GIST: Molecular Profiling Suggests 2nd Therapy

Molecular profiling of circulating tumor DNA (ctDNA) can suggest which of two tyrosine kinase inhibitors (TKI)—ripretinib (Qinlock; Deciphera) or sunitinib (Sutent; Pfizer)—would be a more effective second treatment for individuals with gastrointestinal stromal tumors (GIST), based on the development of secondary resistance mutations in KIT during initial therapy with imatinib.

That conclusion was reported during the January session of the American Society of Clinical Oncology Plenary Series by Sebastian Bauer, MD, of University Hospital Essen in Germany and lead author of the study.

The findings build on data from the 453-patient phase III INTRIGUE trial (J Clin Oncol 2022;40:3918–28). Researchers found that ripretinib was no more effective than sunitinib as a second-line treatment in patients with GIST who developed resistance or could not tolerate imatinib. Although the difference was not statistically significant, in patients with KIT exon 11 primary mutations, the median progression-free survival (PFS) was 8.3 months with ripretinib and 7 months with sunitinib, hinting that additional molecular stratification might aid in therapeutic decision making.

In this new INTRIGUE analysis, researchers tested available plasma from 362 patients and detected ctDNA in 280 of them; 213 had KIT mutations. Digging deeper, they identified primary KIT exon 11 alterations, as well as secondary KIT ATP binding pocket mutations in exons 13 and/or 14 in 41 patients—21 in the ripretinib group and 20 in the sunitinib group. They also uncovered primary KIT exon 11 alterations, as well as secondary KIT ATP loop mutations in exons 17 and/or 18 in 52 patients—27 in the ripretinib group and 25 in the sunitinib group.

Significant differences in survival emerged, Bauer reported. For patients with exon 13/14 mutations, median PFS was 4 months for those who received ripretinib and 15 months for those who received sunitinib; median overall survival (OS) was 24.5 months and not reached, respectively. For patients with exon 17/18 mutations, median PFS was 14.2 months with ripretinib and 1.5 months with sunitinib; median OS was not reached and 17. 5 months, respectively.

Bauer added that in the subgroup with exon 11 and 17/18 alterations, there were no objective responses to sunitinib, but 44.4% of patients responded to ripretinib.

“These data have the potential to change practice, and [they suggest] that patients progressing on imatinib consider mutational testing by ctDNA prior to selecting a second-line treatment regimen,” said study discussant Breelyn Wilky, MD, of the University of Colorado Anschutz Medical Campus in Aurora. Referencing the earlier report, she noted that the data “are compelling evidence of the power of ctDNA to identify predictive biomarkers and allow for critical signal finding even in negative trials.”

George Demetri, MD, of Dana-Farber Cancer Institute in Boston, MA, who is not connected to the INTRIGUE trial, noted that about 40% of patients were excluded from the analysis because no ctDNA could be detected. “Even when ctDNA was detected, not all of them had detectable KIT mutations,” he said.

“We simply do not have fully reliable tools for detection of the mutations which are present,” Demetri continued, “and we do not know what we do not know about the comprehensiveness of the true mutational burden versus whatever is detected.”

The study also raises several questions, Wilky noted. For example, how should oncologists care for patients who do not have detectable resistance mutations? When resistance mutations are present, in what order should the drugs be given?

Given the small number of patients included in the report, Wilky and Demetri agreed that the proposed INSIGHT trial, which aims to enroll 54 patients with GIST who test positive for exon 11 plus 17/18 mutations, needs to confirm INTRIGUE's findings.

Patients and their doctors, Demetri stressed, need “to be aware of such testing and trials so that we can continue to aim for even better outcomes—and even cures—for patients.” –Suzanne Rose

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