Inclusion Criteria:
* Histologically or cytologically confirmed anaplastic thyroid cancer, AJCC 8th Edition Stage IVB-C.
* Disease must be deemed unresectable, or resectable only with unacceptable functional morbidity (e.g., requiring total laryngectomy, total pharyngectomy, or extensive aerodigestive resection), as determined by multidisciplinary tumor board consensus.
* BRAF-V600E positive by IHC.
* Measurable disease per RECIST 1.1.
* At least 18 years of age.
* ECOG performance status ≤ 2 (Karnofsky ≥ 60%)
* Adequate bone marrow and organ function as defined below:
* Absolute neutrophil count ≥ 1.5 K/cumm
* Platelets ≥ 100 K/cumm
* Hemoglobin ≥ 9.0 g/dL
* Total bilirubin ≤ 1.5 x IULN
* AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN
* Creatinine clearance \> 30 mL/min by Cockcroft-Gault
* Ability to swallow pills or have percutaneous enteric access (G-tube or J-tube) allowing for administration of dabrafenib-trametinib pills.
* Dabrafenib and trametinib are known teratogenic agents, and dabrafenib can render hormonal contraceptives ineffective. For this reason, women of childbearing potential and men must agree to use adequate contraception prior to study entry, for the duration of study participation, and for 2 weeks after the last dose of dabrafenib or 4 months after the last dose of trametinib, whichever dose is later. Should a woman become pregnant or suspect she is pregnant while participating in this study or should a man suspect he has fathered a child, s/he must inform the treating physician immediately.
* Ability to understand and willingness to sign an IRB approved written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants.
Exclusion Criteria:
* Prior radiation therapy to the head and neck or spinal cord.
* Prior systemic therapy for thyroid cancer.
* Prior immunotherapy for any indication.
* Prior or concurrent malignancy whose natural history has the potential to interfere with the safety or efficacy assessment of the investigational regimen. Patients with prior or concurrent malignancy that does NOT meet that definition are eligible for this trial
* Patients with endoluminal (intraluminal/transmural) invasion of the trachea or esophagus by the primary tumor, as determined by cross-sectional imaging or endoscopy, are excluded. Tumor abutment of, or radiographic contact with, the tracheal or esophageal wall without endoluminal extension does not, by itself, meet this exclusion.
* Currently receiving any other investigational agents.
* A history of allergic reactions attributed to compounds of similar chemical or biologic composition to dabrafenib, trametinib, pembrolizumab, or other agents used in the study.
* Use of any strong inhibitors of CYP3A4 or CYP2C8, or sensitive substrates of CYP3A4, CYP2C8, CYP2C9, CYP2C19, or CYP2B6, within 7 days prior to enrollment and during the course of this study.
* Uncontrolled intercurrent illness including, but not limited to: ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia. Patients with a known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Function Classification; to be eligible for this trial, patients should be a class 2B or better.
* Active autoimmune disease that has required systemic treatment in past 2 years (i.e. - with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment.
* Prior allogeneic tissue/solid organ transplant.
* Use of any immunosuppressive medications within 7 days prior to enrollment.
* Use of live or live attenuated vaccines within 30 days prior to enrollment.
* Pregnant and/or breastfeeding. Women of childbearing potential must have a negative serum or urine pregnancy test within 5 days prior to enrollment.
* HIV-infected if not on effective anti-retroviral therapy with undetectable viral load for 6 months. Patients with HIV who are receiving effective anti-retroviral therapy and have had an undetectable viral load for at least 6 months are eligible. HIV testing not required in the absence of known history of infection.
* Evidence of chronic hepatitis B virus (HBV) that is detectable on suppressive therapy. Patients with evidence of chronic HBV infection with undetectable HBV viral load on suppressive therapy are eligible. HBV testing not required in the absence of known history of infection.
* History of hepatitis C virus (HCV) infection that has not been cured or that has a detectable viral load. Patients with a history of HCV that has been treated and cured are eligible. Patients with HCV infection who are currently on treatment and have an undetectable HCV viral load are eligible. HCV testing not required in the absence of known history of infection.
