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Ref Type Journal Article
PMID (31186313)
Authors Kurzrock R, Ball DW, Zahurak ML, Nelkin BD, Subbiah V, Ahmed S, O'Connor A, Karunsena E, Parkinson RM, Bishop JA, Ha Y, Sharma R, Gocke CD, Zinner R, Rudek MA, Sherman SI, Azad NS
Title A Phase I Trial of the VEGF Receptor Tyrosine Kinase Inhibitor Pazopanib in Combination with the MEK Inhibitor Trametinib in Advanced Solid Tumors and Differentiated Thyroid Cancers.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 25
Issue 18
Date 2019 Sep 15
URL
Abstract Text Differentiated thyroid cancer (DTC) responds to VEGF receptor inhibitors. VEGF signals through RAS/RAF/MEK signaling. We evaluated the safety and efficacy of the VEGF receptor inhibitor pazopanib and MEK inhibitor trametinib in advanced solid tumors and DTC.Patients with advanced solid tumors were enrolled in a phase I, multicenter 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 6 months of treatment.Twenty-six patients were enrolled in five dose levels. MTD was not reached; the recommended phase II dose was pazopanib 800 mg orally and trametinib 2 mg orally every day. 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% confidence interval, 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 (Spearman ρ = -0.71; P = 0.05). NRAS mutation was associated with response (Fisher exact P = 0.008).Pazopanib + trametinib was tolerable at full single-agent doses with clinical activity in DTC but did not achieve the prespecified response rate target.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown Advanced Solid Tumor not applicable Pazopanib + Trametinib Phase I Actionable In a Phase I trial, combination treatment with Votrient (pazopanib) and Mekinist (trametinib) was tolerable and resulted in partial response in 12% (3/25), and stable disease in 72% (18/25) of patients with advanced solid tumors, and 9 patients remained on study for more than 6 cycles, including patients with differentiated thyroid cancer (n=3), colorectal cancer (n=2), melanoma (n=1), cholangiocarcinoma (n=1), ovarian cancer (n=1), and synovial cell sarcoma (n=1) (PMID: 31186313; NCT01438554). 31186313
Unknown unknown differentiated thyroid gland carcinoma not applicable Pazopanib + Trametinib Phase I Actionable In a Phase I trial, treatment with the combination of Votrient (pazopanib) and Mekinist (trametinib) was tolerable and resulted in an objective response rate of 33% (4/12, all partial responses), stable disease in 50% (5/12), a median progression-free survival (PFS) of 10.7 months, a 2-year PFS of 25%, and a median overall survival of 29.3 months in patients with differentiated thyroid cancer in the dose expansion cohort (PMID: 31186313; NCT01438554). 31186313
NRAS mutant differentiated thyroid gland carcinoma predicted - sensitive Pazopanib + Trametinib Phase I Actionable In a Phase I trial, of 10 differentiated thyroid cancer patients, 3 of 3 responders (all partial responses) to treatment with the combination of Votrient (pazopanib) and Mekinist (trametinib) harbored NRAS mutations, while none of the seven patients with stable disease or progressive disease had NRAS mutations (PMID: 31186313; NCT01438554). 31186313