Vemurafenib and Cobimetinib for the Treatment of Patients With High Risk Differentiated Thyroid Carcinoma With BRAFV600E Mutation

Inclusion Criteria: * Documented informed consent of the participant and/or legally authorized representative * Willingness to be followed for about 14 months * Males or females aged ≥ 18 years at the time of informed consent * Patients with thyroid carcinoma of follicular origin (papillary, follicular or Hurthle cell) * Known positive BRAFV600E mutation (determined on a previous analysis and/or on a representative formalin-fixed paraffin embedded (FFPE) tumor samples or on a biopsy sample) * High risk for recurrence according to the American Thyroid Association (ATA) guideline defined as having one or more of the features below: * Gross extrathyroidal extension * FTC with extensive vascular invasion (\> 4), although less likely to have BRAF mutation * PTC with vascular invasion * Advanced nodal disease of (any node \>3 cm, \> 4 nodes, or extra-nodal extension) * BRAF+TERT promoter mutation * Post op thyroglobulin (TG) suggestive of distant metastasis * Distant metastatic sites (only for exploratory arm) * Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 * Blood pressure (BP) ≤ 140/90 mm Hg at screening with or without antihypertensive medications and no change in antihypertensive medications within 1 week prior to treatment start * Creatinine clearance ≥ 50 mL/min according to the Cockcroft and Gault formula * Absolute neutrophil count (ANC) ≥ 1.5 x 109/L * Hemoglobin ≥ 9.0 g/dL * Platelet count ≥ 100 x 109/L * Normal blood coagulation function as evidenced by an International Normalized Ratio (INR) ≤ 1.5 * Bilirubin ≤ 1.5 × upper limit of normal (ULN) except for unconjugated hyperbilirubinemia or Gilbert's syndrome * Alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤ 3 × ULN (≤ 5 × ULN if subject has liver metastases) * Women of childbearing potential must have a negative urine or serum β-HCG pregnancy test within 7 days prior to the administration of the first study treatment * Agreement by women of childbearing potential (WOCBP) and males of childbearing potential\* to use an effective\*\* method of birth control\*\* for at least 3 months prior to screening through 1 year of study follow-up. * Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for \> 1 year (women only) * Effective birth control defined as hormonal and/or barrier contraception * Non-English speaking persons and adults lacking capacity to consent are not excluded from participation Exclusion Criteria: * Prior RAI treatment * Prior anti-BRAF, anti-MEK treatment such as sorafenib, dabrafenib, vemurafenib, encorafenib, binimetinib, cobimetinib, trametinib, d selumitinib and other TKIs like, lenvatinib, sunitinib, axitinib, cabozantenib, vandatinib, pazopanib use * Low to intermediate risk differentiated thyroid cancer (DTC) cases (not having the high-risk features as described above) * RAI contraindication * Undifferentiated or Medullary (MTC) carcinoma of the thyroid * Major surgery within 4 weeks prior to the first dose of treatment * Subjects having \> 1 + proteinuria on urine dipstick testing will undergo 24 h urine collection for quantitative assessment of proteinuria. Subjects with urine protein ≥ 1 g/24 h will be ineligible * Need for locoregional treatment such as surgery, external beam radiation or thermoablation at inclusion * External beam radiation, for thyroid cancer, \<4 weeks prior initiation of treatment * Gastrointestinal malabsorption or any other condition that in the opinion of the investigator might affect the absorption of the drugs * History of congestive heart failure greater or equal to than New York Heart association (NYHA) Class II, unstable angina, myocardial infarction, or stroke within 6 months of the first dose of treatment, or cardiac arrhythmia associated with significant cardiovascular impairment and uncontrolled hypertension * Electrocardiogram (ECG) with QT interval (QTc) interval ≥ 480 msec * Active hemoptysis (bright red blood of at least 0.5 teaspoon) within 2 months prior to the first dose of treatment and any other active bleeding, coagulopathy or pathologic condition that would confer a high risk of bleeding * Active infection requiring systemic therapy * Active malignancy (except for DTC, or definitively treated melanoma in-situ, basal or squamous cell carcinoma of the skin, or carcinoma in-situ of the cervix or bladder) within the past 24 months * Any history of or concomitant medical condition that, in the opinion of the investigator, would compromise subject's ability to safely complete the protocol * Females who are pregnant or breastfeeding * Patients with an injection of radio-contrast agent within 12 weeks prior to enrollment (can be enrolled after 12 weeks) * Previous history of retinal vein occlusion * Previous history of central serious retinopathy * Known hypersensitivity to the study drugs or to any of the excipients * Any other condition (including psychosocial condition) that would, in the Investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures * Any other condition that would confound study results * Noncompliance * Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)