Lenvatinib - About a Resilient Anticancer Drug

Overview:

Lenvatinib is a medication for treating thyroid carcinoma. It acts by slowing the progression of cancer growth by interrupting cell functions. Lenvatinib is available as an oral capsule. It is also used to treat other cancers, including endometrial, liver, and kidney cancer. The United States Food and Drug Administration (FDA) approved Lenvatinib for the treatment of thyroid cancer in 2015. Patients are advised to inform the healthcare provider regarding any planned surgery before starting the therapy with Lenvatinib. Female patients are recommended to use effective contraceptive measures during therapy and till one month after the last dose of the regimen.

How Does Lenvatinib Work?

Lenvatinib is a tyrosine kinase inhibitor that works by blocking the activity of specific proteins (tyrosine kinases) involved in the growth and spread of cancer cells. By inhibiting the activity of these proteins, Lenvatinib can slow down or stop the growth of cancer cells, leading to shrinkage of the tumor or slowing its progression.

For Patients:

What Is Thyroid Cancer?

Thyroid cancer is a type of cancer that originates from the thyroid gland, a butterfly-shaped gland located in the neck that produces hormones that regulate metabolism. Thyroid cancer is classified into different types, including papillary, follicular, medullary, and anaplastic thyroid cancer, each with its own characteristic features and behaviors. Thyroid cancer is generally treatable, especially when diagnosed early, but some forms of the disease can be aggressive and difficult to cure. Treatment options may include surgery, radiation therapy, hormone therapy, and chemotherapy.

Before Starting Lenvatinib:

Lenvatinib is a prescription medication to treat thyroid carcinoma. It is taken orally in the form of a tablet, usually once a day. The specific dosing regimen, duration of treatment, and reasons for taking Lenvatinib will vary based on the individual patient and their specific medical condition. It is important to take Lenvatinib exactly as the doctor prescribes and follow their instructions for monitoring and managing any potential side effects. Be sure to talk to the doctor about why to take Lenvatinib and how to take it.

How Effective Is Lenvatinib?

The effectiveness of Lenvatinib for the treatment of thyroid cancer varies depending on the specific type and stage of the disease, as well as the individual patient and their medical history. However, clinical studies have shown that Lenvatinib can be an effective treatment option for certain types of thyroid cancer, particularly differentiated thyroid cancer that has moved to other body parts (metastatic disease).

In clinical trials, Lenvatinib has been shown to shrink and slow the progression of tumors in a significant number of patients with metastatic differentiated thyroid cancer. In some cases, the treatment has led to long-lasting remissions or control of the disease.

What Are the Guidelines to Inform the Doctor Before Taking Lenvatinib?

Inform the doctor if any of the following conditions are present before taking Lenvatinib:

• Under treatment for high blood pressure.

• Have a history of heart conditions or strokes.

• Have liver or kidney issues.

• Have just undergone surgery or radiotherapy. If the patient is planning to have major surgery, the doctor might think about stopping Lenvatinib since it can interfere with wound healing. Once enough wound healing occurs, the drug may be resumed.

• Weigh less than 60 kg.

• Have a history of abnormal vascular connections (called fistulas) between various body organs or from an organ to the skin.

• Have or had swelling or sores inside the mouth, numbness or a heavy feeling in the jaw, or tooth sensitivity. If jaw bone deterioration (osteonecrosis) has been recorded in Lenvatinib patients, the patient should get a dental examination before beginning Lenvatinib. In particular, if the patient has recently received bisphosphonates injections (used to treat or prevent bone diseases), the dentist should know if the patient needs any invasive dental work.

• The patient is using or has taken certain cancer medications that affect the growth of blood vessels (known as angiogenesis inhibitors) or antiresorptive medications used to treat osteoporosis, as these medications may raise the risk of jawbone damage.

What Are the Side Effects of Lenvatinib?

Inform the doctor right away if the patient has any of the following adverse effects:

• Experiencing numbness or weakness on one side of the body, a strong headache, a seizure, disorientation, difficulty speaking, vision changes, or feeling dizzy – these symptoms could indicate a stroke, brain hemorrhage, or the impact of a severe rise in blood pressure on the brain.

• Chest pain or pressure, pain in the arms, back, neck, or jaw, shortness of breath, a rapid or irregular heartbeat, coughing, bluish discoloration to the lips or fingers, and extreme exhaustion.

• Severe abdominal pain may be caused by a fistula (a hole in the gut that connects to another area of the body or the skin), a hole (perforation) in the gut wall, or both.

• Black, tarry, or bloody feces, as well as blood coming up while coughing, could indicate internal bleeding.

• Yellowing of the eye whites, tiredness, confusion, and poor concentration.

• Diarrhea, feeling and acting sick (nausea and vomiting) are very frequent side effects that might get dangerous if the patient is dehydrated, which can result in renal failure.

• Signs of jaw bone deterioration include discomfort in the mouth, teeth, or jaw joint, sores or swelling inside the mouth, a feeling of numbness or heaviness in the jaw, or in some cases, loosening of the teeth (osteonecrosis).

These side effects are serious and require immediate medical attention. Some of the common side effects that may be countered during drug use include:

• Appetite loss or weight loss.

• Experiencing nausea and vomiting, as well as constipation, diarrhea, abdominal pain, and indigestion.

• Rash, feeling drained or weak, hoarse voice, swelling in the legs.

• Joint or muscular discomfort, feeling lightheaded, strange taste sensation, dry, painful, or inflamed mouth, and hair loss.

• Bleeding (most frequently nosebleeds, but sometimes blood in the urine, bruises, bleeding from the gums or gut wall).

• Difficulty in falling asleep.

• Backache, redness, discomfort, and swelling of the hands and feet.

• Underactive thyroid (tiredness, weight gain, constipation, feeling cold, dry skin).

• Alterations in calcium and potassium levels (low) found in blood tests.

• A reduction in the white blood cell count and changes in liver function blood test results.

• Low platelet counts can cause bruising and make wound healing difficult; changes in magnesium, cholesterol, and thyroid stimulating hormone blood test results; changes in kidney function and kidney failure blood test results; and low platelet counts.

• A rise in amylase and lipase (enzymes involved in digestion).

If these effects become persistent or do not go away on their own, contact the doctor immediately.

Dietary Alterations:

Some of the dietary changes that may be recommended while taking Lenvatinib include:

1. Avoiding High-fat Meals: Lenvatinib can be affected by the amount of fat in the digestive system, so high-fat meals should be avoided.

2. Staying Hydrated: Lenvatinib can cause dehydration, so it is important to drink plenty of water and other non-alcoholic beverages.

3. Avoiding Grapefruit and Grapefruit Juice: Grapefruit and grapefruit juice can interact with Lenvatinib and increase the amount of the drug in the bloodstream, which can increase the risk of side effects.

4. Avoiding Alcohol: Alcohol can increase the risk of side effects while taking Lenvatinib, so it is best to avoid alcohol or limit the intake amount.

Follow the dietary recommendations provided by the healthcare provider or pharmacist to help ensure the safe and effective use of Lenvatinib. In case of any questions or concerns about dietary restrictions while taking Lenvatinib, make sure to discuss them with the healthcare provider.

What Should Be Done if a Dose Is Missed?

If the patient misses a dose of Lenvatinib, it is important to take the missed dose as soon as one remembers, unless it is close to the time for the next scheduled dose. In such cases, skip the missed dose and continue with the regular dosing schedule. Refrain from doubling up on the next dose to make up for the missed one. If multiple doses are missed, it is important to talk to the healthcare provider as soon as possible. Your healthcare provider may adjust the dosing schedule or provide additional instructions on how to make up for missed doses.

What Should Be Done to Treat Lenvatinib Overdose?

Cases of overdose should be reported to the nearest poison control center or emergency department of the nearest hospital. The treatment will be based on the amount of drug ingested and the duration since the overdose.

How to Store Lenvatinib?

• Lenvatinib should be stored at a temperature between 20°C and 25°C (68°F and 77°F) and protected from light and moisture.

• Keep the medication and all medications out of reach of children and pets.

• Stored the medication away from sources of heat, such as a stove or radiator, and from cold sources, such as a freezer.

• Keep track of the expiration date of Lenvatinib and dispose of the expired medication properly.

Avoid Self-medication:

Lenvatinib is used to treat specific types of cancer and is not appropriate for everyone. The healthcare provider will assess the individual health status and determine if the drug is an appropriate choice of treatment for the condition. Self-medicating with Lenvatinib can increase the risk of an overdose or underdose, which can have serious consequences. Also, it can be dangerous if the patient has underlying health conditions or other medical conditions that would contraindicate its use.

For Doctors:

Indication:

Lenvatinib is used for the treatment of the following conditions:

• Thyroid carcinoma: Differentiated, metastatic, or locally recurrent, progressing, and resistant to radioactive iodine.

• Carcinoma of the uterus, In patients with disease progression after prior systemic therapy in any setting who are not candidates for curative surgery or radiation, patients with advanced cancer that is mismatch repair proficient (pMMR) or not microsatellite instability-high (MSI-H) may be treated with pembrolizumab in combination.

• Liver cancer is the first treatment for incurable conditions.

What Is the Dosing Schedule for Lenvatinib?

Condition	Dosing
Thyroid carcinoma	24 mg (two 10 mg capsules and one 4 mg capsule) to be prescribed once daily at the same time each day. Therapy is to be continued until disease progression is noted or any unacceptable toxicity is observed.

Pharmacology:

Mechanism of Action:

Lenvatinib is identified as a receptor tyrosine kinase (RTK) inhibitor that prevents VEGF receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 from kinase activity (FLT4). Lenvatinib also inhibits other RTKs, such as the fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4, platelet-derived growth factor receptor alpha (PDGFR), KIT, and RET, which have been linked to pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions.

The activation of signal transduction pathways involved in the normal regulation of cellular processes, such as migration, apoptosis, cell proliferation, and differentiation, as well as in pathogenic angiogenesis, lymphogenesis, tumor growth, and cancer progression, is a key function of these receptor tyrosine kinases (RTKs) found in the cell membrane. Particularly, it has been found that VEGF is a key regulator of both pathologic and physiological angiogenesis and that higher VEGF expression is linked to a poor prognosis in a variety of malignancies.

Pharmacokinetics:

Absorption:

Lenvatinib is absorbed into the bloodstream after oral administration and reaches maximum plasma concentrations within one to four hours.

Distribution:

The distribution of Lenvatinib is not well characterized, but the drug has been shown to have a large volume of distribution in preclinical studies. Lenvatinib is highly protein bound, with more than 99 percent bound to plasma proteins.

Metabolism:

Lenvatinib is primarily metabolized in the liver, with the primary active metabolite, E7080, and is extensively metabolized by CYP3A4 and CYP3A5.

Excretion:

The drug and its metabolites are primarily excreted in the feces, with a small fraction excreted in the urine.

Clinical Studies:

A Phase 2 trial evaluated the efficacy and safety of Lenvatinib in patients with advanced refractory differentiated thyroid cancer (DTC). The study enrolled 58 patients, and results showed that Lenvatinib treatment resulted in a confirmed overall response rate (ORR) of 31.0 percent and a disease control rate (DCR) of 68.9 percent. The median progression-free survival (PFS) was 4.2 months, and the median duration of response (DOR) was 8.9 months. The most common adverse effects reported were diarrhea, nausea, and vomiting.

Warnings and Precautions:

• Hypertension: Blood pressure should be under control before and during treatment. Despite receiving the best antihypertensive care, the therapy is withheld for Grade 3 hypertension. For Grade 4 hypertension, the drug’s usage is stopped..

• Cardiac Dysfunction: Monitor for any indicators or clinical symptoms of cardiac dysfunction. For cardiac dysfunction in Grade 3, the therapy is withheld or stopped. For cardiac dysfunction Grade 4, it is discontinued.

• Arterial Thromboembolic Events: Using the medication is stopped immediately if thromboembolic events are experienced.

• Hepatotoxicity: Prior to and occasionally during therapy, liver function is monitored. In the case of Grade 3 or 4 hepatotoxicities, the therapy is withheld or stopped. For hepatic failure, it is stopped.

• Renal Failure or Impairment: The therapy is discontinued or paused if renal failure or impairment occurs.

• Proteinuria: Monitoring for proteinuria should be done both before and during the treatment. The drug is withheld if proteinuria of 2 grams every 24 hours is detected. For nephrotic syndrome, it is stopped.

• Diarrhea: This condition can be severe and recurrent. supportive treatment is started for severe diarrhea right away, depending on the intensity.

• Gastrointestinal: Patients who develop Grade 3 or 4 fistulas or any Grade gastrointestinal perforations should stop the treatment.

• QT Prolongation: Electrolyte imbalances to prevent QT interval prolongation are monitored and treated. The therapy is withheld if the baseline QT interval increases by at least 60 ms or if the QT interval is more than 500 ms.

• Hypocalcemia: Monitor blood calcium levels at least once a month, and provide calcium as needed depending on the intensity.

• Hematologic: Depending on the severity, the treatment is modified for hemorrhagic events.

• Impaired Thyroid Stimulating Hormone Suppression or Thyroid Dysfunction: Prior to treatment and once a month while receiving it, thyroid function should be monitored.

• Impaired Wound Healing: Elective surgery is avoided for at least one week after stopping Lenvatinib. Also after major surgery and for at least two weeks, the administration is avoided to allow for proper wound healing. The safety of continuing Lenvatinib after wound healing issues have been resolved has not been proven.

• Osteonecrosis of the Jaw: Before receiving Lenvatinib treatment, consider preventive dentistry. invasive dental operations are avoided, especially for individuals who are more vulnerable.

• Embryo-Fetal Toxicity: The drug may be harmful to the fetus. Mention the use of effective contraception and possible risks to an unborn child.

Contraindications:

Specific contraindications are not yet determined for Lenvatinib.

Specific Population:

Lenvatinib in Pregnant Women:

The use of Lenvatinib in pregnant women has not been studied and is not recommended. Lenvatinib can cause harm to a developing fetus, and there is a potential risk for birth defects. Women who are taking Lenvatinib should use effective contraception to prevent pregnancy during treatment and for at least four weeks after the final dose of Lenvatinib.

Lenvatinib in Lactating Women:

The use of Lenvatinib in lactating women has not been studied, and it is not known if the drug is excreted in human milk. It is recommended that women avoid breastfeeding while taking Lenvatinib, as there is a potential risk of harm to a nursing infant.

Lenvatinib in Pediatrics:

Lenvatinib is not currently approved by the U.S. Food and Drug Administration (FDA) for use in pediatric patients.

Lenvatinib in Patients With Renal Impairment:

Lenvatinib can cause renal impairment and patients with pre-existing renal impairment may be at higher risk for developing further renal problems while taking this medication. In clinical trials, Lenvatinib was associated with reductions in estimated glomerular filtration rate (eGFR). The recommended dose of Lenvatinib may need to be adjusted in patients with renal impairment. Patients with moderate to severe renal impairment (eGFR < 50 mL/min) should not receive Lenvatinib, while those with mild renal impairment (eGFR 50-80 mL/min) may receive a reduced dose. Patients taking Lenvatinib should have their renal function monitored regularly, and dose adjustments should be made if necessary.

Lenvatinib in Patients With Hepatic Impairment:

The recommended dose of Lenvatinib may need to be adjusted in patients with hepatic impairment. Patients with moderate to severe impairment in hepatic function (Child-Pugh class B or C) should not receive Lenvatinib.