What is Lenvima (lenvatinib)?

Lenvatinib (Lenvima): A Multi-Kinase Inhibitor for Advanced Cancers

Lenvatinib is an oral multi-kinase inhibitor that targets vascular endothelial growth factor receptors (VEGFR1-3), fibroblast growth factor receptors (FGFR1-4), platelet-derived growth factor receptor alpha (PDGFRα), RET, and KIT proto-oncogenes, approved for treatment of advanced hepatocellular carcinoma (HCC), differentiated thyroid cancer, renal cell carcinoma, and endometrial carcinoma. 1, 2

Mechanism of Action and Pharmacology

• Lenvatinib inhibits multiple tyrosine kinase receptors involved in tumor angiogenesis, cell proliferation, and cancer progression 1, 3
• Following oral administration, lenvatinib is rapidly absorbed and extensively metabolized prior to excretion 3
• The drug has a predictable pharmacokinetic profile that supports once-daily dosing 3
• Lenvatinib is available in 4 mg and 10 mg capsules for oral administration 2

Approved Indications

• First-line treatment for unresectable hepatocellular carcinoma (HCC) in patients with Child-Pugh A liver function 1
• Treatment of radioiodine-refractory differentiated thyroid cancer (DTC) 2, 4
• Treatment of advanced renal cell carcinoma (RCC):
  • In combination with pembrolizumab as first-line therapy 1, 2
  • In combination with everolimus after one course of anti-angiogenic therapy 2, 4
• Treatment of advanced endometrial carcinoma in combination with pembrolizumab 2

Dosing in Hepatocellular Carcinoma

• Weight-based dosing: 12 mg daily for patients ≥60 kg; 8 mg daily for patients <60 kg 1
• Should be taken once daily with or without food 2
• Dose adjustments may be required based on tolerability 5, 2

Clinical Efficacy in HCC

• In a phase III non-inferiority trial comparing lenvatinib to sorafenib in advanced HCC:
  • Lenvatinib demonstrated non-inferiority in overall survival (OS) (median OS: 13.6 months vs. 12.3 months for sorafenib; HR: 0.92; 95% CI 0.79-1.06) 1
  • Lenvatinib showed improved progression-free survival (7.4 months vs. 3.7 months) and time to progression (8.9 months vs. 3.7 months) compared to sorafenib 1
  • Objective response rate was significantly higher with lenvatinib (24.1% vs. 9.2% with sorafenib, p<0.001) 1
• Median time on lenvatinib treatment was 5.7 months compared to 3.7 months for sorafenib 1

Common Adverse Events

• Hypertension (42% of patients, grade 3/4 in 23%) - requires regular blood pressure monitoring 1, 5
• Diarrhea (39% of patients, grade 3/4 in 4%) 1
• Decreased appetite (34%) and weight loss (31%) 5, 6
• Fatigue (approximately 30% of patients) 5, 6
• Hand-foot skin reaction (27% with lenvatinib vs. 52% with sorafenib) 1
• Hypothyroidism (16% of patients) - requires regular thyroid function monitoring 5, 6
• Proteinuria (25% of patients) 5, 6
• Dysphonia (voice changes) in about 24% of patients 5

Management of Adverse Events

• Regular monitoring of blood pressure, thyroid function, and proteinuria is recommended 5, 6
• Adverse events frequently lead to treatment interruptions (82.4% of patients) and dose reductions (67.8%) 5, 7
• Most adverse events occur during the first few weeks of treatment and decrease after treatment interruption 5, 6
• Patients who discontinue lenvatinib due to serious adverse events may have significantly shorter overall survival 5

Special Considerations

• Lenvatinib is only recommended for patients with Child-Pugh A liver function in HCC 1
• Not recommended for patients with main portal vein invasion or >50% tumor to total liver volume occupancy 1
• Contraindicated during pregnancy - can harm the unborn baby 2
• Women should not breastfeed during treatment and for 1 week after the last dose 2
• Should be discontinued at least 1 week before planned surgery 2

Comparison with Other Systemic Therapies

• Lenvatinib and sorafenib are both approved first-line options for advanced HCC 1
• Lenvatinib showed better progression-free survival, time to progression, and objective response rates compared to sorafenib, with non-inferior overall survival 1
• Different side effect profiles: lenvatinib has higher rates of hypertension, while sorafenib has higher rates of hand-foot skin reaction 1
• For patients progressing on first-line therapy, second-line options include regorafenib, cabozantinib, and ramucirumab 1

Lenvatinib represents an important therapeutic option for patients with advanced HCC and other solid tumors, with demonstrated efficacy and a manageable safety profile when appropriate monitoring and dose adjustments are implemented.