Inclusion Criteria:  Patients ≥18 years of age with advanced GIST (unresectable or metastatic). Must have at least progressed on imatinib or have documented intolerance to imatinib. Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. Patients must have a histologic diagnosis of GIST. If a female of childbearing potential, must have a negative pregnancy test. Adequate organ function and bone marrow function  Exclusion Criteria:  Received prior anticancer therapy within 14 days or 5× the half-life whichever is longer) prior to the first dose. Ongoing or prior participation in the DCC-2618-03-002 study. Prior therapy with ripretinib. Prior therapy with MEK inhibitor. History of certain ocular disorders. History of clinically significant hepatobiliary disease. Known active central nervous system metastases. History or presence of clinically relevant cardiovascular abnormalities. Systemic arterial or venous thrombotic or embolic events within 6 months of first dose. History of acute or chronic pancreatitis History of chronic inflammatory bowel disease or Crohn's disease requiring intervention within 12 months of first dose.  Gastrointestinal abnormalities including but not limited to:  inability to take oral medication, malabsorption syndromes