Continuing Education Activity

Lenvatinib is FDA approved for the treatment of radioactive iodine-refractory differentiated thyroid cancer (DTC), unresectable or advanced hepatocellular carcinoma (HCC), and advanced renal cell carcinoma (RCC). It is a multiple receptor tyrosine kinase inhibitor that demonstrates potent antiangiogenic properties. The inhibition of the VEGF receptors prevents tumor angiogenesis, and the inhibition of FGFR, RET, PDGFRa, and KIT prevents the further proliferation of malignant cells. This activity will highlight the mechanism of action, adverse event profile, and other key factors pertinent to members of the interprofessional team in the management of patients with radioactive iodine-refractory differentiated thyroid cancer (DTC), unresectable or advanced hepatocellular carcinoma (HCC), and advanced renal cell carcinoma (RCC).

Objectives:

• Identify the mechanism of action of lenvatinib.
• Describe the adverse effects of lenvatinib.
• Review the appropriate monitoring of lenvatinib.
• Outline how interprofessional coordination and communication can improve therapy with lenvatinib for patients where it is indicated.

Indications

Lenvatinib is a multiple receptor tyrosine kinase inhibitor that demonstrates potent antiangiogenic properties indicated as monotherapy or combination therapy for certain malignancies. Lenvatinib is FDA-approved for radioactive iodine-refractory differentiated thyroid cancer (DTC), unresectable or advanced hepatocellular carcinoma (HCC), and advanced renal cell carcinoma (RCC).[1][2]

Lenvatinib was approved for its use in radioactive iodine-refractory differentiated thyroid cancer following a randomized, multicenter, placebo-controlled Phase III study (SELECT). The trial included 392 participants with radioactive iodine-refractory DIC and was subject to random assignment to either a treatment group of 24 mg lenvatinib once a day or the placebo group at a 2 to 1 ratio.[1][2] The treatment group demonstrated a median progression-free survival (PFS) of 18.3 months and a response rate (RR) of 64.8% compared to the placebo group, 3.6 months and 1.5%, respectively. The overall survival (OS) of both groups did not show a notable difference, which may have been from the crossover from the placebo group to the treatment group.[1][2] Lenvatinib has also been studied for its use in anaplastic thyroid cancer but is currently not FDA-approved for this indication.[3]

The randomized, non-inferiority, Phase III trial REFLECT demonstrated lenvatinib use in HCC as non-inferior to sorafenib, a kinase inhibitor approved to treat HCC. The trial also demonstrated lenvatinib prolonged progression-free survival of 7.3 months and an objective response rate (ORR) of 24% compared to sorafenib, 3.6 months and 9%, respectively. The REFLECT Phase III trial's efficacious results gained FDA approval for its use as first-line therapy in unresectable or advanced HCC in patients not undergoing prior treatment.

Lenvatinib was also approved as a combination therapy with everolimus for RCC based on a randomized phase II trial.[2] The trial compared lenvatinib 24 mg as monotherapy to everolimus 5mg monotherapy and lenvatinib 24 mg and everolimus 5 mg as combination therapy. The combination group demonstrated a lengthened progression-free survival (PFS) of 14.6 months compared to the 5.5 months of everolimus monotherapy and 7.4-month lenvatinib monotherapy. The combination therapy also showed prolonged OS compared to the monotherapies.

FDA Approved Use

• Radioactive iodine-refractory differentiated thyroid cancer (DTC)
• Unresectable or advanced hepatocellular carcinoma (HCC)  
• Advanced renal cell carcinoma (RCC)

Mechanism of Action

Lenvatinib exerts its mechanism of action via inhibition of multiple receptors of tyrosine kinases: VEGFR-1 (FLT1), VEGFR-2( KDR), VEGFR-3 (FLT4), FGFR-1, FGFR-2, FGFR-3, FGFR-4, PDGFRa, RET, and c-KIT. Tumor growth is dependent on the development and proliferation of new blood vessels (neovascularization).[4] Tumor growth and angiogenesis occur when the ligands bind to their respective tyrosine kinase receptors in the cellular membrane, initiating an intracellular signal transduction phosphorylation cascade promoting angiogenesis and cell proliferation.

The inhibition of the VEGF receptors prevents tumor angiogenesis, and the inhibition of FGFR, RET, PDGFRα, and KIT prevents the further proliferation of malignant cells.[2] The concurrent inhibition of both receptor pathways results in the inhibition of nuclear signal transduction and concomitant suppression of the activity of factors involved in tumor growth.

Administration

Lenvaitnib is available in 4 mg and 10 mg capsule dosages for oral consumption.[4]

Radioactive Iodine-refractory Differentiated Thyroid Cancer (DTC)

• 24 mg orally once a day.

Advanced Renal Cell Carcinoma (RCC)

• First-line treatment: 20 mg orally once a day in combination with pembrolizumab for up to two years; then can be given as monotherapy. 
• Previously treated disease: 18 mg orally once daily in combination with everolimus.

Unresectable Hepatocellular Carcinoma (HCC)  

The suggested dose should be determined based on the patient's body weight: 

• 12 mg orally once a day for patients' body weight greater than or equal to 60 kg.
• 8 mg orally once a day for patients weighing less than 60 kg.

Advanced Endometrial Carcinoma

• 20 mg orally once daily; for patients with non-microsatellite instability-high (MSI-H) or non-mismatch repair deficient (dMMR) progressive disease who are not candidates for X-ray therapy or curative surgery, use with pembrolizumab.

Dosing modifications are necessary for patients with hepatic and renal impairments. Lenvatinib is metabolized enzymatically in the liver by CYP450 isoform CYP3A and aldehyde oxidase and excreted from the body in the form of feces and urine.[5] The half-life of lenvatinib is 28 hours.[4] Approximately two-thirds of the drug is eliminated in the feces, with approximately 25% eliminated in the urine.[6] Patients with severe renal dysfunction (creatinine clearance of 15 to 29 mL/min) may have reduced drug clearance and increased plasma concentrations of lenvatinib; therefore, dosages in this population should be reduced.

Adverse Effects

• Hypertension
• Gastrointestinal: diarrhea, constipation, abdominal pain
• Nausea and vomiting
• Headache
• Fatigue
• Decreased weight
• Suppressed appetite
• Dysphonia
• Dysgeusia
• Rash
• Myalgia
• Cardiac dysfunction
• Arterial thromboembolic event
• Hepatotoxicity
• Renal failure or impairment
• Proteinuria
• Gastrointestinal perforation
• Fistula formation 
• QT prolongation
• Reversible posterior leukoencephalopathy syndrome
• Hypocalcemia
• Thyroid dysfunction
• Wound healing complications

Hypertension is one of the most common adverse effects of lenvatinib therapy and is more prominent in subjects older than 75 years.[1][2][7] During the phase III SELECT trials for radioactive iodine-refractory DIC, patients from the treatment group reported fistula formation causing bleeding from the tumor. Adverse effects from therapy should be managed supportively with dosing adjustments and discontinuation of treatment if necessary.[7]

Contraindications

Lenvatinib is metabolized in the liver by CYP3A4 and aldehyde oxidase.[5] Agents that induce or inhibit the CYP-450 system may alter the plasma concentration of lenvatinib, but no clinically relevant drug-drug interactions have been reported.[8]

Monitoring

Due to toxicity, several subjects treated with lenvatinib may have their dosage reduced or the drug discontinued. At baseline, creatinine, a pregnancy test for female patients, oral exam, blood pressure, and urine protein tests are recommended. Routine monitoring of renal function and liver function is advised. If nephrotic syndrome occurs, treatment should be terminated immediately.[9] ECG monitoring should also be routinely performed since cardiac impairment and QT interval prolongation is adverse effects associated with using lenvatinib. Thyroid function should be monitored every month, as hypothyroidism may also occur while on therapy. 24-hour blood pressure monitoring is also advised to detect hypertension from lenvatinib use.[7]

Clinical trials of lenvatinib commonly revealed elevations in serum aminotransferase levels, occurring in 52% of patients. However, values exceeding five times the upper limit of normal (ULN) only appeared in 3% to 5% of subjects. Similarly, elevations in serum alkaline phosphatase were also common, occurring in 28% of patients, but were above three times ULN in only 2%.[8]

Toxicity

Fetal harm was observed in animal trials during the administration of lenvatinib at a dosage below the recommended range. Currently, no reproductive studies have been done to analyze the toxicity in humans. Pregnant women should be counseled and advised of possible toxicity to the fetus. Lenvatinib may also be present during lactation, and it is recommended to halt breastfeeding for possibly one week following the last dosage.[10]

Enhancing Healthcare Team Outcomes

Lenvatinib is a multiple receptor tyrosine kinase inhibitor that is FDA-approved and indicated for the treatment of radioactive iodine-refractory differentiated thyroid cancer (DTC), unresectable hepatocellular carcinoma (HCC), and advanced renal cell carcinoma (RCC). The care for patients suffering from such malignancies prompts critical care from an interprofessional team of healthcare professionals. Early diagnosis and management can decrease life-long complications, increase the quality of life and decrease mortality. The interprofessional team includes a primary care clinician, an oncologist, a nurse, and a pharmacist.

Primary care physicians and specialists should thoroughly educate their patients about the disease course and management and the potential adverse effects of therapy that may arise. The primary care clinician, oncologist, and pharmacy oncology specialist team should routinely monitor renal function and liver enzymes, as lenvatinib is metabolized and cleared in the liver and kidneys, respectively, and dosage modifications may be necessary. When treating HCC, the body weight should also be routinely monitored as the dosage of therapy is determined based on actual body weight. This is where a specialized oncology pharmacist can provide valuable input to the interprofessional healthcare team.

Lenvatinib has a wide array of adverse effects, and routine follow-ups are vital to prevent complications and long-term harm. Anti-emetics should be considered with the use of lenvatinib due to nausea and vomiting. An EKG should be done, and the QT interval should be reviewed prior to selecting which medication to use, as certain anti-emetics can prolong the QT interval. Cardiac impairment and QT-interval prolongation are also adverse effects of lenvatinib.

Hypertension is the most reported side effect, and routine blood pressure checks are advised. Early detection can be made by 24-hour blood pressure monitoring while taking lenvatinib. Pateints with an underlying history of hypertension should have their blood pressure controlled and maintained in a stable range before initiating therapy. Patients with uncontrolled increases in their blood pressure while receiving optimal therapy for blood pressure should discontinue lenvatinib. In the occurrence of cardiac impairment such as heart failure, cardiomyopathy, or ventricular dysfunction, a cardiologist should be consulted. Thyroid function monitoring should also be routine as lenvatinib use can result in a hypofunctiong thyroid. 

During reproductive animal investigations, lenvatinib has been shown to cause harm to the fetus and be present in breast milk. Pregnant women should be advised about its likely effects on the fetus and should discontinue breastfeeding for one week following the last dosage of lenvatinib. Interprofessional interaction between healthcare providers and patients is essential to strengthening patient rapport and forming a therapeutic alliance. Patients' compliance with therapy is vital in the management of malignancies. This will, in turn, minimize treatment delays and enhance outcomes and the quality of life.[7] With an interprofessional team approach to care that involves all clinicians, specialists, nursing staff, pharmacists, and the patient and their family, the odds of successful therapeutic outcomes increase, with a decreased potential for adverse events. [Level 5]