Location of KIT Mutations Impacts Response to TKIs in Patients With GIST

The location of KIT mutations is associated with response to tyrosine kinase inhibitors (TKIs) in patients with previously treated gastrointestinal stromal tumors (GIST), according to research presented in an ASCO Plenary Series presentation.

Researchers found that patients who had a KIT exon 11 mutation and a mutation in the activation loop (encoded by exons 17 and 18) had better outcomes with ripretinib than with sunitinib. 

Patients who had a KIT exon 11 mutation and a mutation in the ATP-binding pocket (encoded by exons 13 and 14) had better outcomes with sunitinib than with ripretinib.

These findings come from the phase 3 INTRIGUE study (ClinicalTrials.gov Identifier: NCT03673501). The study included 453 patients with GIST who had progressed on or could not tolerate imatinib. They were randomly assigned to receive 1 of 2 other TKIs — ripretinib (n=226) or sunitinib (n=227).

Researchers performed circulating tumor DNA analysis on 362 patient samples (175 in the ripretinib arm and 187 in the sunitinib arm). KIT mutations were seen in 213 samples (109 in the ripretinib arm and 104 in the sunitinib arm).

The researchers found that patients with KIT exon 11 plus 17/18 mutations had longer progression-free survival (PFS) if they received ripretinib than if they received sunitinib. The median PFS was 14.2 months with ripretinib and 1.5 months with sunitinib (hazard ratio [HR], 0.22; 95% CI, 0.11-0.44; P <.0001). 

In contrast, patients who had KIT exon 11 plus 13/14 mutations had shorter PFS if they received ripretinib than if they received sunitinib. The median PFS was 4.0 months with ripretinib and 15.0 months with sunitinib (HR, 3.94; 95% CI, 1.71-9.11; P =.0005). 

Overall survival (OS) among patients with KIT exon 11 plus 17/18 mutations was better with ripretinib than with sunitinib. The median OS was not reached with ripretinib and was 17.5 months with sunitinib (HR, 0.34; 95% CI, 0.15-0.76; P =.0061). 

There was a nonsignificant trend toward improved OS with sunitinib among patients with KIT exon 11 plus 13/14 mutations. The median OS was not reached with sunitinib and was 24.5 months with ripretinib (HR, 1.75; 95% CI, 0.72-4.24; P =.2085). 

Researchers are planning to further evaluate the predictive role of KIT mutations in the phase 3 INSIGHT trial. In this study, researchers will compare ripretinib with sunitinib in patients with advanced GIST previously treated with imatinib and harboring KIT exon 11 plus 17/18 mutations.

Disclosures: This study was supported by Deciphera Pharmaceuticals, LLC. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.

Reference

Bauer S, Jones RL, George S, et al. Mutational heterogeneity of imatinib resistance and efficacy of ripretinib vs sunitinib in patients with gastrointestinal stromal tumor: ctDNA analysis from INTRIGUE. ASCO Plenary Series: January 2023. Abstract 397784.

This article originally appeared on Cancer Therapy Advisor