‘Provocative’ Data Emerge From INTRIGUE Trial ctDNA Analysis for GIST, Expert Says


Data from a ctDNA analysis of the phase 3 INTRIGUE study indicate that KIT mutational status may be associated with response to certain Tyrosine kinase inhibitors in GIST, according to an expert from the Yale Cancer Center in New Haven, Massachusetts.

KIT mutational status appeared predictive of response to Tyrosine kinase inhibitors (TKI) ripretinib and sunitinib in patients with advanced, imatinib (Gleevec)–resistant gastrointestinal stromal tumors (GIST) in a circulating tumor DNA (ctDNA) analysis of the phase 3 INTRIGUE study (NCT03673501), according to Pamela Kunz, MD.

The analysis was recently presented at the January 2023 American Society of Clinical Oncology (ASCO) Plenary Session, presented by Sebastian Bauer, MD.

In an interview with CancerNetwork®, Kunz, an associate professor of Internal Medicine, director of the Center for Gastrointestinal Cancer, and Vice Chief of Diversity, Equity, and Inclusion, Medical Oncology, at the Smilow Cancer Hospital and Yale Cancer Center in New Haven, Massachusetts, spoke to how it may be possible to identify patients for treatment with a TKI based on resistance mechanisms.


[INTRIGUE] was a randomized phase 3 study for patients with advanced [GIST] in the second-line setting who had progressed or were intolerant to imatinib. Patients [were randomly assigned to] either ripretinib or sunitinib.

This study already reported and showed that in all-comers, there was no significant difference between those 2 arms. What we know about GIST is that mutations in the c-KIT gene can evolve over time. That's how patients acquire resistance to some of these [TKIs].

What was provocative about this subsequent study that was conducted by the authors of the INTRIGUE study was that they collected circulating tumor DNA and evaluated for some of these mutations in the KIT gene that can potentially lead to resistance.

When looking at it that way, it separated patients based on the resistance mechanisms and indicated that circulating tumor DNA can predict response to certain types of second-line treatments, specifically, in this case, it was ripretinib and sunitinib.

They looked at 2 different types of KIT mutations. One was in KIT exon 11 + 13/14, which is the ATP-binding pocket mutation. Those patients who had that mutation had a greater clinical benefit from sunitinib but not ripretinib. Then a second mutation in KIT exon 11 + 17/18, which is the activation loop, had a greater benefit from ripretinib compared with sunitinib.

[These are] interesting results demonstrating that these 2 mutations have very different responses to these [TKIs].


Bauer S, Jones RL, Gelderblom H, et al. Mutational heterogeneity of imatinib resistance and efficacy of ripretinib vs sunitinib in patients with gastrointestinal stromal tumor: ctDNA analysis from INTRIGUE. J Clin Oncol; 41(36):397784. doi:10.1200/JCO.2023.41.36_suppl.397784

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