Lenvatinib: A Breakthrough Targeted Therapy for Multiple Cancer Types

Lenvatinib (Lenvima) is an orally active multiple receptor tyrosine kinase (RTK) inhibitor with a novel mechanism of action that allows it to target key pathways involved in tumor growth and progression. Since its approval, lenvatinib has emerged as a breakthrough therapy for several difficult-to-treat cancer types. This article provides an overview of lenvatinib, its mechanism of action, clinical uses, safety profile, and place in cancer therapy.

Introduction

Lenvatinib is approved for the treatment of radioactive iodine-refractory differentiated thyroid cancer (RAI-refractory DTC), advanced renal cell carcinoma (RCC), unresectable hepatocellular carcinoma (HCC), and advanced endometrial carcinoma (EC). It is the first TKI approved for RAI-refractory DTC based on a pivotal phase 3 study showing significant improvements in progression-free survival and response rate versus placebo. For RCC, lenvatinib plus everolimus demonstrated superior efficacy over everolimus alone in the second-line setting post anti-VEGF therapy. In first-line RCC, the combination of lenvatinib plus pembrolizumab showed significantly longer PFS and OS versus sunitinib. Lenvatinib also became the first TKI to show statistically significant OS benefit versus sorafenib for unresectable HCC based on the REFLECT trial. Most recently, lenvatinib plus pembrolizumab was approved for advanced EC based on significantly improved OS, PFS, and ORR over chemotherapy in the second-line setting.

Mechanism of Action

Lenvatinib inhibits multiple pro-angiogenic and oncogenic RTKs involved in tumor growth, including VEGFR1-3, FGFR1-4, PDGFRα, KIT, and RET. It directly inhibits tumor cell proliferation in vitro and decreases tumor-associated macrophages, while increasing cytotoxic T cells in vivo. The combination of lenvatinib and everolimus showed enhanced antiangiogenic and antitumor activity in preclinical models. Lenvatinib does not prolong the QT interval at therapeutic doses.

Pharmacokinetics

After oral administration, lenvatinib is rapidly absorbed with peak plasma levels achieved in 1-4 hours. Exposure increases dose-proportionally over 3.2 to 32 mg daily dosage. Steady state is achieved after 2 weeks of daily dosing with minimal accumulation. It is highly bound to plasma proteins, mainly albumin. Lenvatinib undergoes extensive hepatic metabolism via CYP3A4 and aldehyde oxidase (AO). Elimination is primarily via feces (two-thirds) with one-fourth excreted in urine.

Dosing and Administration

The recommended starting dose is 24 mg once daily for DTC, 20 mg plus pembrolizumab 200 mg Q3W for RCC and EC, 18 mg plus everolimus 5 mg daily for RCC post VEGF therapy, and 8-12 mg once daily based on body weight for HCC. Dose adjustments may be required based on individual safety and tolerability. For toxicity management, lenvatinib should be interrupted, dose reduced, or discontinued as necessary. Upon improvement/resolution, treatment can be resumed at a reduced dose.

Clinical Uses

Differentiated Thyroid Cancer

In the pivotal SELECT trial, lenvatinib demonstrated significantly improved PFS (18.3 vs 3.6 months), ORR (64.8% vs 1.5%), and median time to progression (15.1 vs 3.6 months) versus placebo in RAI-refractory DTC.
The response consisted of both partial and complete responses.
Lenvatinib led to rapid and durable tumor shrinkage in the majority of responders.
Based on these findings, Lenvatinib Mesilate became the first TKI approved for RAI-refractory DTC.

Renal Cell Carcinoma

Study 205 showed lenvatinib plus everolimus improved PFS (14.6 vs 5.5 months), ORR (43% vs 27%), and median OS (25.5 vs 15.4 months) compared to everolimus alone in the second-line RCC setting after VEGF-targeted therapy.
In the first-line setting, Study 307 demonstrated lenvatinib plus pembrolizumab led to significantly longer PFS (23.9 vs 9.2 months) and OS (not reached vs 35.7 months) compared to sunitinib.
ORR was also nearly double with lenvatinib plus pembrolizumab compared to sunitinib (71.0% vs 36.1%).
These findings established lenvatinib plus pembrolizumab as a new first-line standard for advanced RCC.

Hepatocellular Carcinoma

In the REFLECT trial, lenvatinib showed statistically significant improvement in OS compared to sorafenib (13.6 vs 12.3 months) in unresectable HCC.
PFS (7.4 vs 3.7 months), TTP (8.9 vs 3.7 months), and ORR (24% vs 9%) were also significantly improved.
This was the first positive phase 3 trial establishing an alternative to sorafenib for first-line HCC.

Endometrial Carcinoma

Study 309 investigated lenvatinib plus pembrolizumab versus chemotherapy (doxorubicin or paclitaxel) in advanced EC after prior systemic therapy.
The lenvatinib plus pembrolizumab arm showed significantly prolonged OS (17.4 vs 12 months), PFS (6.6 vs 3.8 months), and ORR (32% vs 15%).
These results led to the first immunotherapy-TKI combination approved for advanced EC.

Safety Profile

The most common adverse reactions are hypertension, diarrhea, decreased appetite, decreased weight, nausea, fatigue, vomiting, and proteinuria.
Serious risks include hepatic impairment, arterial thromboembolic events, hemorrhage, gastrointestinal perforation/fistula, QT interval prolongation, hypocalcemia, reversible posterior leukoencephalopathy syndrome, impaired wound healing, and osteonecrosis of the jaw.
Intensive blood pressure control is required and dose interruptions or adjustments may be necessary to manage toxicity.

Place in Cancer Therapy

Lenvatinib provides a novel targeted therapy option for RAI-refractory DTC, advanced RCC, unresectable HCC, and advanced EC.
It has shown proven efficacy for tumors refractory to radioiodine, antiangiogenic agents, immunotherapy, and chemotherapy.
The combination with everolimus or pembrolizumab allows Lenvatinib Mesilate to be integrated with other standard therapies for enhanced efficacy in RCC and EC.
Further studies are underway investigating lenvatinib in other solid tumor types and combination regimens.
With its multitargeted mechanism, lenvatinib is poised to continue expanding its role in precision cancer medicine.

In summary, lenvatinib is an oral TKI targeting VEGFR, FGFR, and other pro-oncogenic pathways to inhibit tumor angiogenesis and proliferation. It is approved for RAI-refractory DTC, RCC, HCC, and EC based on significant efficacy and survival benefits shown in phase 3 trials. While lenvatinib has a distinct toxicity profile requiring close monitoring and management, its emergence as a new standard of care across multipletumor types highlights the promise of precision therapy targeting key vulnerabilities in refractory cancers.