Lenvatinib

Thyroid Cancer

Lenvatinib is used to treat differentiated thyroid cancer (DTC) that is locally recurrent or metastatic and can no longer be treated with radioactive iodine.

Kidney Cancer

For advanced renal cell carcinoma (a type of kidney cancer), lenvatinib is used in two specific ways:

• In combination with everolimus: For patients who have already received one prior course of treatment for their cancer.
• In combination with pembrolizumab: As a first-line treatment for adults with advanced kidney cancer.

Liver Cancer

Lenvatinib is used as a first-line treatment for people with hepatocellular carcinoma (HCC), a type of liver cancer, when the tumor cannot be removed by surgery.

Endometrial Cancer

Lenvatinib is used in combination with pembrolizumab to treat advanced endometrial carcinoma (cancer of the lining of the uterus) in patients whose disease has progressed following prior systemic therapy and is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).

Mechanism of Action

Lenvatinib belongs to a class of drugs called kinase inhibitors. It works by identifying and blocking specific proteins, known as kinases, that are found on the surface of both cancer cells and healthy cells. These proteins act as signaling pathways that tell cells when to grow and divide.

Blocking Blood Vessel Growth

A key way lenvatinib works is by inhibiting vascular endothelial growth factor (VEGF) receptors. Cancerous tumors often trigger the growth of new blood vessels to supply themselves with the oxygen and nutrients they need to expand. By blocking these receptors, lenvatinib interferes with this process, which is known as angiogenesis, effectively helping to starve the tumor.

Targeting Multiple Pathways

Lenvatinib is considered a multi-kinase inhibitor because it targets several different types of proteins at once, including:

• Fibroblast growth factor (FGF) receptors
• Platelet-derived growth factor (PDGF) receptors
• RET and KIT proteins

By interfering with these multiple signaling pathways, the medication helps slow or stop the spread of cancer cells throughout the body.

Common Side Effects

• Tiredness and weakness
• Loss of appetite and weight loss
• Nausea, vomiting, and stomach pain
• Diarrhea or constipation
• Mouth sores
• Joint or muscle pain
• Headache
• Cough or hoarseness
• Hand-foot syndrome (redness, swelling, or pain on the palms of the hands or soles of the feet)
• Rash

Serious Side Effects

Seek medical attention immediately if you experience any of the following serious symptoms:

• Severe high blood pressure
• Heart problems, such as chest pain, shortness of breath, or swelling in the legs
• Signs of a blood clot, including sudden numbness, weakness, or vision changes
• Severe or persistent diarrhea
• Liver problems, such as yellowing of the skin or eyes and dark urine
• Signs of a tear in the stomach or intestinal wall, such as severe abdominal pain
• Severe bleeding or coughing up blood
• Kidney problems, including changes in urination
• Neurological symptoms like seizures, confusion, or severe headache
• Low calcium levels, which may cause muscle spasms or cramps

Cardiovascular and Blood Pressure Risks

High blood pressure (hypertension) is a very common side effect and can be severe. Blood pressure is typically controlled before starting treatment and monitored regularly thereafter. Lenvatinib may also cause serious heart problems, including heart failure, heart attack, or changes in the heart's electrical rhythm known as QT prolongation.

Organ Toxicity and Internal Complications

• Liver Function: Serious and sometimes fatal liver damage has been reported. Liver function tests are performed before and during treatment to monitor for injury.
• Kidney Function: This medication can cause kidney impairment or failure. Healthcare providers monitor for protein in the urine and other signs of declining kidney health.
• Gastrointestinal Risks: There is a risk of developing tears (perforations) in the stomach or intestinal wall, or abnormal connections between different parts of the body (fistulas).
• Bleeding: Serious bleeding episodes, including internal bleeding, can occur during therapy.

Neurological and Electrolyte Issues

A rare brain condition called reversible posterior leukoencephalopathy syndrome (RPLS) has been observed. Symptoms may include seizures, headache, confusion, or vision changes. Additionally, the drug can cause low levels of calcium (hypocalcemia) and other electrolyte imbalances, which require monitoring through blood tests.

Wound Healing and Pregnancy

• Wound Healing: Lenvatinib can interfere with the body's ability to heal wounds. It is generally stopped for a period of time before and after elective surgeries.
• Thyroid Function: The drug can cause thyroid dysfunction or changes in thyroid-stimulating hormone (TSH) levels, often requiring hormone replacement therapy.
• Fetal Harm: Lenvatinib can cause significant harm to a developing fetus. Effective contraception is required for individuals of reproductive potential during treatment and for a specific duration after the final dose.

Pregnancy

Lenvatinib may cause fetal harm if taken during pregnancy. It is important to inform a healthcare provider if you are pregnant or planning to become pregnant before starting this medication. If you become pregnant while taking this drug, notify your doctor immediately.

Contraception Requirements

Because of the risks to a developing fetus, healthcare providers typically recommend the following:

• For females: Use effective birth control during treatment and for at least 30 days after the final dose.
• For males: Men with female partners who can become pregnant should use effective contraception during treatment and for at least 30 days after the last dose.

Breastfeeding

It is not known whether lenvatinib passes into human breast milk. Due to the potential for serious side effects in a nursing infant, breastfeeding is generally not recommended during treatment with lenvatinib and for at least one week following the last dose.

Dosage Forms

Lenvatinib is available as a capsule for oral administration. These capsules are typically provided in blister cards.

If the capsules cannot be swallowed whole, they may be dissolved in water or apple juice to create a liquid mixture. This preparation should be handled according to specific medical instructions to ensure the full dose is received.

FDA Approval and Indications

Lenvatinib was first approved by the U.S. Food and Drug Administration (FDA) in 2015. It is currently approved for the following clinical uses:

• Differentiated Thyroid Cancer (DTC): For the treatment of patients with local recurrence or metastatic, progressive differentiated thyroid cancer that is refractory to radioactive iodine treatment.
• Renal Cell Carcinoma (RCC): Approved for use in combination with everolimus for patients with advanced kidney cancer following one prior anti-angiogenic therapy. It is also approved in combination with pembrolizumab as a first-line treatment for adults with advanced RCC.
• Hepatocellular Carcinoma (HCC): As a first-line treatment for patients with unresectable liver cancer.
• Endometrial Carcinoma: In combination with pembrolizumab for patients with advanced endometrial carcinoma that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), whose disease has progressed following prior systemic therapy and who are not candidates for curative surgery or radiation.

Regulatory Safety Information

The FDA has not issued a Boxed Warning for lenvatinib, and there is currently no Risk Evaluation and Mitigation Strategy (REMS) program required for its distribution. However, the FDA requires the manufacturer to provide a Medication Guide for patients to highlight potential serious risks, such as high blood pressure, heart problems, and gastrointestinal perforations. The drug is also listed in the FDA Table of Pharmacogenomic Biomarkers because its use in endometrial cancer is specific to the MSI-H or dMMR status of the tumor.

Insurance and Out-of-Pocket Costs

The price of lenvatinib is largely determined by individual health insurance plans. Patients may be responsible for copayments, coinsurance, or meeting a deductible before coverage begins. Because it is a specialty medication, it is often placed on a higher tier of an insurance formulary, which can result in higher out-of-pocket costs.

Specialty Pharmacy Access

Lenvatinib is typically not available at local retail pharmacies. It is usually dispensed through specialty pharmacies that handle complex medications. These pharmacies often provide additional services, such as help with insurance navigation and financial assistance applications.

Financial Assistance Programs

Various programs may help reduce the cost of lenvatinib for eligible patients:

• Manufacturer Assistance: Programs may be available to provide the medication at no cost or a reduced cost for those who meet specific income and insurance requirements.
• Co-pay Support: Patients with commercial insurance may qualify for co-pay cards to lower their monthly expenses.
• Charitable Foundations: Independent organizations sometimes offer grants to help patients cover the costs of oncology medications.

Patients are encouraged to speak with their healthcare provider or a social worker to explore available financial resources.