A non-invasive blood test may help to determine the most effective treatment for patients with advanced gastrointestinal stromal tumors (GIST) that has progressed or is intolerant to first-line imatinib.

These results were presented during the January 2023 session of the American Society of Clinical Oncology (ASCO) Plenary Series.

Understanding GIST

Approximately 80% of patients with GIST have primary mutations in KIT. Imatinib is effective against KIT-mutated GIST, but the vast majority of patients with GIST will ultimately develop resistance to imatinib, most commonly due to the development of secondary mutations in KIT. Sunitinib is effective against some imatinib-resistant mutations.

In the phase 3 INTRIGUE trial, 453 adult patients with advanced GIST who no longer benefited from or had intolerance to imatinib were randomized to ripretinib or sunitinib.[1] In this study, researchers conducted an exploratory baseline analysis of the circulating tumor DNA (ctDNA) results from INTRIGUE to detect secondary mutations in the kinase domain of KIT. ctDNA is DNA released by cancerous cells into the blood stream.

“It is increasingly recognized that somatic mutations in cancer evolve over time and can lead to drug resistance. We need tools other than traditional invasive biopsies to evaluate the mutational landscape in order to personalize therapies in real time. The team of INTRIGUE investigators has discovered that specific mutations identified in ctDNA of patients with advanced GIST may predict their response to second-line treatments. If confirmed in future studies, this approach could be practice changing,” says Pamela Kunz, MD, ASCO expert in gastrointestinal cancer.

Roughly 80% (362 of 453) of samples from the INTRIGUE trial were analyzed. ctDNA was detected in 77% (280 out of 362) of analyzed patients and of those patients, 76% (213 out of 280) were found to have KIT-mutated GIST.

Patients with KIT exon 11 + 17/18 (−9/13/14) mutations had superior progression-free survival (PFS), objective response rate (ORR), and overall survival (OS) when treated with ripretinib, while patients with KIT exon 11 + 13/14 (−9/17/18) mutations had better PFS, ORR, and OS when treated with sunitinib.

“This non-invasive blood test may be a highly meaningful tool to select the most effective drug in patients with GIST who progressed while receiving the first-line treatment with imatinib,” says Sebastian Bauer, MD, from University Hospital Essen in Essen, Germany and lead author of the study. “Our analysis shows that patients with concurrent mutations in KIT exons 11 + 17/18 in the absence of other mutations showed even better overall survival when treated with ripretinib compared to those treated with sunitinib. We plan to validate these data in a new, pivotal phase 3 study. Apart from that, the magnitude of this difference suggests plasma testing to become part of routine care for patients with GIST in the future.”


INTRIGUE: A phase III, randomized, open-label study to evaluate the efficacy and safety of ripretinib versus sunitinib in patients with advanced gastrointestinal stromal tumor previously treated with imatinib