Cabozantinib: Multi-kinase Inhibitor of MET, AXL, RET, and VEGFR2

Area of Science:

• Oncology
• Pharmacology

Background:

• Cabozantinib targets multiple receptor tyrosine kinases (RTKs), including MET, RET, AXL, and VEGFR2.
• RET mutations are key in medullary thyroid cancer (MTC) tumorigenesis, while MET and AXL mediate resistance to VEGFR-targeted therapy in renal cell cancer (RCC).

Purpose of the Study:

• To evaluate the efficacy of cabozantinib in preclinical tumor models and its clinical effectiveness in treating MTC and RCC.
• To assess cabozantinib's impact on metastasis, invasiveness, and patient outcomes, especially in RCC after VEGFR-TKI progression.

Main Methods:

• Preclinical studies assessed cabozantinib's activity across various tumor models.
• The METEOR phase III trial compared cabozantinib to everolimus in advanced RCC patients progressing after first-line VEGFR-TKI therapy.

Main Results:

• Cabozantinib demonstrated reduced metastasis and invasiveness compared to placebo or VEGFR-targeted agents lacking MET activity.
• In the METEOR trial, cabozantinib significantly improved survival (4.9 months) and response rates versus everolimus in RCC patients.
• Benefits were more pronounced in patients with bone metastases, who typically have a poorer prognosis.

Conclusions:

• Cabozantinib is a clinically approved TKI for MTC and second-line RCC, showing broad preclinical activity.
• Its dual inhibition of MET and AXL, alongside other targets, contributes to its efficacy in overcoming resistance mechanisms.
• Cabozantinib offers a significant therapeutic advantage in advanced RCC, particularly for patients with bone involvement.