lenvatinib

Overview

Lenvatinib is a multi-targeted tyrosine kinase inhibitor used in oncology, particularly in advanced liver cancer and other solid tumors. Its therapeutic relevance stems from inhibition of angiogenic and growth-factor signaling pathways, making it a clinically important antiangiogenic agent in settings where tumor vascularization and proliferative signaling contribute to disease progression. In the recent literature provided, lenvatinib is repeatedly discussed as a cornerstone therapy for unresectable hepatocellular carcinoma (HCC) and as a comparator or backbone for combination regimens in thyroid cancer, renal cell carcinoma, lung adenocarcinoma, and biliary tract malignancies.

Across these studies, lenvatinib is most often positioned within combination strategies involving anti-PD-1/PD-L1 monoclonal antibodies such as pembrolizumab, sintilimab, durvalumab, nivolumab, and cadonilimab, as well as locoregional therapy, hepatic arterial infusion chemotherapy, stereotactic body radiotherapy, and surgery. The overall research emphasis is on improving response rates, overcoming resistance, and enabling conversion therapy in unresectable disease.

Focus of Latest Publications

Recent studies have extensively evaluated lenvatinib in combination with immunotherapy agents across hepatocellular carcinoma and other malignancies. In unresectable HCC, triple-combination approaches—including lenvatinib with immunotherapy and chemotherapy or radiotherapy—have demonstrated promising efficacy. The HILL trial reported median progression-free survival of 15.8 months and 2-year overall survival of 94% with lenvatinib combined with FOLFOX-based hepatic arterial infusion chemotherapy and durvalumab, achieving objective response rates of 75% with a favorable safety profile. Conversion therapy studies using lenvatinib with the PD-1 inhibitor sintilimab showed successful conversion in 56% of patients with unresectable HCC, and among those achieving conversion, subsequent surgical resection yielded a 5-year survival rate of 73.9%. For advanced renal cell carcinoma, the CLEAR trial demonstrated lenvatinib plus pembrolizumab efficacy in East Asian patients, while real-world comparisons in Japanese RCC populations examined this regimen against nivolumab plus cabozantinib. However, a large comparative trial (CheckMate 9DW) found that nivolumab plus ipilimumab produced superior overall survival and response rates compared to lenvatinib or sorafenib as first-line therapy for unresectable HCC.

Multiple studies have identified mechanisms underlying lenvatinib resistance and strategies to overcome it. The RPRD1A-ITGA5-FAK signaling axis emerged as a key driver of lenvatinib resistance in HCC, with combined therapy using ITGA5 inhibitor volociximab or FAK inhibitor defactinib restoring drug sensitivity in preclinical models. Environmental exposure to the plasticizer DEHP was shown to induce epithelial-mesenchymal transition and reduce lenvatinib responsiveness through SPAG4-dependent MAPK/ERK signaling activation, effects reversible by SPAG4 silencing or MAPK/ERK inhibition. Lenvatinib also triggers adaptive ferroptosis resistance through an EGR1-ZNF768-SLC7A11 response, while lactate-driven lactylation of ABHD6 shifts the protein toward a mitochondrial scaffolding function that stabilizes hyperfused mitochondria and suppresses lenvatinib-induced apoptosis—a phenotype reversed by lactate inhibition or catalytic site occupation strategies.

Beyond HCC, lenvatinib demonstrated activity in other malignancies with variable comparative positioning. In anaplastic thyroid carcinoma, lenvatinib combined with pembrolizumab showed promising clinical outcomes in a real-world Italian case series. For intrahepatic cholangiocarcinoma, the GOLP regimen (gemcitabine-oxaliplatin, lenvatinib, and anti-PD-1 antibody) demonstrated efficacy with manageable safety as neoadjuvant therapy in high-risk resectable disease. In molecular-directed therapy, a multi-omics analysis of hepatitis B virus-associated HCC identified KX2-391, a dual SRC/ABL inhibitor, as superior to lenvatinib in preclinical models of high-risk disease. Biomarker-guided approaches in clear cell renal carcinoma revealed that patients with low FLT1-centered network expression showed improved immunotherapy responses, while high FLT1 expression may benefit from combination therapy targeting FLT1, Akt1, and VEGFA alongside conventional inhibitors.