Outcomes of novel tyrosine kinase inhibitors in rare GIST subtypes: A clinico-genomic analysis from the Flatiron Health–Foundation Medicine database.

838 Background: Gastrointestinal stromal tumors (GIST) with KIT or PDGFRA mutations respond well to imatinib, but rare molecular subtypes—including KIT/PDGFRA wild-type, succinate dehydrogenase (SDH)–deficient, and NF1-associated GIST—have limited therapeutic options. The efficacy of newer TKIs such as regorafenib, ripretinib, and avapritinib in these populations remains poorly described in real-world settings. Methods: We performed a retrospective cohort study using the Flatiron Health–Foundation Medicine clinico-genomic database (2016–2024). Adult patients with advanced GIST who underwent comprehensive genomic profiling and received at least one TKI beyond imatinib were included. Patients were stratified into rare subgroups (KIT/PDGFRA wild- type, SDH-deficient, NF1-associated) and compared with KIT/PDGFRA-mutant GIST. Primary endpoint was overall survival (OS) from initiation of post-imatinib therapy. Secondary endpoints included progression-free survival (PFS) and treatment sequence patterns. Kaplan–Meier and Cox regression analyses were applied. Results: Among 824 GIST patients with genomic annotation, 142 (17%) had rare subtypes: 61 SDH-deficient, 47 KIT/PDGFRA wild-type, and 34 NF1-associated. Median OS after imatinib failure was 27.3 months for KIT/PDGFRA-mutant, 19.4 months for SDH- deficient, 15.2 months for KIT/PDGFRA wild-type, and 13.6 months for NF1-associated tumors. Use of regorafenib and ripretinib improved outcomes compared with sunitinib alone in SDH-deficient cases (median OS 22.1 vs. 14.2 months, p = 0.03). In KIT/PDGFRA wild-type tumors, ripretinib conferred the longest PFS (median 7.9 months) compared with regorafenib (5.1) or sunitinib (4.4). Avapritinib demonstrated activity in select PDGFRA-exon18 rare variants but limited benefit in SDH-deficient tumors. Conclusions: In this real-world, genomically annotated cohort, newer TKIs provided clinically meaningful benefit in rare GIST subtypes, particularly SDH-deficient and KIT/PDGFRA wild-type tumors, though outcomes remained inferior to classical KIT/PDGFRA-mutant GIST. These findings support the integration of comprehensive genomic profiling to optimize sequencing of TKIs beyond imatinib in rare GIST populations.