Expert Consensus on the Clinical Application of Multi-Target Anti-Cancer Drug Cabozantinib
1. Background and Molecular Characteristics of Drug Development
Cabozantinib (Cabozantinib, trade name Cabometyx) is an innovative multi-target tyrosine kinase inhibitor developed by Exelixis, a biopharmaceutical company in the United States. The drug was first approved by the U.S. Food and Drug Administration (FDA) on November 29, 2012, for the treatment of progressive metastatic medullary thyroid carcinoma (MTC), marking a significant breakthrough in targeted therapy for malignant tumors.
From a molecular structure perspective, cabozantinib is a small molecule quinoline compound whose unique chemical structure allows it to simultaneously target multiple receptor tyrosine kinases closely related to tumor occurrence and development. Studies have shown that cabozantinib significantly inhibits several key signaling pathways including MET, VEGFR1/2/3, RET, ROS1, AXL, NTRK, KIT. This broad-spectrum inhibitory effect gives it a unique advantage in cancer treatment known as "one drug with multiple targets," which clinical experts vividly refer to as "the all-purpose drug among targeted therapies."
2. Pharmacological Mechanisms and Molecular Pathways
The anti-tumor effects of cabozantinib are primarily achieved through three key mechanisms: First, regarding tumor angiogenesis inhibition: cabozantinib effectively suppresses new blood vessel formation by specifically blocking the activity of vascular endothelial growth factor receptors (VEGFR1/2/3). The VEGFR signaling pathway is central to tumor angiogenesis regulation; its inhibition can significantly reduce blood supply to tumor tissues thereby limiting their growth and spread. Secondly, concerning direct suppression of tumor cell proliferation: cabozantinib interferes with pro-proliferative signal transduction within tumor cells by targeting receptor tyrosine kinases encoded by proto-oncogenes such as MET and RET. Overactivation of MET receptors is closely associated with aggressive growth in various malignancies while mutations in RET genes are important driving factors for MTC progression. Thirdly, regarding anti-tumor metastasis: cabozantinib reduces migration and invasion capabilities of tumor cells by inhibiting AXL receptor tyrosine kinase activity. AXL receptors belong to the TAM receptor family; their overexpression correlates strongly with distant metastasis and resistance formation in tumors. The multi-target synergistic action makes cabozantinib uniquely advantageous against tumor metastasis.
3. Clinical Indications and Evidence-Based Medicine Evidence
3.1 Renal Cell Carcinoma (RCC) In advanced renal cell carcinoma treatment field ,cabozatinibs efficacy has been validated through numerous pivotal clinical trials .METEOR study was an international multicenter randomized controlled phase III trial showing that median progression-free survival(PFS )in patients treated with cab oz antin ib reached7 .6 months ,significantly better than4 .4 months observed in everolimus control group(HR=0 .51,P<0 .001 ). In terms total survival(OS ),cab oz antin ib group also showed obvious advantages(21 .4months vs16 .5months ). nCABOSUN study further confirmed valueofcab oz antin ib intreatmentoffirst-line RCC.This research indicated comparedwith standard therapeutic agent sunitin ib,cab oz antin ib extended median PFS from5 .6monthsto8 .2months(HR=0 .66,P=0 ..012).Basedon these findings,NCCN guidelines have listedcab oz antin ibas first-lineand second-line optionsforadvanced RCCpatients. n3..2 Hepatocellular Carcinoma(HCC) nCELESTIALstudy evaluatedefficacyofcab ozantini binthe second-linetreatmentofadvancedH CC.In this globalphaseIIIclinicaltrial707previouslytreatedpatientswithsorafenibb were enrolled.Results revealedmedian OSincab oza nt ini bgroupwas10..2 monthssignificantly surpassingplacebo's8..0months(H R =0 ..76,P=0...0049).Moreover,inprogression-freesurvival,cab oza nt ini bgroupalso exhibitedremarkable superiority(5...2 monthsvs1...9 months). n3..3 Medullary Thyroid Carcinoma(M TC) nEXAMstudy servesascriticalregistrationresearchforcab oza ntini binmedullarythyroidcarcinomawherea randomizeddouble-blindplacebocontrolledphaseIIIclinicaltrialshowedthatcabo zanti nibextendedmedianPFSfrom11....1monthsofplacebogroupto26....6months(H R =0 ...28,P<0 ....001).Basinguponthisbreakthroughresult,c ab o za nti ni bbecamefirsttargeteddrugapprovedbyFDAfortreatingmetastaticmedullarythyroidcar cinoma... and so forth.