Gunagratinib

Lenvatinib: A Tyrosine Kinase Inhibitor of VEGFR 1-3, FGFR 1-4, PDGFRα, KIT, and RET

Abstract

Lenvatinib is an orally administered receptor tyrosine kinase inhibitor (TKI) that targets vascular endothelial growth factor receptors (VEGFR) 1-3, fibroblast growth factor receptors (FGFR) 1-4, platelet-derived growth factor receptor alpha (PDGFRα), as well as the proto-oncogenes KIT and RET. Lenvatinib is approved for the treatment of radioiodine-refractory differentiated thyroid cancer and, in combination with everolimus, for advanced renal cell carcinoma following anti-VEGF therapy. In hepatocellular carcinoma, lenvatinib has demonstrated non-inferiority to sorafenib as a first-line treatment, with improved progression-free survival, and approval in this indication is anticipated. Lenvatinib is under investigation for further indications as both a single agent and in combination regimens. Common side effects include hypertension, diarrhea, hypothyroidism, and fatigue, which are typical of TKI-induced toxicities.

Introduction

Lenvatinib exhibits potent activity against VEGFR 1-3, FGFR 1-4, PDGFRα, KIT, and RET. Activation of these tyrosine kinase receptors initiates intracellular signaling pathways, notably the RAS and PI3K/AKT pathways, leading to cell growth and differentiation. Overexpression, mutation, or constitutive activation of these receptors can drive oncogenesis. In renal cell carcinoma (RCC), two pivotal events are commonly observed: loss of function of the von Hippel-Lindau (VHL) tumor suppressor gene and activation of the mechanistic target of rapamycin (mTOR) pathway. Loss of VHL leads to persistent hypoxic signaling, upregulating growth factors such as VEGF and PDGF, which in turn activate mTOR and further enhance hypoxia-inducible factor (HIF) expression, creating a positive feedback loop that promotes tumor growth.

In papillary thyroid cancers, most tumors harbor driver mutations affecting the MAPK and PI3K-mTOR pathways. Binding of ligands such as RET, PDGFR, cKIT, FGFR, or VEGFR to their receptors results in dimerization and autophosphorylation, activating downstream proliferative, angiogenic, and metastatic signals. High expression of FGFR and VEGF family members in thyroid cancer is associated with more aggressive disease, larger tumors, and BRAF mutations.

Structure and Mechanism of Action

Lenvatinib (formerly E7080) is a quinoline-based oral TKI that binds to the ATP binding site of VEGFR2 and adjacent allosteric regions, adopting a “DFG-in” conformation. This unique binding mode, classified as Type V, contributes to its high kinase selectivity and favorable association/dissociation kinetics. Lenvatinib inhibits VEGFR1-3, FGFR1-4, PDGFRα, KIT, and RET, thereby blocking multiple pro-angiogenic and oncogenic pathways. Preclinical studies have demonstrated its antitumor, anti-angiogenic, and anti-lymphangiogenic activity in diverse tumor models, including non-small cell lung cancer, breast cancer, sarcoma, thyroid cancer, and colorectal cancer. Lenvatinib potently inhibits VEGF- and FGF-driven proliferation and tube formation of endothelial cells, and suppresses angiogenesis and tumor growth in vivo.

Clinical Data

Pharmacokinetics and Safety Profile

Lenvatinib is rapidly absorbed after oral administration, reaching peak plasma concentrations within three hours. It is highly protein-bound (>96%) and primarily metabolized in the liver via CYP3A4. Excretion occurs mainly via feces (64%) and to a lesser extent in urine (25%). Food intake, gastric pH modifiers, and CYP3A4 inhibitors or inducers do not significantly affect lenvatinib exposure. The half-life is approximately 28 hours. Dose adjustments are recommended in patients with severe hepatic or renal impairment. Lenvatinib is not dialyzable due to high protein binding. Common adverse effects include hypertension, proteinuria, diarrhea, hypothyroidism, fatigue, and other class-related toxicities. QTc prolongation has been observed in cancer patients but not in healthy volunteers.

Phase I Trials

Early phase I studies established lenvatinib’s maximum tolerated dose and demonstrated antitumor activity in various solid tumors, including colorectal cancer, sarcoma, melanoma, and RCC. Dose-limiting toxicities included hypertension, proteinuria, and fatigue. Combination studies with chemotherapy (e.g., paclitaxel and carboplatin) and other targeted agents (e.g., everolimus) have shown manageable safety profiles and preliminary efficacy.

Lenvatinib in Thyroid Cancer

In phase II and III trials, lenvatinib demonstrated significant efficacy in radioiodine-refractory differentiated thyroid cancer (DTC), with objective response rates around 50% and median progression-free survival (PFS) exceeding 12 months. The SELECT phase III trial showed a median PFS of 18.3 months with lenvatinib compared to 3.6 months with placebo. The benefit was consistent across histological subtypes and independent of prior TKI therapy. Adverse events were common and led to dose reductions or discontinuation in a substantial proportion of patients. Lenvatinib has also shown efficacy in medullary thyroid cancer.

Lenvatinib in Renal Cell Carcinoma

A phase II trial in metastatic RCC compared lenvatinib alone, lenvatinib plus everolimus, and everolimus alone after prior VEGF-targeted therapy. The combination of lenvatinib and everolimus significantly prolonged PFS (14.6 months) compared to everolimus alone (5.5 months). Single-agent lenvatinib also improved PFS versus everolimus. Objective response rates were highest in the combination arm. Toxicities were manageable and consistent with known profiles of the drugs. Lenvatinib in combination with everolimus is approved for advanced RCC following anti-VEGF therapy.

Lenvatinib in Hepatocellular Carcinoma

In a phase III trial (REFLECT), lenvatinib demonstrated non-inferiority to sorafenib as a first-line treatment for unresectable hepatocellular carcinoma (HCC), with a median overall survival of 13.6 months versus 12.3 months for sorafenib. Secondary endpoints, including progression-free survival, time to progression, and objective response rate, favored lenvatinib. Toxicities were similar to those observed in other indications, and dose adjustments were required based on patient body weight and tolerability.

Ongoing and Future Clinical Trials

Lenvatinib is being evaluated in numerous ongoing trials as a single agent and in combination with other therapies for various malignancies, including breast cancer, neuroendocrine tumors, anaplastic thyroid cancer, endometrial cancer, and non-small cell lung cancer. Combination regimens with immune checkpoint inhibitors (e.g., pembrolizumab) and other targeted agents are under active investigation.

Conclusion and Future Perspectives

Lenvatinib is a multi-targeted TKI with demonstrated efficacy in thyroid cancer, RCC, and HCC. Its unique binding mode and broad kinase inhibition profile contribute to its antitumor and anti-angiogenic effects. Positive clinical trial results have led to regulatory approvals in several indications,Gunagratinib and ongoing studies will further define its role in cancer therapy, both as monotherapy and in combination regimens.