Circulating tumor DNA (ctDNA) analysis of KIT exon mutations may help predict which second-line therapy is best for patients with advanced gastrointestinal stromal tumor (GIST), according to data presented by Bauer et al during the January ASCO Plenary Series session (Abstract 397784).
An exploratory analysis in the phase III INTRIGUE study found that patients with resistance mutations in the KIT activation loop derived meaningful clinical benefit from ripretinib but not sunitinib, while those with KIT ATP-binding pocket mutations had better responses to sunitinib vs ripretinib.
“This is the largest, global phase III trial in second-line, imatinib-resistant GIST that demonstrates the significance of ctDNA next-generation sequencing–based analysis of the complex landscape of KIT mutations and correlates mutational status with treatment response,” said presenting author Sebastian Bauer, MD, of the Department of Medical Oncology and Sarcoma Center/West German Cancer Center, University Hospital Essen, University Duisburg-Essen and German Cancer Consortium (DKTK), Partner Site University Hospital Essen. “Further research is needed to validate these findings, but if confirmed, it could lead to better quality of life and improved prognosis for patients suffering from this condition.”
As Dr. Bauer explained, GIST is the most common sarcoma of the gastrointestinal tract, and most GIST cases have activating mutations in KIT (approximately 80%) or PDGFRA (5% to 10%). Although imatinib, a KIT/PDGFRA tyrosine kinase inhibitor (TKI) has been shown to induce objective responses or stable disease in most cases of advanced GIST, most imatinib-treated patients will experience tumor progression due to development of secondary resistance mutations in KIT or PDGFRA.
According to Dr. Bauer, the primary mechanism of imatinib resistance is the emergence of heterogenous KIT secondary mutations in the kinase domain, which occurs in approximately 90% of patients. These KIT secondary mutations occur in exons 13/14 (ATP-binding pocket) or exons 17/18 (activation loop).
INTRIGUE Trial Design
The INTRIGUE trial was an open-label, phase III study that enrolled adult patients with advanced GIST who had previously progressed on or developed intolerance to imatinib. Participants were randomly assigned to receive either ripretinib at 150 mg once daily or sunitinib at 50 mg per day for a 4-week period followed by a 2-week break. Baseline peripheral whole blood samples were analyzed using Guardant360, a 74-gene ctDNA next-generation sequencing-based assay. Only KIT mutations were reported.
Ripretinib and Sunitinib Show Different Responses
Out of 453 participants in the overall intent-to-treat population, 362 samples were analyzed, with ctDNA detected in 280 of 362 (77%) samples and 213 of 280 samples displaying KIT mutations (76%).
Common resistance mutations were found in the KIT activation loop (42%) and ATP-binding pocket (38%), and in both populations, said Dr. Bauer, results showed efficacy consistent with primary analysis based on tumor data used for random assignment. Additionally, subgroup safety profiles remained consistent across all parameters tested throughout the study duration.
As Dr. Bauer reported, ctDNA analysis identified key differences between ripretinib and sunitinib in terms of efficacy in patients with advanced GIST.
The median progression-free survival was 4 months for those treated with ripretinib and 15 months for those treated with sunitinib; the median overall survival was 24.5 months for ripretinib and not yet reached for sunitinib.
In contrast, however, for patients who had a primary exon 11 mutation and a secondary exon 17 and 18 mutation, the median progression-free survival was 14 months for ripretinib vs 1.5 months for sunitinib. The median overall survival for ripretinib was not reached for this group of patients and was 17.5 months for patients in the sunitinib arm.
“Efficacy data in this cohort of patients with activation loop mutations showed no responses in patients who had received sunitinib,” said Dr. Bauer. “In contrast, 44% of patients in the ripretinib arm achieved a partial response, with a median duration of response of 16.7 months.”
Next Steps and Future Research
According to Dr. Bauer, these findings demonstrate how valuable next-generation sequencing can be when predicting which treatment option will yield optimal results for patients with GIST and suggest that analyzing each patient’s unique tumor DNA may be essential to understanding which drug will be most effective at treating their condition.
Based on this subgroup analysis of the INTRIGUE trial, the phase III, randomized, multicenter, open-label INSIGHT trial will evaluate ripretinib vs sunitinib in patients with advanced GIST previously treated with imatinib harboring KIT exon 11 and 17 and/or 18 mutations. Unlike the INTRIGUE study, the INSIGHT trial will allow patients who have been randomly assigned to receive sunitinib arm to cross over to receive ripretinib.
Disclosure: For full disclosures of the study authors, visit coi.asco.org.
