Background Ripretinib is a switch-control tyrosine kinase inhibitor approved in the US and EU for patients (pts) with gastrointestinal stromal tumor (GIST) who received prior treatment with 3 or more kinase inhibitors, including imatinib. Sunitinib is approved for advanced GIST after imatinib failure. In an exploratory analysis of baseline circulating tumor DNA (ctDNA) from the INTRIGUE trial, pts with primary mutations in KIT exon 11 and secondary mutations exclusively in KIT exons 17/18 (KIT exon 11 + 17/18) received clinical benefit from ripretinib but not sunitinib (Heinrich MC, et al. Nat Med. 2024). Here, we present final overall survival (OS) and updated safety in pts with KIT exon 11 + 17/18 mutations from INTRIGUE. Methods INTRIGUE (NCT03673501) is an open-label, phase 3 study of adults with advanced GIST who had disease progression on or intolerance to imatinib. Randomization was 1:1 to ripretinib 150 mg once daily (QD) or sunitinib 50 mg QD (4 wks on/2 wks off). Final OS analysis was prespecified to occur with ≥200 and ≥145 events in the all-patient intention-to-treat (ITT) and KIT exon 11 ITT populations, respectively. Baseline peripheral whole blood was analyzed by Guardant360, a 74-gene ctDNA next-generation sequencing-based assay. Data cutoff was March 15, 2023. Results Of 453 pts, ctDNA was analyzed in an exploratory analysis for 362; 52 had mutations exclusively in KIT exon 11 + 17/18 (ripretinib, n = 27; sunitinib, n = 25). Pts with KIT exon 11 + 17/18 mutations had better OS with ripretinib vs sunitinib (median, not reached vs 17.5 months; HR, 0.37; 95% CI, 0.17 to 0.80; nominal P = 0.0091). Fewer of these pts had grade 3/4 drug-related treatment-emergent adverse events and serious adverse events with ripretinib vs sunitinib (33% vs 50% and 3.7% vs 13%, respectively). Median treatment duration in these pts for ripretinib vs sunitinib was 15.6 vs 3.0 months. Conclusions In this updated exploratory analysis from INTRIGUE, OS was longer for ripretinib vs sunitinib for pts with KIT exon 11 + 17/18 mutations identified by baseline ctDNA. The safety profile was consistent and more favorable for ripretinib vs sunitinib in these pts. Clinical trial identification NCT03673501. Editorial acknowledgement Medical writing and editorial support were provided by Steven Walker, PhD, of AlphaBioCom, a Red Nucleus company, and were funded by Deciphera Pharmaceuticals, LLC. Legal entity responsible for the study Deciphera Pharmaceuticals, LLC and the INTRIGUE study investigators. Funding Deciphera Pharmaceuticals, LLC.