Introduction
Lenvatinib (marketed as Lenvima®) is an oral multi-kinase inhibitor approved for the treatment of various advanced malignancies. This targeted therapy represents a significant advancement in the management of thyroid cancer, hepatocellular carcinoma, and certain endometrial cancers. As a tyrosine kinase inhibitor, lenvatinib disrupts multiple signaling pathways involved in tumor angiogenesis and proliferation.
Mechanism of Action
Lenvatinib inhibits multiple receptor tyrosine kinases (RTKs) including VEGF receptors 1-3, FGF receptors 1-4, PDGF receptor α, RET, and KIT. By blocking these pathways, lenvatinib primarily exerts two anticancer effects: 1. Anti-angiogenic activity: Inhibition of VEGFR and FGFR signaling disrupts tumor blood vessel formation 2. Direct antitumor activity: Inhibition of RET and other kinases directly affects tumor cell proliferation and survival
This dual mechanism provides comprehensive targeting of both tumor cells and their supporting vasculature.
Indications
Lenvatinib is FDA-approved for:
- Differentiated Thyroid Cancer: Treatment of locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer
- Hepatocellular Carcinoma: First-line treatment of unresectable hepatocellular carcinoma
- Renal Cell Carcinoma: In combination with pembrolizumab for first-line treatment of advanced renal cell carcinoma
- Endometrial Carcinoma: In combination with pembrolizumab for advanced endometrial carcinoma that is not MSI-H or dMMR, and has progressed following prior systemic therapy
Dosage and Administration
Standard dosing:- Differentiated thyroid cancer: 24 mg orally once daily
- Hepatocellular carcinoma: 8 mg orally once daily (for patients ≥60 kg) or 12 mg orally once daily (for patients ≥60 kg)
- Renal cell carcinoma: 20 mg orally once daily in combination with pembrolizumab
- Endometrial carcinoma: 20 mg orally once daily in combination with pembrolizumab
- Administer with or without food
- Swallow capsules whole; do not crush or open
- Take at approximately the same time each day
- For missed doses: Skip if next dose is due within 12 hours
Dose reductions (to 20 mg, 14 mg, 10 mg, or 8 mg daily) or interruptions are recommended based on toxicity severity. Specific guidelines are provided for management of hypertension, cardiac dysfunction, renal impairment, hepatic impairment, and other adverse reactions.
Special populations:- Hepatic impairment: Reduce dose in severe impairment (Child-Pugh B or C)
- Renal impairment: No initial adjustment needed for mild-moderate impairment; use caution in severe impairment
- Elderly: No initial dose adjustment required
Pharmacokinetics
Absorption: Peak plasma concentrations reached within 1-4 hours post-dose. Absolute bioavailability is approximately 85%. High-fat meal increases AUC by 19-25%. Distribution: Protein binding >98%, primarily to albumin. Steady-state volume of distribution is approximately 53.4 L. Metabolism: Primarily metabolized by CYP3A4 and aldehyde oxidase. Multiple metabolites identified, but parent drug is the major circulating component. Elimination: Half-life of approximately 28 hours. Excretion primarily fecal (64%) with renal elimination accounting for approximately 25% of the dose.Contraindications
- Hypersensitivity to lenvatinib or any component of the formulation
- Use in pregnancy
Warnings and Precautions
Boxed Warning: Embryo-fetal toxicity - Lenvatinib can cause fetal harm when administered to pregnant women. Cardiovascular:- Hypertension: Monitor blood pressure after 1 week, then至少每月一次; may require antihypertensive therapy
- Cardiac dysfunction: Monitor for signs/symptoms of cardiac failure
- QT interval prolongation: Monitor ECG and electrolytes in patients at risk
- Arterial thromboembolic events: Discontinue for myocardial infarction or cerebrovascular accident
- Hemorrhagic events: Serious and sometimes fatal hemorrhages reported
- Gastrointestinal perforation and fistula formation: Monitor for symptoms
- Hepatotoxicity: Monitor LFTs at baseline and during treatment
- Renal impairment and failure: Monitor renal function
- Proteinuria: Monitor urine protein regularly
- Reversible posterior leukoencephalopathy syndrome (RPLS)
- Hypothyroidism: Monitor thyroid function; may require thyroid hormone replacement
- Impaired wound healing: Withhold至少1 week before elective surgery
Drug Interactions
Strong CYP3A4 inhibitors: Avoid concomitant use with strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin) or reduce lenvatinib dose if coadministration unavoidable Strong CYP3A4 inducers: Avoid concomitant use with strong CYP3A4 inducers (e.g., rifampin, carbamazepine) Acid-reducing agents: Proton pump inhibitors may decrease lenvatinib exposure; separate administration by至少2 hours Other interactions: Use caution with drugs that prolong QT intervalAdverse Effects
Very common (≥20%):- Hypertension (73%)
- Fatigue (67%)
- Diarrhea (67%)
- Decreased appetite (54%)
- Weight loss (51%)
- Nausea (47%)
- Proteinuria (47%)
- Palmar-plantar erythrodysesthesia syndrome (32%)
- Headache (38%)
- Vomiting (36%)
- Stomatitis (35%)
- Constipation (31%)
- Dysphonia (31%)
- Hemorrhagic events (2%)
- Gastrointestinal perforation (2%)
- QT interval prolongation (9%)
- Hepatotoxicity (5%)
- Renal impairment (3%)
- Arterial thromboembolism (5%)
- Heart failure (2%)
Monitoring Parameters
Baseline assessment:- Complete blood count, comprehensive metabolic panel
- Thyroid function tests
- ECG with QT assessment
- Blood pressure
- Urine protein assessment
- Pregnancy test in women of reproductive potential
- Blood pressure: Weekly for first 2 months, then至少每月一次
- ECG: At baseline and periodically during treatment
- LFTs: At baseline and every 2 weeks for first 2 months, then至少每月一次
- Urine protein: At baseline and periodically during treatment
- Thyroid function: At baseline and至少每月一次
- Renal function: At baseline and regularly during treatment
- Signs/symptoms of cardiac dysfunction, bleeding, GI perforation, and wound healing complications
Patient Education
Administration:- Take exactly as prescribed at the same time each day
- Swallow capsules whole; do not crush or open
- Report missed doses to your healthcare provider
- Severe headache, visual changes, seizures (possible RPLS)
- Chest pain, shortness of breath (cardiac events)
- Severe diarrhea, abdominal pain (GI perforation)
- Unusual bleeding or bruising
- Yellowing of skin or eyes (liver problems)
- Swelling in hands or feet
- Blood pressure monitoring at home may be recommended
- Maintain adequate hydration
- Report all medications, including over-the-counter drugs and supplements
- Use effective contraception during treatment and for至少30 days after final dose
- Inform all healthcare providers about lenvatinib therapy before any procedures
- Small, frequent meals may help manage nausea and appetite changes
- Maintain good oral hygiene to manage stomatitis
- Report significant weight loss
References
1. FDA Prescribing Information: Lenvima (lenvatinib). Revised 2023. 2. Schlumberger M, et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med. 2015;372(7):621-630. 3. Kudo M, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391(10126):1163-1173. 4. Motzer R, et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021;384(14):1289-1300. 5. Makker V, et al. Lenvatinib plus pembrolizumab for advanced endometrial cancer. N Engl J Med. 2022;386(5):437-448. 6. National Comprehensive Cancer Network (NCCN) Guidelines. Various cancer sites. 2023 editions.