A phase II open-label trial in patients with BRAF V600E–mutated locally advanced or metastatic anaplastic thyroid cancer shows results with dabrafenib, a BRAF inhibitor, and trametinib, a MEK inhibitor. Data on efficacy and safety of the regimen, the first demonstrated to have clinical activity in this rare and aggressive cancer, have been recently published on The Journal of Clinical Oncology.
Anaplastic thyroid carcinomas are rare, highly aggressive, undifferentiated tumors with no systemic therapies with clinical benefit: response rates to standard systemic therapies are less than 15% and there are no curative options for patients who have exhausted locoregional therapies. Molecular profiling studies have begun to elucidate the molecular drivers associated with anaplastic thyroid cancer tumorigenesis: between 20% and 50% of them harbor activating BRAF V600 mutations, with unknown prognostic significance. To investigate the role of BRAF inhibition, in this trial sixteen 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. All patients had received prior radiation treatment and/or surgery, and six had received prior systemic therapy. The confirmed overall response rate was 69%; 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. Common adverse events were fatigue (38%), pyrexia (37%), and nausea (35%), with no new safety signals detected. «For most rare cancers, conventional drug development programs are not possible because of the low incidence of disease and the infeasibility of conducting a randomized controlled trial. These challenges may reduce the incentive to explore the potential benefit of new targeted therapies for rare cancers. An alternative, and likely more feasible approach, may be based on the detection of BRAF V600E mutations in these rare cancers as a common denominator for the investigation of BRAF plus MEK inhibition in well-defined patient populations», authors say. «Dabrafenib plus trametinib is a highly promising new combination targeted therapy for patients with BRAF V600E–mutated anaplastic thyroid cancer, demonstrating a high overall response rate, prolonged duration of response, and prolonged survival with manageable toxicity. This is the first regimen to demonstrate robust clinical activity in BRAF V600E–mutated anaplastic thyroid cancer: data indicate that tumor mutation screening should be performed for patients with anaplastic thyroid cancer as it has the potential to transform outcomes for these patients», authors conclude.