Please note this may not be a complete list of eligibility criteria. We have included a few examples of study criteria to help you better understand how your eligibility in the study will be determined; your study team will go through the study eligibility criteria with you to verify if you qualify for participation in this study.

Inclusion Requirements

You can participate in this study if you

• Patient must be equal or greater than 18 years of age

• Patient must have differentiated thyroid cancer (DTC) with BRAF V600E mutation as determined by local testing

• Patient must have been previously treated with or deemed ineligible for treatment with Iodine-131 for DTC, and must be receiving thyroxine suppression therapy

• Patient must have had prior treatment with at least one of the following vascular endothelial growth factor receptors (VEGFR)-targeting tyrosine kinase inhibitor (TKI) agents for DTC: lenvatinib or sorafenib

• Patient must have measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) 1·1 on chest CT (computed tomography)/abdominal/pelvis CT/MRI (magnetic resonance imaging) performed within 4 weeks prior to randomization

• Patient must have radiographic progression by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 over any time interval on or after most recent prior systemic treatment
• Patient must have completed any prior local therapy (e.g., surgery, radiation, ablation) at least 4 weeks prior to randomization, with complete wound healing and resolution of clinically relevant complications from prior local therapy

• Patient must not have had major surgery (e.g., GI surgery, removal or biopsy of brain metastasis) within 8 weeks prior to randomization. Complete wound healing from major surgery must have occurred 4 weeks prior to randomization and from minor surgery (e.g., simple excision, tooth extraction) at least 10 days prior to randomization

• Patient must not have had prior treatment with cabozantinib or any prior BRAF targeted therapy for thyroid cancer

• Patient must not be pregnant or breast-feeding due to the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used.

• Patient must have the ability to understand and the willingness to sign a written informed consent document. Patients with impaired decision-making capacity (IDMC) who have a legally authorized representative (LAR) or caregiver and/or family member available will also be considered eligible

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of randomization are eligible for this trial

• Patients with treated brain metastases are eligible if follow-up brain imaging obtained after central nervous system (CNS)-directed therapy (radiotherapy and/or surgery) shows no evidence of progression. CNS disease must be stable for at least 4 weeks prior to randomization; patients must be neurologically asymptomatic and without corticosteroid treatment at time of randomization

• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial

• Patient must be English or Spanish speaking to be eligible for the quality of life (QOL) component of the study.