cabozantinib

Overview

Cabozantinib is a small-molecule, multi-target tyrosine kinase inhibitor (TKI) that exerts its therapeutic effects primarily through inhibition of vascular endothelial growth factor receptors (VEGFRs), MET (hepatocyte growth factor receptor), AXL, and RET, among other kinases. Originally developed by Exelixis and approved by the U.S. Food and Drug Administration, cabozantinib is clinically indicated for the treatment of advanced renal cell carcinoma (RCC), hepatocellular carcinoma, and medullary thyroid cancer. By simultaneously blocking multiple oncogenic signaling axes — notably the VEGFR-driven angiogenesis pathway and the MET pathway implicated in tumor invasiveness and resistance — cabozantinib disrupts tumor growth, metastatic spread, and immune evasion in a coordinated manner.

Beyond its established role in oncology, emerging research has begun to reveal previously unrecognized biological activities for cabozantinib, including modulation of innate immune cell death pathways. Its broad kinase inhibitory profile positions it as a candidate for drug repurposing, extending potential therapeutic applications into inflammatory and immune-mediated diseases.

Focus of Latest Publications

Recent publications on cabozantinib have focused primarily on its use in renal cell carcinoma, especially in combination regimens and in difficult-to-treat disease settings. In a nationwide multicenter retrospective cohort study from the Republic of Korea, cabozantinib plus nivolumab was evaluated in 62 patients with advanced non-clear cell renal cell carcinoma across multiple lines of therapy, most commonly in the first-line setting. The combination produced an objective response rate of 45.2% and a disease control rate of 93.6%, with responses observed across several histologic subtypes, including papillary, FH-deficient, TFE3-rearranged, chromophobe, collecting duct, and unclassified tumors. Median progression-free survival was 9.7 months and median overall survival was 22.0 months, while grade 3-4 treatment-emergent adverse events occurred in 46.8% of patients and toxicity-related discontinuation in 6.5%.

Additional renal cancer studies have examined cabozantinib in other clinically challenging contexts. A phase II trial, CABRAMET, assessed cabozantinib in patients with non-locally pretreated brain metastases from renal cell carcinoma, aiming to generate prospective data in a setting with historically limited treatment options. Another real-world study compared pembrolizumab plus lenvatinib with nivolumab plus cabozantinib in Japanese patients with metastatic renal cell carcinoma, reflecting ongoing interest in defining the relative effectiveness and safety of first-line combination strategies. Separately, a pharmacovigilance study was initiated to explore sex-specific adverse events and cardiovascular toxicity associated with cabozantinib in renal cell carcinoma, highlighting continued attention to its real-world safety profile.

Outside renal cancer, cabozantinib has also been used as a type II MET inhibitor in a case of metastatic non-small cell lung cancer with a KIF5B::MET fusion. After progression on chemotherapy and immunotherapy, the patient developed acquired MET resistance mutations on ctDNA analysis and was switched to cabozantinib, which led to radiographic disease stabilization and a marked decline in tumor marker levels. In a separate mechanistic and translational study, cabozantinib was repurposed as an inhibitor of necroptosis by blocking MLKL oligomerization, and it reduced epidermal hyperplasia and inflammatory cytokine expression in an imiquimod-induced psoriasis mouse model. Another publication described casdatifan, a HIF-2α inhibitor, noting promising clinical activity in combination with cabozantinib and ongoing phase 3 evaluation of that combination in advanced clear cell renal cell carcinoma.