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

Abstract

Purpose 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. Methods In 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. Results Sixteen 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. Conclusion Dabrafenib 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.

Trial registration: ClinicalTrials.gov NCT02034110.

Fig 1.

Maximum percent change from baseline in the sum of target lesion diameters in the anaplastic thyroid cancer intent-to-treat population. (A) Change from baseline in target lesion diameter was determined according to RECIST v1.1. The gray horizontal line indicates a 30% decrease, which is the minimum change needed to qualify for partial response according to RECIST. Best confirmed response (bar color) and best unconfirmed response (bar height) are as indicated. One patient experienced progression of disease in the brain at week 1 and, thus, a percent change could not be calculated. (*) An anaplastic thyroid cancer B-Raf kinase (BRAF) V600E mutation identified locally was not centrally confirmed in this patient. (B) Computed tomography scans of a representative patient with anaplastic thyroid cancer collected at baseline and after 8 weeks of treatment with dabrafenib plus trametinib. (Top) A patient presented with anaplastic thyroid cancer and symptomatic metastasis to the lung (grade 2 cough). The patient also had grade 2 dysphagia caused by a paratracheal mass and grade 2 dyspnea secondary to pericardial effusion (arrows indicate lesion locations). Cough and dyspnea both resolved after receiving dabrafenib plus trametinib combination therapy for 2 weeks. (Bottom) The size of all lesions was visibly reduced after 8 weeks of treatment.

Fig 2.

Treatment duration and time to events in individual patients with B-Raf kinase (BRAF) V600E–mutated anaplastic thyroid cancer. Data presented are the best investigator-assessed responses in the intent-to-treat population. Each bar denotes an individual patient, with bar length representing the duration of treatment and bar color denoting the best confirmed response. The blue arrowhead is positioned at the time of first radiologic response. The dagger denotes a patient in whom an anaplastic thyroid cancer BRAF V600E mutation that was identified locally was not centrally confirmed. The gray vertical line indicates the 12-month (52-week) time point. AE, adverse event.