Combination of dabrafenib (DAB).

Abstract

6085Background: BRAFV600E mutations (BRAFm) are the most common mutations in thyroid cancer. BRAF inhibitors are active in BRAFm melanoma, but there is less activity noted in BRAFm thyroid cancer. Preclinically, BRAF inhibitors inhibit BRAFm thyroid cancers only transiently due to activation of HER2/HER3, driven by a neuregulin-dependent autocrine loop. The addition of LAP, a HER2/HER3 kinase inhibitor, sensitizes the cell to growth suppression by BRAF inhibitors (Cancer Discov 5(3):520, 2013). A phase I study evaluating the combination of DAB, a BRAF inhibitor, and LAP was initiated to evaluate the safety and pharmacodynamic changes the combination. Methods: Eligibility included thyroid cancers with the presence of a BRAFV600E mutation. Any prior treatment was allowed. All patients received DAB 150 mg bid starting 2 weeks prior to LAP. Doses of daily lapatinib were escalated in a standard 3+3 design at (1) 750 mg; (2) 1250 mg; (3) 1500 mg. Toxicities, including Dose Limiting Toxicities (DLT), were noted ...