Lenva

Approved Indications:

• Differentiated Thyroid Cancer (DTC):
  For the treatment of locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer, including papillary, follicular, and Hürthle cell subtypes.
• Renal Cell Carcinoma (RCC):
• In combination with pembrolizumab as first-line treatment for advanced RCC.
• In combination with everolimus for patients with advanced RCC following prior anti-angiogenic therapy.
• Hepatocellular Carcinoma (HCC):
  For the first-line treatment of unresectable hepatocellular carcinoma in adults.
• Endometrial Carcinoma:
  In combination with pembrolizumab for patients with advanced endometrial carcinoma that is not MSI-H or dMMR, following prior systemic therapy and not amenable to curative surgery or radiation.

Clinically Accepted Off-Label Uses:

• Anaplastic Thyroid Carcinoma:
  Used in select cases under specialist supervision.
• Soft Tissue Sarcoma and Rare Tumors:
  Investigational use in certain chemotherapy-refractory solid tumors.

Route of Administration: Oral (capsules swallowed whole), with or without food, at the same time each day.

Adults:

• DTC: 24 mg orally once daily until disease progression or unacceptable toxicity.
• RCC:
• With pembrolizumab: 20 mg orally once daily.
• With everolimus: 18 mg orally once daily (10 mg lenvatinib + 5 mg everolimus).
• HCC:
• Body weight ≥60 kg: 12 mg orally once daily.
• Body weight <60 kg: 8 mg orally once daily.
• Endometrial Carcinoma (with pembrolizumab): 20 mg orally once daily, plus pembrolizumab 200 mg IV every 3 weeks.

Elderly: No dose adjustment required; monitor tolerability.

Pediatrics: Not approved for pediatric use.

Renal Impairment:

• Mild to moderate: No adjustment.
• Severe: Consider dose reduction.
• End-stage renal disease: Not recommended.

Hepatic Impairment:

• Mild: No adjustment.
• Moderate to severe: Reduce dose to 14 mg once daily.

Dose Modification:
Reduce dose in case of adverse events according to severity; typical steps are to reduce from 24 mg to 20 mg, 14 mg, 10 mg, and 8 mg.

Lenvatinib is a multi-targeted receptor tyrosine kinase inhibitor. It inhibits key pro-angiogenic and oncogenic signaling pathways by targeting vascular endothelial growth factor receptors (VEGFR1–3), fibroblast growth factor receptors (FGFR1–4), platelet-derived growth factor receptor alpha (PDGFRα), RET, and KIT. By blocking these receptors, lenvatinib reduces tumor angiogenesis, cellular proliferation, and promotes tumor cell apoptosis. This dual antiangiogenic and antiproliferative activity underlies its effectiveness in multiple solid tumors.

• Absorption: Rapid; peak plasma levels occur within 1–4 hours after oral administration.
• Bioavailability: ~85%
• Distribution: Volume of distribution ~50 L; ~98% bound to plasma proteins.
• Metabolism: Primarily metabolized by CYP3A4, aldehyde oxidase, and non-enzymatic pathways.
• Half-life: ~28 hours
• Elimination: ~64% via feces and ~25% via urine (mostly as metabolites).
• Steady-State: Reached within 7 days of daily dosing.
• Food Effect: Minimal effect; may be taken with or without food.

• Pregnancy:
  Lenvatinib may cause fetal harm. It is contraindicated in pregnancy. Women of reproductive potential should use effective contraception during treatment and for at least 30 days after the final dose.
• Lactation:
  Unknown if lenvatinib is excreted in breast milk. Breastfeeding is not recommended during treatment and for at least 1 week after the final dose due to potential harm to the infant.

• Primary Class: Antineoplastic agent
• Subclass: Multi-targeted tyrosine kinase inhibitor (TKI)

• Hypersensitivity to lenvatinib or any of its components
• Pregnancy
• Severe uncontrolled hypertension
• Recent arterial thromboembolic events (within 6 months)

• Hypertension: Common and potentially severe. Monitor and manage blood pressure throughout treatment.
• Cardiac Dysfunction: Risk of heart failure, arrhythmias, and myocardial infarction. Use with caution in patients with cardiac disease.
• Thromboembolic Events: Increased risk of arterial and venous thrombosis, including stroke and pulmonary embolism.
• Hepatotoxicity: Monitor liver function tests regularly; fatal hepatic failure has occurred.
• Renal Toxicity: May cause renal failure, especially with dehydration.
• Proteinuria and Nephrotic Syndrome: Monitor urine protein; discontinue in case of nephrotic syndrome.
• QT Prolongation: Monitor ECGs in patients with risk factors or using QT-prolonging drugs.
• Hemorrhage: Increased risk, especially in hepatocellular carcinoma. Use caution in patients with bleeding risk.
• Wound Healing: Temporarily withhold therapy before major surgery and resume postoperatively once healing is adequate.

Common Adverse Effects (≥10%):

• General: Fatigue, weight loss, asthenia
• Cardiovascular: Hypertension
• Gastrointestinal: Diarrhea, nausea, decreased appetite, vomiting, stomatitis
• Musculoskeletal: Arthralgia, myalgia
• Dermatologic: Palmar-plantar erythrodysesthesia (hand-foot syndrome), rash
• Laboratory: Elevated liver enzymes, proteinuria, hypocalcemia

Serious Adverse Effects:

• Arterial and venous thromboembolism (e.g., myocardial infarction, stroke)
• Cardiac dysfunction (e.g., heart failure)
• Liver failure
• Renal impairment or failure
• QT interval prolongation
• Posterior reversible encephalopathy syndrome (PRES)
• Gastrointestinal perforation or fistula
• Hemorrhage (including fatal events)

• CYP3A4 Inhibitors: May increase lenvatinib levels; monitor for toxicity.
• CYP3A4 Inducers: May reduce lenvatinib effectiveness; monitor clinical response.
• QT-Prolonging Drugs: Increased risk of QT prolongation; avoid or monitor closely.
• Antihypertensives: Monitor blood pressure; dose adjustment may be necessary.
• Food and Alcohol: No significant interactions reported.

• FDA Approvals:
  Expanded approvals include combination with pembrolizumab for advanced RCC and endometrial carcinoma.
• ESMO/NCCN Guidelines:
  Lenvatinib with pembrolizumab is now a first-line option in advanced RCC and a second-line option in endometrial carcinoma.
• Updated Hepatocellular Carcinoma Protocols:
  Reinforce body weight-based dosing and emphasize liver function monitoring.

• Temperature: Store at 20°C to 25°C (68°F to 77°F); allow excursions between 15°C and 30°C.
• Light & Humidity: Store in original container to protect from light and moisture.
• Handling:
• Do not crush or open capsules.
• Wash hands after handling.
• Disposal: Dispose of unused medicine in accordance with local hazardous waste protocols.