Mutational ctDNA analysis helps predict benefit of 2L ripretinib or sunitinib in GIST

Next-generation sequencing (NGS)–based analysis of circulating tumour DNA (ctDNA) helps predict benefit of second-line (2L) ripretinib or sunitinib therapy in patients with imatinib-resistant advanced gastrointestinal stromal tumours (GIST), an exploratory subanalysis of the INTRIGUE trial has shown.

In patients with KIT exon 11 + 17/18 (activation loop) mutations without exon 9/13/14 mutations, 2L ripretinib was associated with superior progression-free survival (PFS; median, 14.2 months vs 1.5 months; hazard ratio [HR], 0.22; 95 percent confidence interval [CI], 0.11–0.44; p<0.0001), overall survival (OS; not estimable [NE] vs 17.5 months; HR, 0.34; 95 percent CI, 0.15–0.76; p=0.0061) and objective response rate (ORR; 44.4 percent vs 0 percent) vs sunitinib. [Bauer S, et al, ASCO Plenary Series January 2023 Session, abstract 397784]

“No progressive disease was observed in ripretinib recipients. Among ripretinib responders, the median duration of response was 16.7 months,” reported Dr Sebastian Bauer of University Hospital Essen, Germany.

In patients with KIT exon 11 + 13/14 (ATP-binding pocket) mutations without exon 9/17/18 mutations, 2L sunitinib provided better PFS, OS and ORR than ripretinib. Median PFS was 4.0 months in ripretinib recipients vs 15.0 months in sunitinib recipients (HR, 3.94; 95 percent CI, 1.71–9.11; p=0.0005), while median OS was 24.5 months vs NE (HR, 1.75; 95 percent CI, 0.72–4.24; p=0.2085). ORR was 9.5 percent vs 15.0 percent.

“No PFS or OS benefit was observed in patients with KIT activation loop and KIT ATP-binding pocket comutations [median PFS, 8.1 months vs 10.9 months with ripretinib vs sunitinib; HR, 1.07; 95 percent CI, 0.41–2.84] [median OS, 14.7 months vs 20.3 months; HR, 2.61; 95 percent CI, 0.95–7.19],” said Bauer. “However, the patient numbers were small [ripretinib, n=11; sunitinib, n=11] in this population.”

The phase III open-label INTRIGUE trial included 453 patients (median age, 60 years) with GIST whose disease had progressed on or were intolerant of imatinib. The patients were randomized 1:1 to receive 2L ripretinib (150 mg QD; n=226; exon 11 intent-to-treat [ITT] population, n=163) or sunitinib (50 mg QD, 4 weeks on, 2 weeks off; n=227; exon 11 ITT population, n=164). Previously reported results in the exon 11 ITT population showed no significant difference in PFS between ripretinib and sunitinib (median, 8.3 months vs 7.0 months; HR, 0.88; 95 percent CI, 0.66–1.16; p=0.36). [J Clin Oncol 2022;doi:10.1200/JCO.2022.40.36_suppl.359881]

In the current exploratory analysis, ctDNA was analyzed with an NGS-based assay for 362 peripheral whole blood samples collected at baseline. ctDNA was detected in 280 samples, with KIT mutations detected in 213 samples (ripretinib, n=109; sunitinib, n=104), including exon 11 + 13/14 mutations without exon 9/17/18 mutations in 41 samples (ripretinib, n=21; sunitinib, n=20), and exon 11 + 17/18 mutations without exon 9/13/14 mutations in 52 samples (ripretinib, n=27; sunitinib, n=25).

“V654 mutation in exon 13 was the most common imatinib resistance mutation. However, overall, KIT activation loop mutations were more common than KIT ATP-binding pocket mutations,” said Bauer.

“Our efficacy results showed that patients with KIT exon 11 + 17/18 [activation loop] mutations derived clinical benefit from ripretinib but not sunitinib, while those with KIT exon 11 + 13/14 [ATP-binding pocket] mutations derived clinical benefit from sunitinib but not ripretinib,” he said.

“Safety profiles in the KIT exon 11 + 17/18 population were consistent with the study’s primary results. Overall, ripretinib appeared to have a more favourable safety profile than sunitinib, despite a longer median treatment duration of 14 months compared with 3 months for sunitinib,” he continued.

In the KIT exon 11 + 17/18 population, grade 3/4 drug-related treatment-emergent adverse events were reported in 33 percent vs 50 percent of ripretinib vs sunitinib recipients.