A Study of Avutometinib and Defactinib in People With Thyroid Cancer

Inclusion Criteria: Cohort A will enroll RAIR, R/M DTC patients with RAF dimer-driven disease. Cohort B will enroll ATC patients with RAF dimer-driven disease. * Cohort A only: Patients must have pathologically or cytologically confirmed differentiated thyroid cancer of follicular origin (including papillary thyroid carcinoma, follicular thyroid carcinoma, hurthle cell carcinomas, poorly differentiated thyroid carcinoma and their respective variants). * Cohort B only: Patients must have anaplastic thyroid carcinoma. * Confirmation in a CLIA certified laboratory that one of the patient's thyroid tumors (primary tumor, recurrent tumor, or metastases) possess at least one of the following genetic alterations: RAS mutation, NF1 mutation, RET rearrangement, NTRK rearrangement, ALK rearrangement, Class 2 or 3 BRAF alterations (non-V600E/K mutations or rearrangements). * Cohort A only: Evidence of progressive disease (e.g. presence of new or growing lesion(s) on radiologic imaging and/or new or worsening tumor-related symptoms) within 14 months of study enrollment. * Cohort A only: Patients must have recurrent or metastatic disease not amenable to curative surgery or radiation. * Patients with any number of prior therapies will be eligible. * Patients must have RECIST v1.1 measurable disease. * Age ≥ 18 years. * ECOG performance status of 0 or 1. * For Cohort A only: Patients must have not had recent treatment for thyroid cancer as defined as: * No prior RAI therapy is allowed…