Active Ingredient: Lenvatinib
Lenvatinib is indicated for the treatment of adults with advanced renal cell carcinoma (RCC) in combination with pembrolizumab, as first-line treatment.
For this indication, competent medicine agencies globally authorize below treatments:
For:
Oral, 20 milligrams lenvatinib, once daily.
The recommended dose of lenvatinib is 20 mg orally once daily in combination with pembrolizumab either 200 mg every 3 weeks or 400 mg every 6 weeks administered as an intravenous infusion over 30 minutes. The daily dose of lenvatinib is to be modified as needed according to the dose/toxicity management plan. Lenvatinib treatment should continue until disease progression or unacceptable toxicity. Pembrolizumab should be continued until disease progression, unacceptable toxicity or the maximum duration of therapy as specified for pembrolizumab.
See the Summary of Product Characteristics (SmPC) for pembrolizumab for full pembrolizumab dosing information.
Management of adverse reactions may require dose interruption, adjustment, or discontinuation of lenvatinib therapy. 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. Severe (e.g., Grade 3) or intolerable adverse reactions require interruption of lenvatinib until improvement of the reaction to Grade 0 to 1 or baseline.
Optimal medical management (i.e., treatment or therapy) for nausea, vomiting, and diarrhoea should be initiated prior to any lenvatinib therapy interruption or dose reduction; gastrointestinal toxicity should be actively treated in order to reduce the risk of development of renal impairment or renal failure.
For toxicities thought to be related to lenvatinib (see Table 2), upon resolution/improvement of an adverse reaction to Grade 0 to 1 or baseline, treatment should be resumed at a reduced dose of lenvatinib as suggested in Table 1.
Table 1. Dose modifications from recommended lenvatinib daily dosea:
| Lenvatinib dose in combination with pembrolizumab | |
|---|---|
| Recommended daily dose | 20 mg orally once daily |
| First dose reduction | 14 mg orally once daily |
| Second dose reduction | 10 mg orally once daily |
| Third dose reduction | 8 mg orally once daily |
a Limited data are available for doses below 8 mg
When used in combination with pembrolizumab, one or both medicines should be interrupted as appropriate. Lenvatinib should be withheld, dose reduced, or discontinued as appropriate. Withhold or discontinue pembrolizumab in accordance with the instructions in the SmPC for pembrolizumab. No dose reductions are recommended for pembrolizumab.
All treatments should be discontinued in case of life-threatening reactions (e.g., Grade 4) with the exception of laboratory abnormalities judged to be non-life-threatening, in which case they should be managed as severe reactions (e.g., Grade 3).
Grades are based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE).
Table 2. Adverse reactions requiring dose modification of lenvatinib:
| Adverse reaction | Severity | Action | Dose reduce and resume lenvatinib |
|---|---|---|---|
| Hypertension | Grade 3 (despite optimal antihypertensive therapy) | Interrupt | Resolves to Grade 0, 1 or 2. |
| Grade 4 | Discontinue | Do not resume | |
| Proteinuria | ≥2 gm/24 hours | Interrupt | Resolves to less than 2 gm/ 24 hours. |
| Nephrotic syndrome | ------- | Discontinue | Do not resume |
| Renal impairment or failure | Grade 3 | Interrupt | Resolves to Grade 0-1 or baseline. |
| Grade 4* | Discontinue | Do not resume | |
| Cardiac dysfunction | Grade 3 | Interrupt | Resolves to Grade 0-1 or baseline. |
| Grade 4 | Discontinue | Do not resume | |
| PRES/RPLS | Any grade | Interrupt | Consider resuming at reduced dose if resolves to Grade 0-1. |
| Hepatotoxicity | Grade 3 | Interrupt | Resolves to Grade 0-1 or baseline. |
| Grade 4* | Discontinue | Do not resume | |
| Arterial thromboembolisms | Any grade | Discontinue | Do not resume |
| Haemorrhage | Grade 3 | Interrupt | Resolves to Grade 0-1. |
| Grade 4 | Discontinue | Do not resume | |
| GI perforation or fistula | Grade 3 | Interrupt | Resolves to Grade 0-1 or baseline. |
| Grade 4 | Discontinue | Do not resume | |
| Non-GI fistula | Grade 4 | Discontinue | Do not resume |
| QT interval prolongation | >500 ms | Interrupt | Resolves to <480 ms or baseline |
| Diarrhoea | Grade 3 | Interrupt | Resolves to Grade 0-1 or baseline. |
| Grade 4 (despite medical management) | Discontinue | Do not resume |
* Grade 4 laboratory abnormalities judged to be non-life-threatening, may be managed as severe reactions (e.g., Grade 3)
Lenvatinib should be taken at about the same time each day.
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