Dabrafenib and Trametinib Treatment in Patients With Locally Advanced or Metastatic BRAF V600–Mutant Anaplastic Thyroid Cancer

Abstract

We report the efficacy and safety of dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) combination therapy in BRAF V600E-mutated anaplastic thyroid cancer, a rare, aggressive, and highly lethal malignancy with poor patient outcomes and no systemic therapies with clinical benefit. MethodsIn this phase II, open-label trial, patients with predefined BRAF V600E-mutated malignancies received dabrafenib 150 mg twice daily and trametinib 2 mg once daily until unacceptable toxicity, disease progression, or death. The primary end point was investigator-assessed overall response rate. Secondary end points included duration of response, progression-free survival, overall survival, and safety. ResultsSixteen patients with BRAF V600E-mutated anaplastic thyroid cancer were evaluable (median follow-up, 47 weeks; range, 4 to 120 weeks). All patients had received prior radiation treatment and/or surgery, and six had received prior systemic therapy. The confirmed overall response rate was 69% (11 of 16; 95% CI, 41% to 89%), with seven ongoing responses. Median duration of response, progression-free survival, and overall survival were not reached as a result of a lack of events, with 12-month estimates of 90%, 79%, and 80%, respectively. The safety population was composed of 100 patients who were enrolled with seven rare tumor histologies. Common adverse events were fatigue (38%), pyrexia (37%), and nausea (35%). No new safety signals were detected. ConclusionDabrafenib plus trametinib is the first regimen demonstrated to have robust clinical activity in BRAF V600E-mutated anaplastic thyroid cancer and was well tolerated. These findings represent a meaningful therapeutic advance for this orphan disease.

Unique mutation patterns in anaplastic thyroid cancer identified by comprehensive genomic profiling

“…Combination therapy with BRAF and MEK inhibitors has been tested in BRAF V600E ‐mutated ATC . The combination of dabrafenib and trametinib thus represents the first approved targeted therapy option for ATC patients in the United States.…”

“…Indeed, molecularly targeted therapies administered to patients with ATC harboring TSC1/2, ALK, or BRAF genomic alterations (GAs) have yielded exceptional responses. By accurately describing the prevalence of genetic abnormalities present in ATC, clinical trials targeting GA can be designed.…”

First-Line Treatment of Widely Metastatic BRAF-Mutated Salivary Duct Carcinoma With Combined BRAF and MEK Inhibition

“…18 Most recently, the FDA also approved the use of dabrafenib and trametinib in the treatment of anaplastic thyroid carcinoma harboring a BRAF V600E mutation, which represents up to 50% of these tumors overall. 19 Responses to targeted therapies have generally been better with fewer prior lines of treatment, and recent trials have shown that BRAF -directed therapy may be used upfront as adjuvant therapy in resected stage III melanoma 20 and as first-line therapy in metastatic NSCLC. 21 Although BRAF V600 mutations are much less common in other malignancies, cases demonstrating the efficacy of combined BRAF and MEK inhibition have been reported in a number of other diverse cancers, including high-grade colorectal neuroendocrine tumors, 22 papillary thyroid carcinoma, 23 and endometrial cancer.…”

Anaplastic thyroid carcinoma: review of treatment protocols

“…In single case reports, impressive response to BRAF inhibitors vemurafenib (Rosove et al 2013, Marten & Gudena 2015, Prager et al 2016, dabrafenib combined with MEK-Inhibitor trametinib (Agarwal et al 2016), ALK-inhibitor crizotinib (Godbert et al 2015) and the mTOR-Inhibitor everolimus (Wagle et al 2014) were reported. Very recently, a phase II trial including 16 BRAFV600E-positive ATC patients reported an overall response rate of 69% when patients were treated with the dabrafenib in combination with trametinib (Subbiah et al 2017). An overview is given in Table 1.…”