The VEGF Receptor Tyrosine Kinase Inhibitor Pazopanib in Combination with the MEK Inhibitor Trametinib in Advanced Solid Tumors and Differentiated Thyroid Cancers

Purpose: Differentiated thyroid cancer (DTC) responds to vascular endothelial growth factor (VEGF) receptors inhibitors. VEGF signals through RAS/RAF/MEK signaling. We evaluated the safety and efficacy of VEGF receptor inhibitor pazopanib and MEK inhibitor trametinib in advanced solid tumors and DTC. Experimental Design: Advanced solid tumor patients were enrolled in a phase I, multi-center trial with a DTC expansion cohort. Patients received pazopanib 400-800 mg and trametinib 1-2 mg daily. Efficacy in the expansion cohort was assessed with objective response (OR) at six months of treatment. Results: Twenty-six patients were enrolled in 5 dose levels. Maximum tolerated dose was not reached; the recommended phase II dose was pazopanib 800 mg po and trametinib 2 mg po qd. There was one dose limiting toxicity on dose level 1 with grade 3 fatigue and muscle weakness. Common grade 3 adverse events were elevated transaminases(19%), diarrhea(15%), hypertension(12%), and fatigue(8%). Thirteen patients were enrolled in the DTC cohort; OR was 33% (95% CI: 9.9, 65.1%) and median progression-free survival was 10.7 months. The cohort was terminated after planned interim analysis suggested insufficiently increased activity against the historical control of pazopanib alone. Reduction in tumor diameter negatively correlated with p-ERK change in tumor (Spearman9s rho = -0.71; p = 0.05). NRAS mutation was associated with response (Fisher9s Exact p=0.008). Conclusions: Pazopanib+trametinib was tolerable at full single-agent doses with clinical activity in DTC but did not achieve the pre-specified response rate target.