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**Casdatifan + cabozantinib** is an investigational oral combination regimen for the treatment of metastatic clear cell renal cell carcinoma (ccRCC). Casdatifan is a small molecule, allosteric inhibitor of hypoxia-inducible factor 2 alpha (HIF-2α), a transcription factor implicated in tumor growth and progression under hypoxic conditions. By binding to a specific hydrophobic pocket of HIF-2α, casdatifan disrupts its heterodimerization and DNA binding, suppressing oncogenic gene expression and cell proliferation[1][5][9]. Cabozantinib is a small molecule tyrosine kinase inhibitor (TKI) targeting multiple receptor tyrosine kinases involved in tumor cell survival, angiogenesis, and metastasis, including vascular endothelial growth factor receptors (VEGFR-1, -2, -3), MET, RET, KIT, FLT3, AXL, and TIE-2[4][6]. The combination is being evaluated for enhanced anti-tumor activity, particularly in patients previously treated for metastatic ccRCC, and has shown promising efficacy and manageable toxicity in early clinical trials[3][5][7].
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