In an exploratory analysis from the phase III INTRIGUE study, the investigators presented the landscape of KIT mutations at the onset of imatinib failure and evaluated the efficacy of ripretinib versus sunitinib in patients with advanced gastrointestinal stromal tumour (GIST) according to baseline KIT mutation status as determined by ctDNA analysis. In patients with the most common class of primary driver mutation in GIST (KIT exon 11 mutation), imatinib-resistant secondary mutations in the KIT ATP-binding pocket correlated with clinical benefit from sunitinib versus ripretinib, whereas secondary mutations in the KIT activation loop indicated clinical benefit from ripretinib but not sunitinib.
Although these results are limited by the exploratory nature of the analysis, the differences in these populations were robust when accounting for multiple treatment comparisons across mutational subgroups with or without adjustment for different baseline characteristics. Findings are published by Dr. Sebastian Bauer of the Department of Medical Oncology and Sarcoma Center, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, and German Cancer Consortium (DKTK), Partner Site University Hospital Essen in Essen, Germany, and colleagues on 5 January 2024 in the Nature Medicine.
Approximately 80% of GIST cases are driven by mutations in KIT, and up to 10% by mutations in PDGFRA. Approximately 90% of patients with KIT-mutated GIST who had disease progression on imatinib harbour newly acquired secondary KIT mutations, which most commonly appear in the ATP-binding pocket (encoded by exons 13/14) and/or activation loop (exons 17/18).
Sunitinib is the approved second-line therapy for patients with advanced GIST following progression on or intolerance to imatinib. In the registrational phase III study, patients treated with sunitinib demonstrated an overall median progression-free survival (PFS) of 5.6 months. However, there was no analysis of secondary mutations in the phase III study, and sunitinib has demonstrated differential efficacy dependent on the location of imatinib-resistant KIT mutations. In a phase I/II study, the median PFS for sunitinib was 7.8 months in patients harbouring secondary resistance mutations in the KIT ATP-binding pocket compared with 2.3 months in patients who had mutations in the activation loop.
Ripretinib is approved for adult patients with advanced GIST who have received prior treatment with 3 or more tyrosine kinase inhibitors (TKIs), including imatinib, based on the results of the phase III INVICTUS study. When compared with sunitinib in the phase III INTRIGUE study, ripretinib demonstrated similar efficacy in patients who had disease progression on or were intolerant to imatinib in the KIT exon 11 intent-to-treat (ITT; median PFS 8.3 versus 7.0 months) and overall ITT populations (median PFS 8.0 versus 8.3 months), suggesting that ripretinib demonstrated comparable efficacy to sunitinib as a second-line treatment.
Ripretinib also demonstrated a more favourable safety profile compared with sunitinib. Based on primary results from the INTRIGUE study, ripretinib was recently included in the NCCN guidelines as a preferred second-line regimen for patients with advanced GIST who are intolerant to sunitinib.
As fourth-line or later therapy, PFS with ripretinib was longer than placebo in all assessed mutational subgroups (KIT exons 9, 11, 13 and 17), suggesting broad activity in this later-line setting, irrespective of baseline mutation status.
In clinical and nonclinical studies, ripretinib and sunitinib have demonstrated differential activity based on the exon location of KIT mutations. Given the differential activity of TKIs depending on the location of KIT mutations as well as the poor activity of sunitinib in patients with secondary KIT exon 17/18 mutations, the study team hypothesized that further investigation by mutational subgroup using ctDNA could provide more insights into the efficacy of these agents as second-line therapies.
In this exploratory analysis (N = 362), baseline peripheral whole blood was analyzed by a 74-gene ctDNA next-generation sequencing (NGS)–based assay. ctDNA was detected in 280 of 362 samples (77%) with KIT mutations in 213 of 362 patients (59%). Imatinib-resistant mutations were found in the KIT ATP-binding pocket (exons 13/14) and activation loop (exons 17/18).
Mutational subgroup assessment showed 2 mutually exclusive populations with differential treatment effects. Patients with only KIT exon 11 plus 13/14 mutations (ripretinib, n = 21; sunitinib, n = 20) had better PFS with sunitinib versus ripretinib (median 15.0 versus 4.0 months; p = 0.0005). Patients with only KIT exon 11 plus 17/18 mutations (ripretinib, n = 27; sunitinib, n = 25) had better PFS with ripretinib versus sunitinib (median 14.2 versus 1.5 months; p < 0.0001).
The authors concluded that the current exploratory analysis suggests that ctDNA could identify a molecular subset of patients who may preferentially benefit from second-line treatment with ripretinib rather than with the recommended second-line treatment with sunitinib. ctDNA analysis may represent a powerful, non-invasive diagnostic tool to identify subgroups of patients with advanced GIST who experienced disease progression on imatinib that may have prolonged clinical benefit from a single TKI. ctDNA analysis may broadly determine the heterogeneity of resistance for an individual patient compared with a tissue biopsy, which provides information on only a single lesion.
Further investigation of the efficacy of ripretinib as a second-line treatment is required. Based on the current findings, a phase III, randomised, multicentre, open-label INSIGHT study evaluating ripretinib versus sunitinib in patients with advanced GIST previously treated with imatinib who harbour KIT exon 11 plus 17 and/or 18 mutations (without co-occurring mutations in KIT exons 9, 13 or 14) is ongoing.
The INTRIGUE study was funded by Deciphera Pharmaceuticals; Guardant Health processed plasma samples.
Reference
Heinrich MC, Jones RL, George S, et al. Ripretinib versus sunitinib in gastrointestinal stromal tumor: ctDNA biomarker analysis of the phase 3 INTRIGUE trial. Nature Medicine; Published online 5 January 2024. DOI: https://doi.org/10.1038/s41591-023-02734-5