Although the combination of the VEGF receptor inhibitor pazopanib and the MEK inhibitor trametinib was tolerated by patients with differentiated thyroid cancer (DTC), it did not meet the response rate target, according to the results of a phase 1 study published in Clinical Cancer Research.
“Molecularly targeted agents have had meaningful efficacy as single agents in multiple tumor types, but have not resulted in durable benefit due to resistance coming often from increased feedback signaling,” wrote authors, led by Razelle Kurzrock, The University of Texas MD Anderson Cancer Center, Houston. “We previously demonstrated that combination targeted therapy of VEGF signaling by signal transduction inhibitors inhibiting at the receptor level and downstream using MAPK kinase (MEK) inhibition was more effective than either drug alone in preclinical models of differentiated thyroid cancer (DTC).”
In the current study, patients were administered pazopanib 400-800 mg/day plus trametinib 1-2 mg/day. Objective response (OR) at 6 months was the primary outcome. In total, 26 patients received one of five dose levels.
Recommended phase 2 dosing for pazopanib was 800 mg/day by mouth and for trametinib was 2 mg/day by mouth, with MTD not reached. Grade 3 treatment-related adverse events included increased liver enzymes, diarrhea, hypertension, and fatigue. In the cohort, there was only one dose-limiting toxicity.
Median progression-free survival (PFS) was 10.7 months and OR was 33% (95% confidence interval, 9.9, 65.1%) in 13 patients comprising the DTC group. Kurzrock et al. closed the trial following a planned interim analysis due to limited evidence of combination activity compared with that of pazopanib alone. Of note, NRAS alteration was related to response, and the authors recommended that combined therapy be investigated in those with DTC molecular subsets.
Using combination targeted inhibition with progrowth signal transduction circuits has been effective in BRAF V600E–mutated metastatic melanoma and colorectal cancer. Because of its success with solid tumors, this approach was thought mechanistically sound by the authors in the current study.
“Inhibition at the signaling receptor level as well as downstream signaling proteins theoretically allows more potent inhibition of a given pathway and the potential to stymie compensatory feedback loops that result in resistance to molecularly targeted agents,” they wrote.
In an exclusive interview with Cancer Network, Jennifer Rui Wang, MD, ScM, Assistant Professor Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, provided some thoughts about the study.
“Kurzrock et al’s study is important because it provides evidence that mutation status influences responses to targeted therapy in thyroid cancer and suggests that future studies should consider mutation status as a part of the trial design,” she said.
In a separate interview with Cancer Network, Peter Oppelt, MD, medical oncologist, Siteman Cancer Center, Assistant Professor of Medicine, Washington University School of Medicine in St. Louis, had the following to say about the Kurzrock et al. study:
“We are nearing 5 years since lenvatinib was approved for the front line treatment of RAI refractory differentiated thyroid cancer, and there remains an enormous need for new treatment options, particularly in the second line setting and beyond. The work by Kurzrock and colleagues should be applauded for taking strong pre-clinical data to the patient in this Phase I study,” he said.
He continued, “The results of a combination of a VEGF inhibitor with a MEK inhibitor, however, had somewhat disappointing results in terms of response rates. In comparison, cabozantinib which targets VEGF and MET has recently demonstrated fairly promising results with a response rate of 40% in a population of patients who had proven refractory to at least 1 previous VEGF inhibitor and is moving forward in a Phase III trial.” 
1. Cabanillas ME et al. Cabozantinib As Salvage Therapy for Patients With Tyrosine Kinase Inhibitor–Refractory Differentiated Thyroid Cancer: Results of a Multicenter Phase II International Thyroid Oncology Group Trial. J Clin Oncol. 2017 Oct 10;35(29):3315-3321. doi: 10.1200/JCO.2017.73.0226. Epub 2017 Aug 17.
Source article: Kurzrock R et al. 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. Clin Cancer Res 2019;25:5475–84 doi: 10.1158/1078-0432.CCR-18-1881.