Navigating Ongoing Challenges in GI Stromal Tumors

GI stromal tumors (GISTs) are mesenchymal neoplasms with variable natural histories, originating in the GI tract, most commonly in the stomach. They are frequently characterized by KIT or platelet-derived growth factor receptor alpha (PDGFRA) oncogenic mutations. Surgical resection remains the cornerstone treatment for localized GISTs. Clinical trials have demonstrated the benefits of adjuvant imatinib in patients selected on the basis of recurrence risk and gene mutations, although the optimal duration of therapy is yet to be established. Some data suggest that longer durations of adjuvant imatinib (>3 years) may provide additional benefit, which is being investigated in ongoing trials. Management of imatinib-related adverse effects is essential during treatment, and longitudinal abdominal imaging is mandatory both during and after adjuvant therapy. Once GISTs are more advanced and unresectable, KIT- and PDGFRA-directed tyrosine kinase inhibitors (TKIs) become the key treatment in most patients with KIT mutation. Several TKIs have regulatory approval for advanced GISTs, but in most patients, resistance to TKIs eventually emerges, mainly from secondary resistance mutations in KIT. Each TKI has different coverage of oncogenic KIT mutations, suggested by preclinical and clinical findings, which has given rationale to an ongoing clinical trial that includes molecular selection as eligibility criteria. Furthermore, novel treatment approaches, from TKI combinations to an antibody-drug conjugate, are being investigated. Despite the significant advance in managing GISTs with KIT mutations, those without KIT or PDGFRA mutation, which consists of 10%-15% of patients with GIST, can be a clinical challenge in the advanced setting. These non-KIT/PDGFRA GISTs could be driven by genomic or epigenomic alterations in SDHx, NF1 mutations, and other genomic alterations. Non-KIT/PDGFRA GISTs are less responsive to currently available TKIs than GISTs driven by KIT/PDGFRA mutations, and each subset of non-KIT/PDGFRA GIST has distinctive biology and clinical features. Therefore, individualized, multidisciplinary, biology-based management and consideration for clinical trial enrollment are critical for non-KIT/PDGRFA GISTs.