Analysis of ctDNA Pinpoints Responders to Second-Line GIST Therapy

Circulating tumor DNA (ctDNA) analysis of KIT mutational status may be able to guide second-line treatment in patients with imatinib-resistant gastrointestinal stromal tumors (GIST), according to an exploratory analysis from the INTRIGUE trial.

Specifically, patients with KIT exon 11 plus 17/18 (activation loop) mutations had superior responses and better survival outcomes with ripretinib (Qinlock) rather than sunitinib (Sutent), reported Sebastian Bauer, MD, of Essen University Hospital in Germany.

However, the opposite appeared to be the case for those with KIT exon 11 plus 13/14 (ATP-binding pocket) mutations, as these patients appeared to benefit more from sunitinib, a switch-control tyrosine kinase inhibitor (TKI).

“This is the largest global phase III trial in second-line imatinib-resistant GIST that demonstrates the significance of ctDNA [next generation sequence]-based analysis of the complex landscape of KIT mutations and correlates mutational status with treatment response,” said Bauer, in presenting the analysis during an American Society of Clinical Oncology (ASCO) virtual plenary.

The INTRIGUE trial is a phase III, randomized, open-label study designed to evaluate the efficacy and safety of ripretinib versus sunitinib in 453 patients with advanced GIST previously treated with imatinib. Primary results presented last year during an ASCO virtual plenary showed no significant PFS benefit with ripretinib compared with sunitinib among all comers.

In the current analysis, Bauer reported only on patients with a KIT mutation. Of 362 samples analyzed from patients in the trial, ctDNA was detected in 280. Of these, KIT mutations were observed in 76%, or 213 of the samples.

Overall, 52 patients had activation loop mutations (KIT exon 11 plus 17/18, excluding 9/13/14). In this group, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) all clearly favored ripretinib:

• ORR: 44.4% vs 0% with sunitinib (nominal P=0.0001)
• Median PFS: 14.2 vs 1.5 months, respectively (HR 0.22, 95% CI 0.11-0.44, nominal P<0.0001)
• Median OS: not evaluable vs 17.5 months (HR 0.34, 95% CI 0.15-0.76)

However, in the 41 patients who had ATP-binding pocket mutations (KIT exon 11 plus 13/14, excluding 9/17/18), outcomes tended to be worse with ripretinib:

• Response rate: 9.5% vs 15% with sunitinib
• Median PFS: 4 vs 15 months, respectively (HR 3.94, 95% CI 1.71-9.11, nominal P=0.0005)
• Median OS: 24.5 months vs not evaluable (HR 1.75, 95% CI 0.72-4.24, nominal P=0.2085)

Significant differences between the two TKIs were not seen in a group of 22 patients with co-mutations (KIT exon 11 plus 13/14/17/18, excluding 9), said Bauer.

In commenting on the results, ASCO discussant Breelyn Wilky, MD, of the University of Colorado in Aurora, said the data presented “are compelling evidence of the power of ctDNA to identify predictive biomarkers and allow for a critical signal finding, even in negative trials.”

Wilky added that the differential responses to ripretinib and sunitinib, depending on the specific mutations identified by ctDNA, are “impressive,” even considering the small numbers of patients in the analyses.

These differences in sensitivity to treatment with TKIs “further cement the importance of mutation testing for GIST patients who are initiating TKI therapy, but also now potentially in the second-line as well,” she said.

Regarding safety, Bauer observed that “ripretinib appears to have a more favorable safety profile compared with sunitinib, even taking into account the median treatment duration of 14 months for ripretinib versus 3 months for sunitinib.”

He said that based on this subanalysis, a phase III trial — INSIGHT — is planned with the objective of evaluating ripretinib versus sunitinib in patients with advanced GIST previously treated with imatinib, and who are harboring KIT exon 11 plus 17 and/or 18 mutations.