Evolving treatment strategies for localized and advanced GIST

Abstract

Gastrointestinal stromal tumors (GIST) can affect anywhere along the gastrointestinal tract and are the most common mesenchymal tumors of these organs. The presence of a constitutive active form of KIT due to mutations in the KIT oncogene is the primary driver of oncogenic signaling in GIST, and several tyrosine kinase inhibitors targeting KIT have revolutionized the treatment and prognosis for GIST. Localized GIST is treated with surgery in the first instance, but good surgical technique is required because GIST tumors carry a high risk of spontaneous rupture and bleeding. Prediction of relapse risk helps to determine which patients are candidates for adjuvant therapy. Imatinib has shown value in this setting, improving progression- and relapse-free survival, but a number of important questions remains, such as the optimal duration of therapy. A number of kinase inhibitors have been used in advanced GIST, including imatinib, sunitinib and regorafenib. Improvements in progression-free survival and time to progression have been noted, but issues include development of resistance to imatinib, and disease progression after initial response. New treatment options under investigation in GIST include ponatinib, linsitinib and immunotherapies. Combination of imatinib with PI3K inhibitors is one option being investigated to overcome imatinib resistance. Recent treatment advances have widened the treatment landscape and improved patient outcomes in GIST, and current research into new options (e.g. immunotherapy) is promising. Tolerability and cost of new therapies and combinations are likely to be issues that will need addressing in the near future.