Lenvatinib — Drug Monograph

Brand names: Lenvima

Drug class: Tyrosine Kinase Inhibitor

Mechanism of Action

Oral multi-kinase inhibitor with a distinct binding mode from most VEGFR inhibitors. Inhibits VEGFR1, VEGFR2, VEGFR3 (primary anti-angiogenic targets), FGFR1–4 (fibroblast growth factor receptors — unique among VEGFR inhibitors; accounts for activity in RAI-refractory thyroid cancer where FGFR signaling is a resistance mechanism), PDGFRα and PDGFRβ, RET, KIT, and NOTCH1. The dual VEGFR + FGFR blockade is mechanistically important in thyroid cancer and endometrial cancer.

FDA Indications

• Differentiated thyroid cancer (DTC) — locally recurrent or metastatic, radioactive iodine (RAI)-refractory (SELECT trial — median PFS 18.3 vs. 3.6 months; HR 0.21)
• Hepatocellular carcinoma (HCC) — first-line unresectable (REFLECT trial — non-inferior to sorafenib; median OS 13.6 vs. 12.3 months)
• Renal cell carcinoma (RCC) — advanced, first-line (with pembrolizumab — CLEAR trial; HR 0.39 for PFS)
• Endometrial carcinoma — advanced, after prior platinum-containing chemotherapy (with pembrolizumab — KEYNOTE-775/Study 309; benefit in all subgroups, particularly mismatch repair-proficient/non-MSI-H tumors)

Common Side Effects

• Hypertension (70–80%; often severe — requires active management)
• Fatigue
• Diarrhea
• Decreased appetite
• Nausea
• Vomiting
• Weight loss
• Hand-foot skin reaction (palmar-plantar erythrodysesthesia)
• Proteinuria
• Dysphonia
• Musculoskeletal pain

Clinical Pearl

Hypertension is nearly universal with lenvatinib and requires proactive antihypertensive initiation or dose titration — do not wait for symptoms. Hand-foot skin reaction (HFSR) management includes keratolytic creams (urea 20–40% or salicylic acid) on callused areas before starting, cushioned insoles, and avoiding tight footwear. In the endometrial cancer indication (KEYNOTE-775), the lenvatinib + pembrolizumab benefit was dramatic in MMR-proficient/non-MSI-H tumors (the subgroup that does NOT…

Related Therapies & Mechanisms

• Cabozantinib (Cabometyx) — Tyrosine Kinase Inhibitor · HCC
• Sorafenib (Nexavar) — Tyrosine Kinase Inhibitor · HCC
• Pembrolizumab (Keytruda) — HCC
• Axitinib (Inlyta) — Tyrosine Kinase Inhibitor · RCC