LENVIMA

What it is

Lenvima is available as hard capsules containing 4 mg or 10 mg of lenvatinib as mesilate. This medicinal product is subject to additional monitoring in Australia to allow quick identification of new safety information.

Approved indications

— Progressive, locally advanced or metastatic, radioactive iodine (RAI) refractory differentiated thyroid cancer (DTC). — First-line treatment of adult patients with advanced renal cell carcinoma (RCC) in combination with pembrolizumab. — Treatment of adult patients with advanced renal cell carcinoma (RCC) whose disease has progressed following one prior vascular endothelial growth factor targeted therapy, in combination with everolimus. — First-line treatment of patients with unresectable hepatocellular carcinoma (HCC). — Treatment of patients with advanced endometrial carcinoma that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation, in combination with pembrolizumab.

Dosing overview

Management of adverse reactions may require dose interruption, adjustment, or discontinuation of Lenvima.

Key safety warnings

Diarrhoea has been reported frequently in patients treated with Lenvima, usually occurring early in the course of treatment. Prompt medical management of diarrhoea should be instituted to prevent dehydration. Lenvima should be discontinued in the event of persistent Grade 4 diarrhoea despite medical management. Patients with baseline renal function less than 60 mL/minute experienced more adverse events, including fatal and serious adverse events and Grade 3 or 4 events, than those with normal renal function. A lower recommended starting dose is required for patients with renal impairment and close monitoring during treatment is advised. The primary risk factors for renal impairment are pre-existing renal impairment and dehydration and/or hypovolemia due to gastrointestinal toxicity. Hypertension has been reported in patients treated with Lenvima, usually occurring early in the course of treatment. Blood pressure should be well controlled prior to treatment and patients known to be hypertensive should be on a stable dose of antihypertensive therapy for at least one week prior to treatment. Early detection and effective management of hypertension are important to minimise the need for dose interruptions and reductions. Serious complications of poorly controlled hypertension, including aortic dissection, have been reported. The use of VEGF pathway inhibitors in patients with or without hypertension may promote the formation of aneurysms and/or artery dissections. This risk should be carefully considered in patients with risk factors such as hypertension or history of aneurysm. Proteinuria has been reported in patients treated with Lenvima, usually occurring early in the course of treatment. Urine protein should be monitored regularly. If urine dipstick proteinuria of 2 or greater is detected, dose interruptions, adjustments, or discontinuation may be necessary. Lenvima should be discontinued in the event of nephrotic syndrome. In differentiated thyroid cancer and renal cell carcinoma, liver-related adverse reactions most commonly reported include increases in alanine aminotransferase, aspartate aminotransferase, and blood bilirubin. Hepatic failure and acute hepatitis have been reported, generally in patients with progressive metastatic liver disease. In hepatocellular carcinoma patients, liver-related adverse reactions including hepatic encephalopathy and hepatic failure were reported at higher frequency, with worse hepatic impairment and greater liver tumour burden at baseline associated with higher risk. Arterial thromboembolic events including cerebrovascular accident, transient ischaemic attack, and myocardial infarction have been reported. Lenvima has not been studied in patients who have had an arterial thromboembolic event within the previous six months and should be used with caution in such patients. Lenvima should be discontinued following an arterial thrombotic event. Serious haemorrhagic events have been reported in patients treated with Lenvima, with mild epistaxis being the most frequently reported event. Serious events of thrombocytopenia have also been reported and may increase risk of developing haemorrhagic events. Serious tumour related bleeds have been reported, including fatal haemorrhagic events. QT/QTc interval prolongation has been reported at higher incidence in patients treated with Lenvima than in patients treated with placebo. The median time to onset of QTc prolongation was 16.1 weeks in the differentiated thyroid cancer study, 31.1 weeks in the hepatocellular carcinoma study for monotherapy, and 30 weeks in the renal cell carcinoma study for combination patients. Lenvima impairs exogenous thyroid suppression. Hypothyroidism has been reported as very common in patients treated with Lenvima in the renal cell carcinoma trial.

Contraindications

Hypersensitivity to the active substance or to any of the excipients.

PBS listing

Lenvima 4 mg and 10 mg hard capsules are listed on the PBS with Authority Required restriction for radioactive iodine refractory differentiated thyroid cancer (RAI-R DTC). An Authority Required (streamlined) listing is also available for unresectable hepatocellular carcinoma. Further pricing and item information from the current PBS schedule was not provided in the available sources.

Regulatory history

Lenvima 4 mg and 10 mg hard capsules were first listed on the ARTG on 28 January 2016. In July 2016, the PBAC recommended a new Authority Required listing for lenvatinib for treatment of radioactive iodine refractory differentiated thyroid cancer on the basis of acceptable cost effectiveness over best supportive care, based on a new offered price and a risk sharing arrangement. In July 2018, the PBAC recommended a change to the Authority Required (streamlined) listing to allow for more flexible prescribing of capsule packs. In November 2018, a new Authority Required (streamlined) listing was recommended for unresectable hepatocellular carcinoma. The TGA approved Lenvima for provisional registration on 17 September 2019 for treatment of advanced endometrial carcinoma in combination with pembrolizumab, based on objective response rate and duration of response from a single-arm trial, with full registration dependent on confirmatory trials.