Beyond KIT and PDGFRA: Molecular landscape and outcomes of wild-type GIST.

e23518 Background: Gastrointestinal Stromal Tumors (GIST) are rare mesenchymal neoplasms of the gastrointestinal tract. Most GISTs harbor activating mutations in KIT or PDGFRA. In contrast, GISTs that are negative for KIT/PDGFRA mutations on next generation sequencing (NGS) are defined as wild-type (WT) GIST. While KIT/PDGFRA-mutant GISTs often respond to TKIs, the biology, treatment responsiveness, and outcomes of WT GIST are not well defined. We present a single institution retrospective review of WT GIST. Methods: 370 patients were screened for pathologically confirmed GIST with an absence of both KIT and PDGFRA mutations on NGS. Demographic information, primary site, molecular genomic profiles, therapeutic regimens, and survival data were included. Results: 365 patients were confirmed on pathology to have GIST. 184 patients had NGS completed; 18 patients met WT criteria (9.8% of 184). The most frequent primary locations were stomach (n = 12, 66.7%) and small intestine (n = 3, 16.7%). SDH-deficient GIST were most common (n = 9, 50%), followed by “quadruple WT” (n = 4, 22.2%), and RAS pathway mutations (n = 3, 16.7%); 2 patients did not have SDH testing (16.7%). At time of diagnosis, most of the cohort had stage IV disease (n = 10, 55.5%), followed by stage III (n = 4, 22.2%), then stage II (n = 2, 11.1%) and stage I disease (n = 2, 11.1%). 17 patients underwent surgical resection; 1 surgery was aborted due to disease burden. Imatinib was the most used systemic therapy (n = 14, 77.8%) and first-line in 13 cases; median imatinib duration was 415 days. It was most often discontinued for disease progression (n = 5, 35.7.5%) or treatment related toxicity (n = 2, 14.3%). Subsequent TKIs (sunitinib, regorafenib, ripretinib) and immune checkpoint inhibitors were used in a subset of later-line settings. Across all WT GIST patients, 5-year overall survival (OS) was 88.9% (95% CI 75.5–100%) with median OS of 129 months; 5-year progression-free survival was 55.6% (95% CI 36.8–84.0%) with median time to first progression of 73 months. Conclusions: KIT/PDGFRA WT GIST represents a rare but clinically important subset at our institution, with pronounced molecular heterogeneity driven predominantly by SDH-deficient and RAS pathway–altered tumors and a distinct minority of quadruple WT cases. In this series, long-term survival was unexpectedly favorable despite a high proportion of patients with advanced-stage disease, highlighting the critical role of comprehensive genomic profiling to correctly classify WT GIST. Robust, multi-institutional cohorts are urgently needed to refine prognostic estimates and to develop and test tailored treatment strategies for SDH-deficient and quadruple WT GIST.