Pembrolizumab, Dabrafenib, and Trametinib Before Surgery for the Treatment of BRAF-Mutated Anaplastic Thyroid Cancer

PRIMARY OBJECTIVES: I. Demonstrate the efficacy of upfront treatment with neoadjuvant pembrolizumab in combination dabrafenib and trametinib by comparing the complete gross surgical resection rate (R0 or R1 surgical resection) to historical control of 5%. II. Demonstrate the efficacy of pembrolizumab in combination with dabrafenib and trametinib by comparing the overall survival (OS) to historical OS rate of 9.6 months. SECONDARY OBJECTIVES: I. Assess the efficacy (Response Evaluation Criteria in Solid Tumors \[RECIST\]) of neoadjuvant dabrafenib, trametinib, and pembrolizumab combination (Part 1) and progression-free survival (PFS) for all patients throughout their treatment course. II. Demonstrate the extent to which neoadjuvant dabrafenib, trametinib, and pembrolizumab changes surgical morbidity/complexity. III. Establish surgical safety for neoadjuvant pembrolizumab in combination with BRAF \& MEK inhibitors, dabrafenib and trametinib; as well as safety for concurrent administration of postoperative adjuvant pembrolizumab with intensity modulated radiation therapy (IMRT). VI. Evaluate changes in patient reported outcomes: quality of life assessed by validated questionnaires at initial diagnosis, through the course of therapy, and during the adjuvant targeted therapy phase. VII. Determine whether features of the tumor genomic landscape and tumor immune microenvironment are associated with response to dabrafenib/trametinib/pembrolizumab (DTP). EXPLORATORY OBJECTIVES: I. Determine if changes of cell free deoxyribonucleic acid (DNA) correlate with response to treatment on DTP and overall survival. II. Evaluate the safety of dabrafenib/trametinib/pembrolizumab plus IMRT in a subset of 15 patients. OUTLINE: PART 1 (NEOADJUVANT PHASE): Patients receive dabrafenib orally (PO) twice daily (BID) and trametinib PO once daily (QD) on days 1-21. Starting in week 4, patients also receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 21 days for 3 cycles in the absence of disease progression or unacceptable toxicity. Patients may receive 2 additional cycles of DTP at the discretion of the treating physicians. Patients whose disease is deemed resectable undergo surgery. Patients who are not surgically resectable after 5 cycles of DTP move to Part 3. PART 2 (ADJUVANT PHASE): 2-4 weeks after surgery and at the discretion of the treating physicians, patients may continue to receive pembrolizumab IV over 30 minutes every 3 weeks and concurrently undergo IMRT with or without cisplatin or carboplatin for 6 weeks. Up to 15 patients also receive dabrafenib PO BID and trametinib PO QD concurrently for 6 weeks. PART 3: Patients receive dabrafenib PO BID, trametinib PO QD on days 1-21, and pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for 17 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months during years 1-2, every 6 months during years 3-4, and then annually thereafter.