The phase 3 INTRIGUE trial compared ripretinib and sunitinib in patients with advanced gastrointestinal stromal tumor (GIST) who had progressed on or were intolerant to imatinib. While ripretinib did not show superior progression-free survival (PFS) compared to sunitinib in the overall population, an exploratory analysis using circulating tumor DNA (ctDNA) revealed distinct subgroups of patients with different KIT mutations. Patients with KIT exon 11 + 13/14 mutations had better PFS with sunitinib, while those with KIT exon 11 + 17/18 mutations had better PFS with ripretinib. ctDNA analysis identified these subgroups, suggesting that ctDNA sequencing could improve the prediction of treatment efficacy. The study highlights the importance of ctDNA in identifying patients who may benefit more from ripretinib, particularly those with KIT exon 17/18 mutations. The results support further evaluation of ripretinib in these patients. The trial also showed that ripretinib had a better safety profile compared to sunitinib. The findings suggest that ctDNA analysis could guide personalized treatment decisions in GIST patients. The study was supported by Deciphera Pharmaceuticals.The phase 3 INTRIGUE trial compared ripretinib and sunitinib in patients with advanced gastrointestinal stromal tumor (GIST) who had progressed on or were intolerant to imatinib. While ripretinib did not show superior progression-free survival (PFS) compared to sunitinib in the overall population, an exploratory analysis using circulating tumor DNA (ctDNA) revealed distinct subgroups of patients with different KIT mutations. Patients with KIT exon 11 + 13/14 mutations had better PFS with sunitinib, while those with KIT exon 11 + 17/18 mutations had better PFS with ripretinib. ctDNA analysis identified these subgroups, suggesting that ctDNA sequencing could improve the prediction of treatment efficacy. The study highlights the importance of ctDNA in identifying patients who may benefit more from ripretinib, particularly those with KIT exon 17/18 mutations. The results support further evaluation of ripretinib in these patients. The trial also showed that ripretinib had a better safety profile compared to sunitinib. The findings suggest that ctDNA analysis could guide personalized treatment decisions in GIST patients. The study was supported by Deciphera Pharmaceuticals.