Lenvima - Drug Monograph

Introduction

Lenvima (lenvatinib) is an oral multi-kinase inhibitor developed by Eisai Co., Ltd. that targets multiple receptor tyrosine kinases involved in angiogenesis and tumor growth. It was first approved by the FDA in 2015 and represents an important therapeutic option for several difficult-to-treat malignancies.

Mechanism of Action

Lenvatinib is a multi-targeted tyrosine kinase inhibitor that primarily inhibits:

• Vascular endothelial growth factor receptors (VEGFR1, VEGFR2, VEGFR3)
• Fibroblast growth factor receptors (FGFR1, FGFR2, FGFR3, FGFR4)
• Platelet-derived growth factor receptor alpha (PDGFRα)
• RET and KIT proto-oncogenes

This broad inhibition profile disrupts multiple signaling pathways involved in angiogenesis, tumor growth, and cancer progression. By blocking VEGFR and FGFR signaling, lenvatinib significantly reduces tumor vascularization and blood supply.

Indications

FDA-approved indications include: 1. Differentiated thyroid cancer (DTC): Radioactive iodine-refractory disease 2. Renal cell carcinoma (RCC): In combination with pembrolizumab for first-line treatment of advanced RCC 3. Hepatocellular carcinoma (HCC): First-line treatment for unresectable disease 4. Endometrial carcinoma: In combination with pembrolizumab for advanced disease that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), and has progressed following prior systemic therapy

Dosage and Administration

• Thyroid cancer: 24 mg orally once daily
• RCC: 20 mg orally once daily (in combination with pembrolizumab)
• HCC: 8 mg orally once daily for body weight ≥60 kg; 12 mg orally once daily for body weight <60 kg
• Endometrial carcinoma: 20 mg orally once daily (in combination with pembrolizumab)

• Take with or without food
• Swallow capsules whole; do not crush or open
• If a dose is missed, take as soon as possible unless the next dose is due within 12 hours

• Required for adverse reactions including hypertension, cardiac dysfunction, renal impairment, proteinuria, and diarrhea
• Multiple dose reduction levels are specified in prescribing information

Pharmacokinetics

• Hepatic impairment: Not recommended in severe impairment
• Renal impairment: No dose adjustment needed for mild-moderate impairment; use caution in severe impairment
• Elderly: No dose adjustment required based on age alone

Contraindications

• Hypersensitivity to lenvatinib or any component of the formulation

Warnings and Precautions

• Hypertension: Monitor blood pressure after 1 week, then monthly
• Cardiac dysfunction: Monitor for symptoms of cardiac failure
• Arterial thromboembolic events: Increased risk of MI, stroke, and other arterial events
• Hepatotoxicity: Monitor liver function tests regularly
• Proteinuria: Monitor urine protein regularly
• Diarrhea: May be severe; manage with antidiarrheal agents and hydration
• Renal impairment and failure: Monitor renal function
• Gastrointestinal perforation and fistula formation: Discontinue if occurs
• QT interval prolongation: Monitor electrolytes and ECG in at-risk patients
• Hypothyroidism: Monitor TSH levels and treat as needed
• Impaired wound healing: Withhold at least 1 week before elective surgery

Drug Interactions

Adverse Effects

• Hypertension
• Fatigue
• Diarrhea
• Arthralgia/myalgia
• Decreased appetite
• Vomiting
• Proteinuria
• Palmar-plantar erythrodysesthesia syndrome
• Weight loss
• Abdominal pain
• Dysphonia

• Hemorrhagic events (including fatal cases)
• Gastrointestinal perforation
• QT interval prolongation
• Hepatotoxicity
• Renal failure
• Arterial thromboembolism
• Cardiac dysfunction
• Reversible posterior leukoencephalopathy syndrome (RPLS)

Monitoring Parameters

• Complete blood count
• Comprehensive metabolic panel (including liver and renal function)
• Thyroid function tests
• ECG (if risk factors for QT prolongation)
• Urinalysis for proteinuria
• Blood pressure

• Blood pressure: Weekly for first month, then monthly
• Proteinuria: Regularly (at least monthly)
• Liver function tests: Every 2 weeks for first 2 months, then monthly
• Thyroid function: Regularly
• ECG and electrolytes: As clinically indicated
• Signs/symptoms of cardiac dysfunction, bleeding, GI perforation

Patient Education

• Take medication at approximately the same time each day
• Report any signs of bleeding, severe diarrhea, chest pain, shortness of breath, or severe headache immediately
• Blood pressure monitoring is essential; patients may need home monitoring equipment
• Maintain adequate hydration, especially if experiencing diarrhea
• Notify all healthcare providers about Lenvima use before any surgical procedures
• Use effective contraception during treatment and for 30 days after final dose
• Do not breastfeed during treatment and for 1 week after final dose
• Be aware of potential drug interactions and discuss all medications (including OTC and supplements) with healthcare provider

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. Motzer R, et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021;384(14):1289-1300. 4. 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. 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 types. 2023 editions. 7. Lenvatinib: clinical pharmacokinetics and pharmacodynamics. Clin Pharmacokinet. 2020;59(8):1003-1017.