ctDNA analysis in gastrointestinal stromal tumors treated with ripretinib or sunitinib

An exploratory mutational analysis using circulating tumor DNA (ctDNA) suggests ctDNA sequencing may improve the prediction of the efficacy of single-drug therapies and support further evaluation of ripretinib in patients with gastrointestinal stromal tumors and specific KIT mutations, as shown by data published on Nature Medicine.

Gastrointestinal stromal tumor is the most common gastrointestinal sarcoma, with approximately 80% of cases driven by mutations in KIT; approximately 90% of patients with KIT-mutant tumors who had disease progression on imatinib, the first-line therapy, harbor newly acquired secondary KIT mutations. Sunitinib is a second-line therapy, ripretinib a choice for adult patients with advanced gastrointestinal stromal tumor who have received prior treatment with three or more tyrosine kinase inhibitor, including imatinib. When compared with sunitinib in the phase 3 INTRIGUE trial, ripretinib demonstrated similar efficacy in patients who had disease progression on or were intolerant to imatinib, with a more favorable safety profile compared to sunitinib. This new analysis of INTRIGUE trial is an exploratory analysis of the landscape of KIT mutations at the onset of imatinib failure, to evaluate the efficacy of ripretinib versus sunitinib in patients with advanced gastrointestinal stromal tumors according to baseline KIT mutation status as determined by ctDNA analysis. Mutational subgroup assessment showed 2 mutually exclusive populations with differential treatment effects. Patients with only KIT exon 11 + 13/14 mutations had better progression-free survival with sunitinib versus ripretinib (median of 15 and 4 months, respectively); patients with only KIT exon 11 + 17/18 mutations had better PFS with ripretinib versus sunitinib (median of 14.2 versus 1.5 months). «Our data suggest that ctDNA analysis may represent a powerful, non-invasive diagnostic tool to identify subgroups of patients with advanced gastrointestinal stromal tumors who experienced disease progression on imatinib that may have prolonged clinical benefit from a single tyrosine kinase inhibitor therapeutic approach. To this end, ctDNA analysis may broadly determine the heterogeneity of resistance for an individual patient compared with a tissue biopsy, which provides information on only a single lesion. Further investigation of the efficacy of ripretinib as a second-line treatment is required and ongoing in the phase 3 INSIGHT trial», authors conclude.