The study evaluated the efficacy and safety of ripretinib versus sunitinib in patients with advanced gastrointestinal stromal tumor (GIST) who progressed on or were intolerant to imatinib. The primary analysis showed no significant difference in progression-free survival (PFS) between the two treatments. However, an exploratory analysis using circulating tumor DNA (ctDNA) biomarker analysis revealed that patients with *KIT* exon 11 mutations and secondary mutations in the activation loop (exons 17/18) had better PFS with ripretinib compared to sunitinib, while those with secondary mutations in the ATP-binding pocket (exons 13/14) had better PFS with sunitinib. This suggests that ctDNA analysis may improve the prediction of treatment efficacy and support personalized therapy. The study highlights the potential value of ctDNA in selecting second-line treatments for advanced GIST, particularly in patients with specific *KIT* mutations.The study evaluated the efficacy and safety of ripretinib versus sunitinib in patients with advanced gastrointestinal stromal tumor (GIST) who progressed on or were intolerant to imatinib. The primary analysis showed no significant difference in progression-free survival (PFS) between the two treatments. However, an exploratory analysis using circulating tumor DNA (ctDNA) biomarker analysis revealed that patients with *KIT* exon 11 mutations and secondary mutations in the activation loop (exons 17/18) had better PFS with ripretinib compared to sunitinib, while those with secondary mutations in the ATP-binding pocket (exons 13/14) had better PFS with sunitinib. This suggests that ctDNA analysis may improve the prediction of treatment efficacy and support personalized therapy. The study highlights the potential value of ctDNA in selecting second-line treatments for advanced GIST, particularly in patients with specific *KIT* mutations.