenic risk regimen.

Read more about preventing anti-cancer therapy induced nausea and vomiting
Hypertension

Patients treated with lenvatinib may experience an increased incidence of hypertension.

Pre-existing hypertension should be adequately controlled prior to commencing treatment and blood pressure should be monitored after 1 week of treatment, then every 2 weeks for the first 2 months and then monthly thereafter. Refer to dose modification section for management of hypertension.
Cardiac toxicity

Tyrosine kinase inhibitors have been associated with cardiac complications of varying degrees and severity.

Patients, especially those with pre-existing cardiovascular disease, should have a baseline cardiac assessment including an electrocardiogram (ECG) and biochemistry and be closely monitored; consider an echocardiogram (ECHO) as clinically indicated.

Cardiac assessment should then be repeated as clinically indicated or when starting new medication which affects the QT interval.

Read more about cardiac toxicity associated with anti-cancer drugs
Diarrhoea

Antidiarrhoeals (e.g. loperamide) are usually prescribed with this treatment.

Read more about treatment induced diarrhoea
Gastrointestinal perforation

Serious cases of gastrointestinal (GI) perforation have been reported with this treatment. Use with caution in patients at risk of GI perforation (e.g. prior surgery or radiation therapy). Patients should be monitored for signs and symptoms of GI perforation.
Haemorrhage

Serious and sometimes fatal haemorrhagic events have been reported with this treatment. Patients should be monitored for signs and symptoms of severe bleeding.  Use with caution in patients with risk of bleeding (ie. coagulopathy, concurrent anticoagulant or antiplatelet medications etc.) In the case of bleeding, dose interruptions, adjustments or discontinuation of therapy may be necessary.
Hand-foot syndrome

Hand-foot syndrome (palmar-plantar erythrodysaesthesia) and rash are common adverse effects with this treatment which generally appear during the first 6 weeks of therapy.

Read more about hand food syndrome or palmar plantar erythrodysaesthesia (PPE)
Hepatotoxicity

Severe hepatotoxicity (including fatal outcomes) has been observed with this treatment.

Monitor for abnormal liver function tests (LFTs), jaundice and tiredness. Refer to blood tests and dose modification sections for specific recommendations.
Hypothyroidism

Thyroid dysfunction in particular hypothyroidism may occur with this treatment. Monitor for signs and symptoms of thyroid dysfunction and manage as clinically appropriate.
Prolongation of QT interval

This treatment may prolong the QT interval and increase the risk of cardiac arrhythmia. Use with caution in patients with a congenital long QT syndrome, patients treated with a high cumulative dose of anthracycline therapy, patients taking medications that may prolong the QT interval and those with electrolyte disturbances. Risk factors (e.g. electrolyte abnormalities) should be corrected, where possible, prior to commencement of treatment and the concurrent use of drugs that may prolong the QT interval should be avoided. Baseline and periodic monitoring of electrocardiogram (ECG) and electrolytes (potassium, magnesium, calcium) should be considered in patients at high risk of QT prolongation.

Read more about drugs that may prolong QTc interval at crediblemeds.org opens in a new tab or window (registration required).
Proteinuria

Proteinuria has been reported in patients treated with lenvatinib, usually occurring early in the course of the treatment.

Diabetes, high blood pressure and kidney disease are risk factors for developing proteinuria.

Monitor for proteinuria by urine dipstick analysis at baseline and regularly during treatment. If proteinuria is detected, consider 24-hour urinary protein determination. For those who develop moderate to severe proteinuria dose interruptions, adjustments, or discontinuation of treatment may be necessary.

Lenvatinib should be discontinued in the event of nephrotic syndrome.
Reversible posterior leukoencephalopathy syndrome (RPLS)

Reversible posterior leukoencephalopathy syndrome (RPLS) has been reported in patients receiving this treatment and may be fatal. Discontinue drug in patients developing RPLS.

Read more about reversible posterior leukoencephalopathy syndrome (RPLS)
Thromboembolism

Both arterial and venous thromboembolic events have been observed in patients with this treatment.
Therefore, use with caution in patients at increased risk or with a history of thrombotic events (i.e., cerebrovascular and cardiovascular disease).
Dental review

Dental review prior to treatment then 6 monthly during treatment. Avoid dental procedures after commencing treatment to minimise risk of osteonecrosis of the jaw.

Read more about medication-related osteonecrosis of the jaw (MRONJ)
Wound healing

Some suggest (Bose et al. 2010- see link to abstract) that antiangiogenic tyrosine kinase inhibitors (TKI's) be interrupted for at least one week (48 hours for agents with short half life) before surgery and not re-initiated until adequate wound healing has occurred. At many institutions, therapy with these agents is held for four weeks after major surgery and for at least two weeks after minor surgery, although there are no prospective data validating this approach. The decision to resume therapy following a major surgical intervention should be based upon clinical judgement of recovery from surgery.

Read more about "Vascular endothelial growth factor targeted therapy in the perioperative setting: implications for patient care" opens in a new tab or window, Bose et al 2010r
Blood tests

FBC, EUC, eGFR, calcium, magnesium, phosphate and TFTs at baseline then monthly or as clinically indicated. LFTs at baseline, then repeat every 2 weeks for first 2 months then monthly or as clinically indicated.
Hepatitis B screening and prophylaxis

The requirement for routine screening for HBsAg and anti-HBc for patients receiving this treatment is unknown. Clinical judgement and individual patient situations should be taken into consideration.

Read more about hepatitis B screening and prophylaxis in cancer patients requiring cytotoxic and/or immunosuppressive therapy
Vaccinations

Live vaccines are contraindicated in cancer patients receiving immunosuppressive therapy and/or who have poorly controlled malignant disease. Possible suboptimal response to inactivated vaccines.

For more information about vaccinations in people with cancer refer to the Australian Immunisation Handbook opens in a new tab or window.
Fertility, pregnancy and lactation

Cancer treatment can have harmful effects on fertility and this should be discussed with all patients of reproductive potential prior to commencing treatment. There is a risk of fetal harm in pregnant women. A pregnancy test should be considered prior to initiating treatment in females of reproductive potential if sexually active. It is important that all patients of reproductive potential use effective contraception whilst on therapy and after treatment finishes. Effective contraception methods and adequate contraception timeframe should be discussed with all patients of reproductive potential. Possibility of infant risk should be discussed with breastfeeding patients.

Read more about the impact of cancer treatment on fertility opens in a new tab or window
Evidence for dose modifications is limited, and the recommendations made on eviQ are intended as a guide only. They are generally conservative with an emphasis on safety. Any dose modification should be based on clinical judgement, and the individual patient’s situation including but not limited to treatment intent (curative vs palliative), the anti-cancer regimen (single versus combination therapy versus chemotherapy versus immunotherapy), biology of the cancer (site, size, mutations, metastases), other treatment related side effects, additional co-morbidities, performance status and patient preferences.Suggested dose modifications are based on clinical trial findings, product information, published guidelines and reference committee consensus . The dose reduction applies to each individual dose and not to the total number of days or duration of treatment cycle unless stated otherwise. Non-haematological gradings are based on Common Terminology Criteria for Adverse Events (CTCAE) opens in a new tab or window unless otherwise specified. Renal and hepatic dose modifications have been standardised where possible. For more information see dosing considerations & disclaimer.

Note: Mild to moderate adverse reactions (e.g.,Grade 1 or 2) generally do not warrant interruption of lenvatinib, unless intolerable to the patient despite optimal management.

Lenvatinib dose reduction steps
Dose level Dose if weight is greater than or equal to 60 kg Dose if weight is less than 60 kg
Starting dose 12 mg once a day 8 mg once a day
First dose reduction 8 mg once a day 4 mg once a day
Second dose reduction 4 mg once a day 4 mg alternate days
Third dose reduction 4 mg alternate days  
Haematological toxicity
Platelets x 109/L
50 to 75 Continue treatment at same dose and monitor as clinically indicated
less than 50 Delay treatment until platelets are greater than 50 and restart lenvatinib at a reduced dose

Note: If platelets are less than 50 prior to commencing treatment, recommend seeking input from a sub-specialist
Kidney dosing recommendations 
eGFR (mL/min/1.73 m2) Recommended dose
≥ 30 No dose modification necessary
< 30 No dose modification information available. Not recommended in hepatocellular carcinoma.
Hepatic impairment
Hepatic dysfunction (at baseline)
Mild (Child-Pugh A) No dose modifications necessary
Moderate to severe (Child-Pugh B or C) No dose modification information available (should not be used for this indication) 
Lenvatinib-induced hepatotoxicity 
Grade 1 or Grade 2  Continue treatment at same dose. 
Grade 3 or non-life-threatening Grade 4 Delay treatment until resolved to baseline and restart lenvatinib at a reduced dose
Life-threatening Grade 4 Permanently discontinue treatment
Hypertension
Standard antihypertensive therapy should be commenced and/or adjusted to control blood pressure (BP)
Blood pressure level Recommended action
At baseline:
Blood pressure ≥ 140/90 Delay commencement of treatment until blood pressure is < 140/90 mmHg
During treatment: 
Systolic BP > 140 mmHg up to < 159 mmHg 
OR
diastolic BP > 90 mmHg up to < 99 mmHg		 Continue treatment at same dose. Initiate, increase dose of, or add antihypertensive therapy
Systolic BP > 160 mmHg 
OR 
diastolic BP > 100 mmHg

Delay treatment and initiate, increase dose of, or add antihypertensive therapy. When systolic BP < 150 mmHg and diastolic BP < 95 mmHg, restart lenvatinib at a reduced dose
Hand and foot syndrome (link to Hand foot syndrome (Palmar-plantar erythrodysaesthesia)
Grade 2 or 3  Delay treatment until toxicity has resolved to Grade 1 or less and consider restarting lenvatinib at a reduced dose
Diarrhoea
Grade 1 Continue treatment at same dose. 
Grade 2 or 3 Delay treatment until toxicity has resolved to Grade 1 or less. 
If early in treatment, restart lenvatinib at a reduced dose. If previously stable on treatment, consider restarting lenvatinib at the same dose.
Grade 4 Delay treatment until toxicity has resolved to Grade 1 or less and restart lenvatinib at a reduced dose
Proteinuria
Grade 3 If urinary protein-to-creatinine ratio is ≥ 3.5, or there is oedema, pleural effusion, ascites or increased serum creatinine, delay treatment until proteinuria has resolved to Grade 1 or baseline:
1st occurrence: restart lenvatinib at same dose
2nd occurrence: restart lenvatinib at reduced dose

The drug interactions shown below are not an exhaustive list. For a more comprehensive list and for detailed information on specific drug interactions and clinical management, please refer to the specific drug product information and the following key resources: 

For more information see References & Disclaimer.

Lenvatinib
  Interaction Clinical management
Drugs that may prolong the QTc interval (e.g. azole antifungals, tricyclic antidepressants, antiarrhythmics etc.) Additive effect with lenvatinib; may lead to torsades de pointes and cardiac arrest Avoid combination or minimise additional risk factors (e.g. correct electrolyte imbalances) and monitor ECG for signs of cardiac arrhythmia
General
  Interaction Clinical management
Warfarin Anti-cancer drugs may alter the anticoagulant effect of warfarin. Monitor INR regularly and adjust warfarin dosage as appropriate; consider alternative anticoagulant.
Direct oral anticoagulants (DOACs) e.g. apixaban, rivaroxaban, dabigatran

Interaction with both CYP3A4 and P-gp inhibitors /inducers.

DOAC and anti-cancer drug levels may both be altered, possibly leading to loss of efficacy or toxicity (i.e. increased bleeding).

Apixaban: avoid concurrent use with strong CYP3A4 opens in a new tab or window and P‑gp opens in a new tab or window inhibitors. If treating VTE, avoid use with strong CYP3A4 opens in a new tab or window and P‑gp opens in a new tab or window inducers. 

Rivaroxaban: avoid concurrent use with strong CYP3A4 opens in a new tab or window and P‑gp opens in a new tab or window  inhibitors.

Dabigatran: avoid combination with strong P‑gp opens in a new tab or window inducers and inhibitors.

If concurrent use is unavoidable, monitor closely for efficacy/toxicity of both drugs.
Digoxin Anti-cancer drugs can damage the lining of the intestine; affecting the absorption of digoxin. Monitor digoxin serum levels; adjust digoxin dosage as appropriate.
Antiepileptics Both altered antiepileptic and anti-cancer drug levels may occur, possibly leading to loss of efficacy or toxicity. Where concurrent use of an enzyme-inducing antiepileptic cannot be avoided, monitor antiepileptic serum levels for toxicity, as well as seizure frequency for efficacy; adjust dosage as appropriate.
Also monitor closely for efficacy of the anti-cancer therapy.
Antiplatelet agents and NSAIDs Increased risk of bleeding due to treatment related thrombocytopenia. Avoid or minimise combination.
If combination deemed essential, (e.g. low dose aspirin for ischaemic heart disease) monitor for signs of bleeding.
Serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs e.g. paroxetine) and serotonin noradrenaline reuptake inhibitors (SNRIs e.g. venlafaxine) Increased risk of serotonin syndrome with concurrent use of 5-HT3 receptor antagonists (e.g. palonosetron, ondansetron, granisetron, tropisetron, dolasetron, etc.) Avoid combination.
If combination is clinically warranted, monitor for signs and symptoms of serotonin syndrome (e.g. confusion, agitation, tachycardia, hyperreflexia).
For more information link to TGA Medicines Safety Update opens in a new tab or window

eviQ provides safe and effective instructions on how to administer cancer treatments. However, eviQ does not provide every treatment delivery option, and is unable to provide a comprehensive list of cancer treatment agents and their required IV line giving set/filter or address chemical compatibilities related to IV drug preparation and administration. There may be alternative methods of treatment administration, and alternative supportive treatments that are also appropriate. Please refer to the individual product information monographs via the TGA opens in a new tab or window and Australian Injectable Drugs Handbook opens in a new tab or window websites for further information.

eviQ is currently updating the way information is presented in the administration section, if you notice any discrepancies please let us know, via feedback@eviq.org.au.

Administration

This is a continuous oral treatment

Any toxicity grade 2 or greater may require dose reduction, delay or omission of treatment and review by medical officer before recommencing treatment.

Anti-cancer drug patient assessment tool prior to each treatment.

Lenvatinib

Prior to administration check:
  • blood pressure
  • urinalysis for protein
Administer lenvatinib
  • administer orally ONCE daily
  • to be swallowed whole with a glass of water; do not break, crush or chew
  • may be taken with or without food
  • capsules may also be dissolved in water or apple juice if patient has swallowing difficulties:
    • place the required number of capsules in a disposable cup and fill with approximately 25 mL of water or apple juice
    • leave the capsules to dissolve (approximately 10 minutes) and then gently stir for at least 3 minutes to dissolve the capsules shells
    • after this the liquid can be swallowed straight away
    • avoid direct contact of the capsules or solution with the skin or mucous membrane. If such contact occurs, wash thoroughly.

Note: if a dose is missed, it should be taken as soon as the patient remembers. If it is less than 12 hours to the next dose, the patient should not take the missed dose.

Continue safe handling precautions (reproductive risk only) for 7 days after completion of drug(s).

Discharge information

Lenvatinib capsules - with written instructions on how to take them.

Antidiarrhoeals - as/if prescribed.

Patient information

Ensure patient receives protocol patient information sheet.

The side effects listed below are not a complete list of all possible side effects for this treatment. Side effects are categorised into the approximate onset of presentation and should only be used as a guide.

Immediate (onset hours to days)
Nausea and vomiting

Read more about prevention of treatment induced nausea and vomiting

Early (onset days to weeks)
Acneiform rash

A skin rash, characterised by papules and pustules affecting the face and upper body. This is commonly associated with small molecule EGFR inhibitors and some monoclonal antibodies (e.g. cetuximab, panitumumab). 

Read more about acneiform rash associated with EGFR inhibitors
Haemorrhage
Diarrhoea

Read more about treatment induced diarrhoea
Hypertension

High blood pressure is commonly associated with many anti-cancer drugs. Pre-existing hypertension should be controlled prior to initiation of drugs capable of causing hypertension.
QT prolongation

This treatment can cause QTc interval prolongation. QTc prolongation can lead to ventricular arrhythmias that may be fatal.
Cardiotoxicity

Cardiotoxicity may manifest as asymptomatic reduction in left ventricular ejection fraction (LVEF), arrhythmia, cardiomyopathy, hypertension, cardiac ischaemia and congestive heart failure (CHF). The risk of cardiotoxicity is increased by a number of factors, particularly a history of heart disease and electrolyte imbalances.

Read more about cardiotoxicity associated with anti-cancer drugs
Gastrointestinal perforation

A rupture of the wall of the stomach, small intestine or large bowel. Symptoms include acute abdominal pain, tenderness and signs of sepsis. 
Proteinuria

Read more about proteinuria
Thromboembolism

Arterial and venous thromboembolic events, including pulmonary embolism, deep vein thrombosis and cerebrovascular accidents can occur. Patients should be carefully assessed for risk factors, and consideration given for antithrombotic prophylaxis in high risk patients.
Reversible posterior leukoencephalopathy syndrome (RPLS)

A neurological disorder which may present with headache, seizures, lethargy, confusion, blindness and/or other visual and neurological disturbances. Mild to severe hypertension may also occur.

Read more about reversible posterior leukoencephalopathy syndrome (RPLS)
Hepatotoxicity

Anti-cancer drugs administered either alone or in combination with other drugs and/or radiation therapy may cause direct or indirect hepatotoxicity. Hepatic dysfunction can alter the metabolism of some drugs resulting in systemic toxicity.
Palmar-plantar erythrodysaesthesia (PPE) - hand-foot syndrome (HFS)

Bilateral erythema, tenderness, pain, swelling, tingling, numbness, pruritus, dry rash, or moist desquamation and ulceration of the palms and soles. It is also known as hand-foot syndrome (HFS). Symptoms appear to be dose dependent and palms are affected more than soles.

Read more about hand-foot syndrome associated with chemotherapy
Thrombocytopenia

A reduction in the normal levels of functional platelets, increasing the risk of abnormal bleeding.  

Read more about thrombocytopenia
Anorexia

Loss of appetite accompanied by decreased food intake.

Read more about anorexia
Constipation
Arthralgia and myalgia

Generalised joint pain or and/or stiffness and muscle aches, often worse upon waking or after long periods of inactivity. Can improve with movement. May be mild or severe, intermittent or constant and accompanied by inflammation. 

Read more about arthralgia and myalgia
Fatigue

Read more about fatigue
Urinary tract infection

Lenvatinib has been associated with urinary tract infection

Late (onset weeks to months)
Hypothyroidism
Anaemia

Abnormally low levels of red blood cells (RBCs) or haemoglobin in the blood. 

Read more about anaemia
Alopecia - partial

Hair thinning and/or patchy hair loss. Patients can also experience mild to moderate discomfort of the hair follicles, and rarely pain as the hair is falling out.

Read more about alopecia and scalp cooling
Osteonecrosis of the jaw (ONJ)

Exposed, necrotic bone in the maxillofacial region is associated with this treatment.  

Read more about medication-related osteonecrosis of the jaw

The evidence supporting this protocol comes from a multicentre, phase 3, randomised, open-label, non-inferiority study of patients with unresectable hepatocellular carcinoma.r

Between March 2013 and July 2015, a total of 954 patients were randomised to receive lenvatinib (12 mg/day for bodyweight ≥ 60 kg or 8 mg/day for bodyweight <60 kg) (n=478) or sorafenib 400 mg twice daily (n=476) in 28 day cycles. Most patients were <65 years old (58%), male (84%), Asian (69%), ≥60 kg (69%), ECOG PS 0 (63%), and Barcelona Clinic Liver Cancer stage C (79%).r

The primary endpoint was overall survival. Secondary endpoints included progression-free survival, time to progression, objective response rate and quality of life measurements. The study was powered to determine non-inferiority if the upper limit of the two-sided 95% CI for HR was less than 1.08.r 

Efficacy

After a median follow up of 27.7 months in the lenvatinib group, and 27.2 months in the sorafenib group, lenvatinib showed non-inferiority in terms of overall survival compared to sorafenib. The median overall survival was 13.6 months in the lenvatinib group and 12.3 months in the sorafenib group, with a hazard ratio of 0.92 (95% CI 0.79 to 1.06).r

© The Lancet 2018

Both groups had similar baseline scores on quality of life measures (EORTC QLQ-C30 and EORTC QLQ-HCC18), and both groups had declining scores over time. A decline in pain, diarrhoea, nutrition and body image occurred earlier in the sorafenib arm compared to the lenvatinib arm, although the summary scores were comparable.r

Toxicity

The most common treatment-related adverse events for lenvatinib were hypertension, diarrhoea, anorexia and weight loss. Of those taking lenvatinib, treatment-related adverse events led to drug interruption in 40% (compared with 32% in the sorafenib arm), dose reduction in 37% (compared with 38%) and withdrawal in 9% (compared with 7%). There were 11 (2%) fatal adverse events in the lenvatinib arm which included hepatic failure (n=3), cerebral haemorrhage (n=3), and respiratory failure (n=2). There were 4 (1%) fatal adverse events in the sorafenib arm, from tumour haemorrhage, ischaemic stroke, respiratory failure and sudden death.r

© The Lancet 2018

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Version 2

Date Summary of changes 
07/09/2023

Protocol updated with ADDIKD guideline recommendations. 

PDF of previous protocol.

Version number changed to V.2.

Version 1

Date Summary of changes 
26/06/2019

New protocol discussed by Medical oncology reference committee (electronically via email)
23/07/2019

Approved and published on eviQ​
23/10/2020 Protocol reviewed electronically by the Medical Oncology Reference committee. Link to ID 3042 Hepatocellular carcinoma (HCC) staging: the BCLC score added in indications section. Next review in 2 years.
21/06/2021 Archived: Changed antiemetic clinical information block to moderate to high, to align with new categories. See ID 7 Prevention of anti-cancer therapy induced nausea and vomiting (AINV) v5 (see row below as 12 mg dose should be minimal or low).
21/12/2021 Changed antiemetic clinical information block to align with new categories. See ID 7 Prevention of anti-cancer therapy induced nausea and vomiting (AINV) v5.
20/10/2022

Protocol reviewed electronically by Medical Oncology Reference Committee. No changes. Next review 2 years.

The information contained in this protocol is based on the highest level of available evidence and consensus of the eviQ reference committee regarding their views of currently accepted approaches to treatment. Any clinician (medical oncologist, haematologist, radiation oncologist, medical physicist, radiation therapist, pharmacist or nurse) seeking to apply or consult this protocol is expected to use independent clinical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. While eviQ endeavours to link to reliable sources that provide accurate information, eviQ and the Cancer Institute NSW do not endorse or accept responsibility for the accuracy, currency, reliability or correctness of the content of linked external information sources. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

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First approved:
Last reviewed:
Review due:

The currency of this information is guaranteed only up until the date of printing, for any updates please check:

https://www.eviq.org.au/p/3603

13 May 2025