Lenvatinib

Lenvatinib is an oral receptor tyrosine kinase (RTK) inhibitor with mainly antiangiogenic properties; direct inhibition of tumour growth has also been seen in laboratory models. It is used on its own for thyroid and liver cancer, and together with pembrolizumab or everolimus for endometrial and kidney cancer. The same capsules are sold under two brand names with different indications, Lenvima and Kisplyx.

Mechanism of Action

• Kinase inhibition: lenvatinib selectively inhibits VEGF receptors 1, 2 and 3 (VEGFR1/FLT1, VEGFR2/KDR, VEGFR3/FLT4) and other pro-angiogenic and oncogenic kinases: FGFR1–4, PDGFRα, KIT and RET. It occupies the ATP-binding site of VEGFR2 and a neighbouring region.
• Antiangiogenic effect: blocking VEGF and FGF signalling limits the growth of the new blood vessels that supply tumours.
• Direct antitumour effect: in hepatocellular carcinoma cell lines that depend on activated FGFR signalling, lenvatinib directly slowed proliferation, which is attributed to FGFR inhibition.
• Immune effects: in mouse tumour models it reduced tumour-associated macrophages and increased activated cytotoxic T cells, and showed more antitumour activity together with an anti-PD-1 antibody than either treatment alone.
• Link to side effects: hypertension is thought to result from VEGFR2 inhibition in vascular endothelium, and proteinuria from reduced VEGFR1 and VEGFR2 signalling in kidney podocytes; neither mechanism has been studied directly.

Pharmacokinetics

• Absorption: rapid; peak plasma levels usually 1–4 hours after the dose. Food slows but does not reduce absorption (the peak is delayed by about 2 hours). Bioavailability is estimated at about 85%. Exposure rises in proportion to dose between 3.2 and 32 mg once daily, with minimal accumulation at steady state.
• Distribution: 98–99% bound to plasma proteins in vitro, mainly albumin. Apparent volume of distribution after the first dose 50.5–92 L. Lenvatinib is a substrate of P-glycoprotein (P-gp) and BCRP.
• Metabolism: extensive. CYP3A4 was the main cytochrome P450 enzyme involved in vitro (over 80% of P450-mediated metabolism), but aldehyde oxidase, glutathione conjugation and other non-P450 routes carry a large share in vivo, so CYP3A4 inducers and inhibitors change exposure very little. Unchanged lenvatinib made up 97% of plasma radioactivity up to 24 hours after a dose.
• Elimination: terminal half-life about 28 hours. After a radiolabelled dose about two-thirds was recovered in faeces and about a quarter in urine.
• Special populations: exposure (AUC) was 119%, 107% and 180% of normal in mild, moderate and severe hepatic impairment, and 101%, 90% and 122% of normal in mild, moderate and severe renal impairment. Age, sex, body weight and race had no clinically relevant effect on clearance.

Lenvatinib is authorised for adults. Lenvima and Kisplyx have separate indications.

• Differentiated thyroid carcinoma (Lenvima): monotherapy for progressive, locally advanced or metastatic differentiated (papillary, follicular or Hürthle cell) thyroid carcinoma that is refractory to radioactive iodine (RAI).
• Hepatocellular carcinoma (Lenvima): monotherapy for advanced or unresectable hepatocellular carcinoma (HCC) in patients who have received no prior systemic therapy.
• Endometrial carcinoma (Lenvima): in combination with pembrolizumab, for advanced or recurrent endometrial carcinoma with disease progression on or following prior platinum-containing therapy in any setting, in patients who are not candidates for curative surgery or radiation.
• Renal cell carcinoma (Kisplyx): advanced renal cell carcinoma (RCC), in combination with pembrolizumab as first-line treatment, or in combination with everolimus following one prior vascular endothelial growth factor (VEGF)-targeted therapy.

• Hypersensitivity to lenvatinib or to any of the excipients.
• Breast-feeding.

In differentiated thyroid carcinoma the most frequent reactions (30% of patients or more) were hypertension (68.6%), diarrhoea (62.8%), decreased appetite (51.5%), weight loss (49.1%), fatigue (45.8%), nausea (44.5%), proteinuria (36.9%), stomatitis (35.8%), vomiting (34.5%), dysphonia (34.1%), headache (34.1%) and palmar-plantar erythrodysaesthesia (32.7%). In hepatocellular carcinoma they were hypertension (44.0%), diarrhoea (38.1%), decreased appetite (34.9%), fatigue (30.6%) and weight loss (30.4%). With pembrolizumab in endometrial carcinoma the most frequent were hypertension (63%), diarrhoea (57%), hypothyroidism (56%), nausea (51%) and decreased appetite (47%). In renal cell carcinoma (Kisplyx) diarrhoea (61.8%), hypertension (51.5%), fatigue (47.1%) and hypothyroidism (45.1%) led with pembrolizumab, and diarrhoea (69.0%), fatigue (41.9%), hypertension (41.7%) and decreased appetite (41.6%) with everolimus.

The frequency groups below follow the Lenvima SmPC, which takes the most conservative estimate across tumour types. They refer to lenvatinib alone; differences with pembrolizumab are listed after the groups. Frequencies for the Kisplyx combinations are given in the Kisplyx SmPC.

Very common (≥1/10): urinary tract infection; thrombocytopenia, lymphopenia, leucopenia, neutropenia; hypothyroidism, raised blood thyroid-stimulating hormone; hypocalcaemia, hypokalaemia, hypercholesterolaemia, hypomagnesaemia, weight loss, decreased appetite; insomnia; dizziness, headache, dysgeusia; haemorrhage (all types), hypertension, low blood pressure; dysphonia; diarrhoea, abdominal and gastrointestinal pain, vomiting, nausea, oral inflammation, oral pain, constipation, dyspepsia, dry mouth, raised lipase and amylase; raised blood bilirubin, hypoalbuminaemia, raised ALT, AST, alkaline phosphatase and gamma-glutamyltransferase; palmar-plantar erythrodysaesthesia syndrome, rash, alopecia; back pain, arthralgia, myalgia, pain in the extremities, musculoskeletal pain; proteinuria, raised serum creatinine; fatigue, asthenia, peripheral oedema.

Common (≥1/100 to <1/10): dehydration; cerebrovascular accident; myocardial infarction, cardiac failure, QT prolongation on the ECG, reduced ejection fraction; pulmonary embolism; anal fistula, flatulence, gastrointestinal perforation; hepatic failure, hepatic encephalopathy, abnormal liver function, cholecystitis; hyperkeratosis; renal failure, renal impairment, raised blood urea; malaise.

Uncommon (≥1/1,000 to <1/100): perineal abscess; splenic infarction; adrenal insufficiency; posterior reversible encephalopathy syndrome (PRES); monoparesis; transient ischaemic attack; pneumothorax; pancreatitis, colitis; hepatocellular injury or hepatitis; osteonecrosis of the jaw; nephrotic syndrome; impaired wound healing.

Rare (≥1/10,000 to <1/1,000): tumour lysis syndrome.

Not known: aortic aneurysm and artery dissection; non-gastrointestinal fistula.

With pembrolizumab, anaemia and hyperthyroidism are also very common; insomnia, low blood pressure, dyspepsia, alopecia, musculoskeletal pain and raised gamma-glutamyltransferase are common rather than very common; adrenal insufficiency, pancreatitis and colitis are common; and cerebrovascular accident, myocardial infarction, cardiac failure, reduced ejection fraction, hepatic failure, hepatic encephalopathy, anal fistula, hyperkeratosis, renal impairment and raised blood urea are uncommon.

Important serious reactions: fatal outcomes have been reported with haemorrhage, hepatic failure, hepatic encephalopathy, cerebrovascular accident, myocardial infarction, pulmonary embolism, renal failure and tumour lysis syndrome. In thyroid cancer the most important serious reactions were renal failure and impairment (2.4%), arterial thromboembolism (3.9%), cardiac failure (0.7%), intracranial tumour haemorrhage (0.7%), PRES (0.2%) and hepatic failure (0.2%). In hepatocellular carcinoma they were hepatic encephalopathy (4.6%), hepatic failure (2.8%), arterial thromboembolic events (2.0%), oesophageal varices haemorrhage (1.4%), renal failure or impairment (1.4%) and cerebral haemorrhage (0.6%); a low neutrophil count was more frequent in liver cancer (8.7%) than in other tumour types (1.4%). Adverse reactions led to dose reduction in 63.1% and discontinuation in 19.5% of thyroid cancer patients, and to dose modification in 62.3% and discontinuation in 20.2% of liver cancer patients. With pembrolizumab in endometrial carcinoma, lenvatinib was stopped for an adverse reaction in 30.6% of patients and both medicines in 15.3%.

• Chemotherapy: carboplatin and paclitaxel given with lenvatinib did not significantly change the pharmacokinetics of any of the three medicines.
• CYP3A and P-gp substrates: in cancer patients, plasma levels of midazolam (a sensitive CYP3A and P-gp substrate) were not changed, so no significant interaction is expected with other CYP3A4 or P-gp substrates. CYP3A4 inducers and inhibitors had minimal effect on lenvatinib exposure.
• Hormonal contraceptives: it is unknown whether lenvatinib reduces their effectiveness, so women using oral hormonal contraceptives should add a barrier method.
• QT-prolonging medicines: extra attention to the ECG is needed with medicines known to prolong the QT interval, including class Ia and III antiarrhythmics.
• Combination partners: for interactions of pembrolizumab or everolimus, see their own SmPCs.
• Food and herbal products: lenvatinib can be taken with or without food, at the same time each day. DrugBank advises avoiding herbal products that raise blood pressure (for example liquorice, bayberry, blue cohosh and cayenne), because lenvatinib can itself cause hypertension.

Treatment should be started and supervised by a healthcare professional experienced in anticancer therapy. The capsules are taken by mouth once daily at about the same time each day, with or without food. Caregivers should not open the capsules, to avoid repeated exposure to the contents. The capsules can be swallowed whole with water, or the whole capsule(s) can be dispersed in water, apple juice or milk and the suspension taken by mouth or given through a feeding tube (prepared with water for tube use). Nausea, vomiting and diarrhoea should be managed optimally before any interruption or dose reduction, because active treatment of gastrointestinal toxicity lowers the risk of renal impairment or failure. Treatment continues as long as there is clinical benefit or until unacceptable toxicity.

Recommended Doses

• Differentiated thyroid carcinoma (Lenvima): 24 mg once daily (two 10 mg capsules and one 4 mg capsule).
• Hepatocellular carcinoma (Lenvima): 8 mg once daily (two 4 mg capsules) for body weight below 60 kg; 12 mg once daily (three 4 mg capsules) for 60 kg or more. Later dose changes follow observed toxicity only, not changes in body weight.
• Endometrial carcinoma (Lenvima): 20 mg once daily (two 10 mg capsules) with pembrolizumab, either 200 mg every 3 weeks or 400 mg every 6 weeks as an intravenous infusion over 30 minutes, until unacceptable toxicity or disease progression. The pembrolizumab SmPC gives its full dosing.
• Renal cell carcinoma, first line (Kisplyx): 20 mg once daily (two 10 mg capsules) with pembrolizumab, 200 mg every 3 weeks or 400 mg every 6 weeks as an intravenous infusion over 30 minutes. Lenvatinib continues until disease progression or unacceptable toxicity; pembrolizumab until progression, unacceptable toxicity or the maximum duration set for pembrolizumab.
• Renal cell carcinoma after one VEGF-targeted therapy (Kisplyx): 18 mg once daily (one 10 mg and two 4 mg capsules) with everolimus 5 mg once daily.

Dose Adjustments for Side Effects

• General rule: mild to moderate (grade 1 or 2) reactions usually do not call for interruption unless intolerable despite optimal management. Severe (grade 3) or intolerable reactions require interruption until the reaction improves to grade 0–1 or baseline, and treatment then resumes at a reduced dose. Life-threatening (grade 4) reactions mean discontinuation, except laboratory abnormalities judged not life-threatening, which are managed as grade 3.
• Thyroid cancer: 24 mg, then 20 mg, 14 mg and 10 mg once daily at each successive reduction; data below 10 mg are limited.
• Liver cancer, 60 kg or more: 12 mg, then 8 mg, 4 mg and 4 mg every other day. For persistent and intolerable grade 2 or grade 3 toxicity, treatment is interrupted until grade 0–1 or baseline and resumed one step lower.
• Liver cancer, below 60 kg: 8 mg, then 4 mg and 4 mg every other day; a further recurrence means discontinuation. For haematological toxicity or proteinuria, the first occurrence needs no dose change.
• Endometrial carcinoma and renal cell carcinoma with pembrolizumab: 20 mg, then 14 mg, 10 mg and 8 mg; data below 8 mg are limited. Pembrolizumab is not dose-reduced; it is withheld or stopped as its own SmPC directs.
• Renal cell carcinoma with everolimus: 18 mg, then 14 mg, 10 mg and 8 mg. If a toxicity is attributed to both medicines, lenvatinib is reduced before everolimus; for everolimus toxicity alone, everolimus is interrupted, reduced to alternate-day dosing or stopped as its SmPC directs.
• Reaction-specific actions: lenvatinib is interrupted for grade 3 hypertension despite optimal treatment, proteinuria of 2 g/24 hours or more, grade 3 renal impairment, cardiac dysfunction, hepatotoxicity, haemorrhage, gastrointestinal perforation or fistula, or diarrhoea, for any grade of PRES, and for QT interval above 500 ms, and resumed at a reduced dose once the reaction has settled (hypertension to grade 0–2, proteinuria below 2 g/24 hours, QT interval below 480 ms or baseline, others to grade 0–1 or baseline). It is stopped permanently for grade 4 reactions of these types, nephrotic syndrome, any arterial thromboembolism, a grade 4 non-gastrointestinal fistula, and grade 4 diarrhoea despite medical management.

Special Populations

• Elderly: no adjustment of the starting dose for age; data are limited from age 75.
• Hepatic impairment: thyroid cancer, no adjustment in mild or moderate impairment, and 14 mg once daily in severe (Child-Pugh C) impairment. Liver cancer, no adjustment in mild impairment (Child-Pugh A); data in moderate impairment (Child-Pugh B) are too limited for a dosing recommendation and need close monitoring; not studied or recommended in severe impairment. Endometrial and renal cell carcinoma, no adjustment in mild or moderate impairment and 10 mg once daily in severe impairment; the Kisplyx combinations are used in severe impairment only if the expected benefit outweighs the risk.
• Renal impairment: no adjustment of the starting dose in mild or moderate impairment. In severe impairment the starting dose is 14 mg once daily in thyroid cancer and 10 mg once daily in endometrial and renal cell carcinoma; there is no dosing recommendation for liver cancer. End-stage renal disease was not studied and use is not recommended.
• Tolerability: in thyroid cancer, patients aged 75 or over, of Asian race, with comorbidities (such as hypertension or hepatic or renal impairment) or weighing under 60 kg appear to tolerate lenvatinib less well; in liver cancer, this applies to age 75 or over, white race, female sex and a worse baseline liver score (Child-Pugh A score of 6 rather than 5). Treatment still starts at the recommended dose and is adjusted by tolerability.
• Race and body weight: no adjustment of the starting dose for race. In renal cell carcinoma none is needed for body weight below 60 kg either, although data with everolimus in these patients are limited.
• Children and adolescents: safety and efficacy in children aged 2 to under 18 years are not established and no posology can be recommended; lenvatinib should not be used in children under 2 years because of safety findings in animals.

Missed Dose

If a dose is missed and cannot be taken within 12 hours, skip it and take the next dose at the usual time.

Hypertension

Blood pressure must be well controlled before starting; patients already on antihypertensives should be on a stable dose for at least 1 week. Blood pressure is checked after 1 week, every 2 weeks for the first 2 months, and monthly after that. Treatment is started or increased as soon as high blood pressure is confirmed. If it stays at 160/100 mmHg or above despite optimal treatment, lenvatinib is withheld and resumed at a reduced dose once pressure is 150/95 mmHg or below on a stable antihypertensive dose for at least 48 hours. Life-threatening consequences (malignant hypertension, neurological deficit, hypertensive crisis) call for urgent intervention and discontinuation. Aortic dissection has been reported with poorly controlled hypertension.

Aneurysms and Artery Dissections

VEGF pathway inhibitors may promote aneurysms and artery dissections, with or without hypertension. The risk is weighed carefully before starting in patients with risk factors such as hypertension or a history of aneurysm.

Proteinuria and Kidney Function

Urine protein is monitored regularly; a dipstick result of 2+ or more may require interruption, dose adjustment or discontinuation. Nephrotic syndrome has been reported and requires discontinuation. Renal impairment and failure have been reported, mainly after dehydration or low blood volume from gastrointestinal toxicity, so vomiting and diarrhoea are treated actively. In severe renal impairment the starting dose is adjusted.

Liver Function

Liver function tests are done before starting, every 2 weeks for the first 2 months, and monthly afterwards. Hepatic failure and acute hepatitis (below 1%) were reported in thyroid cancer, mostly in patients with progressive liver metastases. In hepatocellular carcinoma, hepatic encephalopathy and hepatic failure (including fatal cases) were more frequent than with the comparator sorafenib, especially with worse baseline liver function, a greater liver tumour burden or age 75 and over; patients should be monitored for worsening liver function. Data in Child-Pugh B are very limited and absent in Child-Pugh C. In liver cirrhosis, oesophageal varices should be screened for and treated as per standard of care before starting.

Diarrhoea

Diarrhoea is frequent and usually early in treatment. Prompt medical management prevents dehydration, and lenvatinib is stopped if grade 4 diarrhoea persists despite treatment.

Heart, QT Interval and Electrolytes

Cardiac failure (below 1%) and reduced left ventricular ejection fraction have been reported, so patients are watched for signs of cardiac decompensation. QT/QTc prolongation was more frequent than with placebo. ECGs are checked at baseline and periodically, with particular attention to congenital long QT syndrome, heart failure, bradyarrhythmias and QT-prolonging medicines. Low potassium, calcium or magnesium raises the risk, so electrolytes are corrected before starting and monitored; blood calcium is checked at least monthly and replaced as needed.

Posterior Reversible Encephalopathy Syndrome (PRES)

PRES (below 1%) can present with headache, seizure, lethargy, confusion, altered mental function, blindness or other visual or neurological disturbances, often with hypertension. MRI is needed to confirm it; blood pressure is controlled and lenvatinib interrupted, adjusted or stopped.

Arterial Thromboembolism, Bleeding and Fistulae

• Arterial thromboembolism: stroke, transient ischaemic attack and myocardial infarction have been reported. Lenvatinib was not studied within 6 months of such an event and is used with caution after one; it is stopped after an arterial thrombotic event.
• Bleeding: serious tumour-related bleeding, including fatal haemorrhage, has occurred. Tumour invasion of major blood vessels such as the carotid artery should be considered, because shrinkage or necrosis of the tumour can cause severe bleeding; some bleeding followed fistula formation, for example tracheo-oesophageal fistula. Fatal intracranial haemorrhage has been reported with or without brain metastases.
• Fistulae and perforation: gastrointestinal perforation and fistulae occurred mostly in patients with prior surgery or radiotherapy. Lenvatinib is not started in a patient with a fistula, and is stopped permanently for oesophageal or tracheobronchial involvement and for any grade 4 fistula. Pneumothorax has been reported with and without a bronchopleural fistula.

Wound Healing and Surgery

Impaired wound healing has been reported. Temporary interruption should be considered before major surgery, and the decision to resume is based on clinical judgement that the wound has healed adequately.

Osteonecrosis of the Jaw

Cases have been reported, some in patients who had received antiresorptive bone therapy or other angiogenesis inhibitors. Caution applies when lenvatinib is used with or after these medicines. Invasive dental procedures are a risk factor, so a dental examination and preventive dentistry should be considered before treatment, and invasive dental procedures avoided where possible in patients on or previously on intravenous bisphosphonates.

Thyroid Function

Hypothyroidism is very common. Thyroid function is checked before and during treatment and hypothyroidism treated in the usual way. Lenvatinib weakens suppression of thyroid-stimulating hormone (TSH) by thyroid hormone treatment, so TSH is monitored regularly and the hormone dose adjusted to the target level.

Tumour Lysis Syndrome

Tumour lysis syndrome can occur and can be fatal. Risk factors include a high tumour burden, existing renal impairment and dehydration. These patients need close monitoring, and preventive hydration should be considered.

Other Precautions

• Patients with ECOG performance status 2 or higher were excluded from the studies (except in thyroid carcinoma).
• There are no data on lenvatinib immediately after sorafenib or other anticancer treatment; the shortest washout used in clinical trials was 4 weeks.
• Data are limited in patients of ethnic origin other than Caucasian or Asian and in patients aged 75 or over.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential should avoid pregnancy and use highly effective contraception during treatment and for at least one month after stopping. Women using oral hormonal contraceptives should add a barrier method. It is also unknown whether lenvatinib increases the risk of thromboembolic events when combined with oral contraceptives.
• Pregnancy: there are no data in pregnant women, and lenvatinib was embryotoxic and teratogenic in rats and rabbits. It should not be used in pregnancy unless clearly necessary, after weighing the mother’s needs against the risk to the foetus.
• Breastfeeding: contraindicated; lenvatinib and its metabolites pass into rat milk and a risk to the infant cannot be excluded.
• Fertility: effects in humans are unknown; testicular and ovarian toxicity was seen in rats, dogs and monkeys.

Effect on Driving

Lenvatinib has a minor influence on the ability to drive and use machines because of fatigue and dizziness. Patients with these symptoms should take care.

Store below 25 °C in the original blister, to protect from moisture. If a suspension of the capsule contents has been prepared and is not used at once, it may be kept in a covered container in a refrigerator (2–8 °C) for a maximum of 24 hours; shake it for about 30 seconds after removal from the refrigerator and discard it if it has not been taken within 24 hours. Keep out of the sight and reach of children.

4 years. Do not use after the expiry date on the pack.

Prescription only (Rx), under restricted medical prescription (Annex II B of the marketing authorisation). Treatment is started and supervised by a healthcare professional experienced in anticancer therapy. Lenvatinib capsules are taken at home, so they are supplied to the patient or to the treating clinic on prescription. Pembrolizumab, when combined with lenvatinib, is given separately as an intravenous infusion.