Lenvatinib (Lenvima) is an oral multi-targeted tyrosine kinase inhibitor approved for treatment of differentiated thyroid cancer, hepatocellular carcinoma, renal cell carcinoma, and endometrial carcinoma.
It functions primarily through inhibition of VEGF receptors 1-3 and FGF receptors 1-4, along with additional targets including PDGFR-α, KIT, and RET.
Lenvatinib exerts its antitumor effects through multiple mechanisms.
The drug inhibits vascular endothelial growth factor receptors (VEGFR1-3) and fibroblast growth factor receptors (FGFR1-4), which are critical for tumor angiogenesis.
Beyond its antiangiogenic properties, lenvatinib also targets platelet-derived growth factor receptor alpha (PDGFR-α), KIT, and RET proto-oncogenes.
In preclinical models, it has demonstrated immunomodulatory effects, including decreased tumor-associated macrophages and increased activated cytotoxic T cells, which enhances antitumor activity when combined with anti-PD-1 antibodies.
The current FDA-approved indications include:
Differentiated thyroid cancer (DTC): Locally recurrent or metastatic, progressive, radioactive iodine-refractory disease (24 mg once daily)
Hepatocellular carcinoma (HCC): First-line treatment of unresectable disease (12 mg once daily for ≥60 kg; 8 mg for [1] In the DTC trial, 68% of patients required dose reductions and 18% discontinued treatment due to adverse reactions.
Serious toxicities requiring monitoring include:
Hypertension: Occurs in 50-68% of patients (grade ≥3 in 13-42%); requires blood pressure monitoring after 1 week, then every 2 weeks for 2 months, then monthly.
Cardiac dysfunction: Grade 3 or higher cardiac events occurred in 3% of patients.
Proteinuria: Occurs in 31-32% of patients (grade ≥3 in 6-10%)>
Hepatotoxicity: Particularly important in HCC patients
Arterial thromboembolic events, renal failure, hemorrhagic events, and QT prolongation
The combination of lenvatinib with pembrolizumab in RCC shows a similar safety profile:
In this combination, 82.4% of patients experienced grade ≥3 adverse events, with diarrhea (61%), hypertension (55%), and hypothyroidism (47%) being most common.
Dose modifications are frequently required.
Maintaining the highest tolerable dose is important for efficacy.