ctDNA Analysis Appears Essential for Predicting Treatment Response in Advanced KIT-Mutant GIST

Pamela Kunz, MD

Results from the phase 3 INTRIGUE trial (NCT03673501) have demonstrated the significance of circulating tumor DNA (ctDNA) next-generation sequencing-based analysis to understand the complex landscape of KIT mutations and how mutational status correlates with treatment response in patients with gastrointestinal stromal tumor (GIST).

Of the 213 patients with KIT mutations in the study, results showed that those with KIT exon 11 + 13/14 mutations derived a clinical benefit from sunitinib (Sutent) but not ripretinib (Qinlock). Those with KIT exon 11 + 17/18 mutations derived benefit from ripretinib but not sunitinib.

“An important unmet need is identifying resistance mechanisms for KIT-mutated GIST and tailoring treatment accordingly to these mutations, Pamela Kunz, MD, associate professor of Internal Medicine, director of the Center for Gastrointestinal Cancers at Smilow Cancer Hospital and Yale Cancer Center, chief of GI Medical Oncology, vice chief of Diversity, Equity, and Inclusion, Medical Oncology at Yale School of Medicine, told Targeted Oncology™.

INTRIGUE was a phase 3, interventional, randomized, multicenter, open-label study of ripretinib vs sunitinib in adult patients with advanced GIST after treatment with imatinib (Gleevec). There were 453 patients from sites in North America, South America, Europe, Australia, and Asia. Patients were randomized 1:1 to receive ripretinib 150 mg once daily on a continuous basis (n = 226) or sunitinib 50 mg, following the schedule of 4 weeks on, 2 weeks off (n = 227). There was no crossover option in the study.

The primary end point explored during the INTRIGUE study was progression-free survival (PFS) by independent radiologic review (IRR) using modified RECIST v1.1. The key secondary end points were objective response rate (ORR) by IRR and overall survival.

Patients were stratified by mutational status and intolerance to imatinib. The Guardant 360 assay was utilized for ctDNA analysis and detection. A total of 374 samples were received from patients and of those, 362 were analyzed for ctDNA. Investigators detected ctDNA in 280 samples. Of those, 213 were positive for KIT mutations. Among the 213 patients in the ripretinib arm who were KIT mutation-positive, 41 had KIT exon 11 + 13/14 mutations, and 52 had KIT exon 11 + 17/18 mutations. Overall, 21 patients in the ripretinib arm had KIT exon 11 + 13/14 mutations compared with 20 patients in the sunitinib arm. KIT exon 11 + 13/14 mutations were present in 27 vs 25 patients, respectively.

In the KIT exon 11 + 13/14 population, the median PFS achieved with ripretinib was 4.0 months vs 15.0 months with sunitinib (HR, 3.94; 95% CI, 1.71-9.11; P = .0005). The median PFS in the KIT exon 11 + 17/18 population was 14.2 months in the ripretinib arm vs 1.5 months in the sunitinib arm (HR, 0.22; 95% CI, 0.11-0.44; P = .2085).

The median OS in the KIT exon 11 + 13/14 population was 24.5 months with ripretinib vs not evaluable (NE) with sunitinib (HR, 1.75; 95% CI, 0.72-4.24; P = .2085). Among patients with KIT exon 11 + 17/18 mutations, the median OS was NE in the ripretinib arm vs 17.5 months in the sunitinib arm (HR, 0.34; 95% CI, 0.15-0.76; P = .0061).

In the KIT exon 11 + 13/14 activation loop, the ORR was 9.5% with ripretinib vs 15.0% with sunitinib. However, in the KIT exon 11 + 17/18 activation loop, patients did not have objective responses to sunitinib compared with the ripretinib arm, which showed a 44.4% ORR.Patients with co-mutations achieved an ORR of 27.3% in the ripretinib arm vs 9.1% in the sunitinib arm.

Treatment-emergent adverse event (TEAEs) occurred in most patients in the study. Grade 3/4 drug-related TEAEs were seen in 33.0% of the ripretinib arm vs 50.0% of the sunitinib arm, and drug-related serious TEAEs were observed in 3.7% vs 13.0%, respectively. The most common TEAEs in both treatment arms were alopecia (45%), constipation (43%), fatigue (43%), and hypertension (41%).

“The INTRIGUE ctDNA study demonstrates that ctDNA analysis of KIT mutations can help guide second-line treatment in advanced GIST. These findings need to be validated in a larger phase 3 study before we can apply to clinical practice. Broadly, this study may also have implications on how we can optimize use of ctDNA for selecting treatment in other cancers. However, it is important to acknowledge that many tumors do not shed ctDNA and this testing may not be applicable to all patients,” added Kunz.

Based on the promising from INTRIGUE, the phase 3, randomized, multicenter, open-label INSIGHT study has been planned. The study will evaluate treatment with ripretinib vs sunitinib in patients with advanced GIST who were previously treated with imatinib (Gleevec) and who harbor KIT exon 11 + 17/18 mutations.

REFERENCES:

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. 2023;41 (suppl 36; abstr 397784). doi:10.1200/JCO.2023.41.36_suppl.397784