Results of randomized phase II trial of dabrafenib versus dabrafenib plus trametinib in BRAF-mutated papillary thyroid carcinoma.

Abstract

6022 Background: BRAF mutations are present in ~44% of papillary thyroid carcinoma (PTC) and its role in development of PTC is well established. We hypothesized that dabrafenib (BRAF inhibitor) would have efficacy in BRAF mutated PTC and that combining it with trametinib (MEK inhibitor) would result in greater clinical efficacy than dabrafenib alone, through vertical inhibition of the RAF/MAP/ERK pathway and mitigation of potential mechanisms of resistance. Methods: Patients (pts) with BRAF mutated radioiodine refractory PTC who had evidence of disease progression within 13 months prior were randomized to Arm A (dabrafenib 150 mg PO BID) or Arm B (dabrafenib 150 mg PO BID + trametinib 2 mg PO qd). Cross-over to Arm B was allowed at time of progression. Responses were assessed by modified RECISTv1.1 every 2 months. Primary endpoint was objective response rate (ORR) (complete-, partial- and minor-response). With assumed true ORR of 15% vs 35%; and 90% power to identify the correct regimen as most promising, 26 pts were to be accrued in each Arm. Results: In this randomized phase 2 trial, 53 pts (median age 63 years, 38 females) were enrolled; 25% of pts had 1-3 prior therapy with multi-kinase inhibitors. Median follow up was 13 months. Preliminary efficacy results are outlined in Table. The treatment-related adverse events were similar to previously reported phase III clinical trial of these drugs in melanoma. Conclusions: Single agent dabrafenib, as well as combination of dabrafenib/trametinib are well tolerated therapies that result in similar high objective response rates with durable responses in pts with progressive BRAF-mutated PTC. BRAF-pathway targeted therapies provide novel treatment options. Clinical trial information: NCT01723202. [Table: see text]