GIST treatment options after tyrosine kinase inhibitors

The management of advanced gastrointestinal stromal tumor (GIST) has been dramatically altered by the development of tyrosine kinase inhibitors. The disease, which had a median overall survival of 12 months for patients with unresectable disease, now has a median survival approaching 5 or more years. The challenge faced clinically is how to care for patients when they have progressed on all approved therapies. Clinical trials evaluating the role of novel combination therapies with investigational agents that target AKT/PI3K pathways are of interest especially given the preclinical rationale available. The addition of an mTOR inhibitor can be tried as these are available, but requires care and monitoring for additional toxicities. With improved understanding of this disease, which we thought of as one biology, personalized therapies are being studied and tested and is particularly relevant for GIST that are less responsive to the standard kinase inhibitors, such as platelet-derived growth factor alpha (PDGFRA) D842V and wild-type/succinate dehydrogenase (SDH)-deficient GIST. IGF1R inhibitors as a class are not being developed because of the lack of significant efficacy in many clinical trials and the efficacy in WT GIST has been limited; to date drugs targeting VEGFR, such as sunitinib and regorafenib, appear to be the best agents available for this group of patients. The exciting findings seen with CTLA4 and PD-1/PD-L1 antibodies in melanoma and other solid tumors is exciting, especially because there is a growing body of evidence that such approaches have biologic rationale; clinical trials evaluating these agents are awaited with interest. Last, recent work has shed light on older agents that may have a role in GIST. Moving forward to test these agents alone or in combination with TKIs offers potentially new strategies for treating advanced disease.