Combination therapy with pazopanib and tivantinib modulates VEGF and c-MET levels in refractory advanced solid tumors

Area of Science:

• Oncology
• Molecular Biology
• Clinical Pharmacology

Background:

• Vascular endothelial growth factor (VEGF)/VEGFR and hepatocyte growth factor (HGF)/c-MET pathways synergize in angiogenesis.
• VEGF inhibition may increase phosphorylated c-MET, potentially causing chemoresistance by bypassing VEGF-mediated angiogenesis.

Purpose of the Study:

• To evaluate the safety, pharmacokinetics, and pharmacodynamics of combining pazopanib (VEGF inhibitor) with tivantinib (c-MET inhibitor).
• To assess the impact of this combination on VEGF, VEGFR2, HGF, and c-MET levels in patients with refractory solid tumors.

Main Methods:

• Phase 1 clinical trial involving 32 patients with refractory solid tumors across 5 dose levels.
• Patients received pazopanib and tivantinib combination therapy, with some undergoing an initial pazopanib-only phase with paired tumor biopsies.
• Safety, pharmacokinetics, pharmacodynamics, and circulating/tumor biomarker levels were assessed.

Main Results:

• Hypertension was the most frequent adverse event; the maximum tolerated dose was not reached.
• Twenty of 31 evaluable patients achieved stable disease, with durations up to 22 cycles.
• Tumor c-MET levels (total and phosphorylated) decreased in most patients after 7 days of pazopanib treatment, contrasting with prior reports.

Conclusions:

• The combination of pazopanib and tivantinib demonstrated clinical activity and was generally well-tolerated in patients with refractory solid tumors.
• The observed decrease in tumor c-MET levels challenges previous findings suggesting c-MET elevation upon VEGF inhibition.
• Further investigation into the interplay between VEGF and c-MET signaling in solid tumors is warranted.