Editor's note: Gastrointestinal stromal tumors (GIST) are mesenchymal tumors driven by mutations in oncogenes. In recent years, various types of small-molecule tyrosine kinase inhibitors (TKIs) have provided new treatment options for patients with advanced GIST, but there remains a significant unmet need in clinical care. During the 2024 ESMO Annual Meeting, Dr. Jian Li's team from Peking University Cancer Hospital presented updated data from the follow-up treatment analysis of the INTRIGUE China bridging study on ripretinib, offering further insights into the clinical application of such novel drugs.

Gastrointestinal stromal tumors (GIST) are primarily driven by mutations in genes such as C-KIT or PDGFRA. The first-line treatment for advanced GIST is imatinib, but most patients develop resistance due to new mutations in the kinase domain. Second-line treatment options include dose-escalated imatinib or switching to sunitinib. However, dose-escalated imatinib is associated with increased adverse reactions and poor patient tolerance, while sunitinib can extend progression-free survival (PFS) to some extent, but does not offer an overall survival (OS) benefit and also carries a high rate of adverse effects, impacting both quality of life and efficacy. There is an urgent clinical need for drugs that offer better safety, tolerability, increased survival, and higher objective response rates, in order to improve patient compliance, ensure efficacy, and enhance quality of life, potentially even creating opportunities for surgery.

Ripretinib is a novel, broad-spectrum switch-control inhibitor of C-KIT and PDGFRA that targets various primary and secondary mutations arising from changes in the kinase domain of GIST. It has been approved as a fourth-line treatment for GIST both domestically and internationally. The international phase III INTRIGUE study further evaluated ripretinib as a second-line treatment. Although the study did not achieve superiority in PFS for the intention-to-treat (ITT) population (8.0 vs. 8.3 months), ripretinib showed a trend toward improved PFS in the C-KIT exon 11 mutation group compared to sunitinib (8.3 vs. 7.0 months, HR=0.88; P=0.36) and a significant increase in the objective response rate (ORR) (23.9% vs. 14.6%; P=0.03). Similar results were reported from the INTRIGUE China bridging study at the 2023 ASCO GI meeting, where the ripretinib group demonstrated a numerically longer PFS in the ITT population (10.3 vs. 8.3 months, HR 0.986; P=0.9153), and a significantly prolonged PFS in the KIT exon 11 mutation subgroup compared to sunitinib (NE vs. 4.9 months, HR 0.457, P=0.0264).

At this year’s ESMO conference, further updates on the INTRIGUE China bridging study data were presented. This phase II study enrolled adult GIST patients who had failed or were intolerant to imatinib. The patients were randomized (1:1) to receive either ripretinib 150 mg once daily (QD) or sunitinib 50 mg QD (4 weeks on, 2 weeks off). As of March 15, 2024, 14.8% (16/108) of the patients were still receiving study treatment. After discontinuing the study treatment, 80 patients received third-line (3L) therapy. In the ripretinib group, 82.0% (32/39) of the patients received sunitinib as third-line treatment. In the sunitinib group, most patients (58.5%, 24/41) received regorafenib as third-line therapy.

In the ITT population of all patients (AP), the PFS after any 3L treatment was similar between the two groups (median, 6.0 vs. 5.0 months; HR 0.83; 95% CI: 0.50–1.37). In the AP ITT population, the median PFS for the most common 3L treatments (sunitinib for the ripretinib group and regorafenib for the sunitinib group) was 7.0 months in the ripretinib group and 5.0 months in the sunitinib group (HR 0.67; 95% CI: 0.37–1.21). In the AP ITT population, there were 50 overall survival (OS) events (46.3%). The median follow-up time for both groups was 34.0 months. The median OS for both groups in the AP ITT population was not reached (NR). In the KIT exon 11 mutation ITT population, the median OS for the ripretinib group and the sunitinib group was NR and 28.0 months, respectively (HR 0.70; 95% CI: 0.34–1.42; nominal P=0.32).

In conclusion, this update from the INTRIGUE China bridging study primarily analyzed the subsequent third-line treatment outcomes following second-line therapy. Overall, the PFS for third-line treatment was similar between the ripretinib and sunitinib groups. However, in the most common third-line treatment subgroups (ripretinib group receiving sunitinib, sunitinib group receiving regorafenib), the ripretinib group demonstrated a two-month longer PFS. Additionally, in the KIT exon 11 mutation subgroup, ripretinib showed a 30% reduction in the risk of death. These data further support the therapeutic advantage of ripretinib in the KIT exon 11 mutation population and provide some reference for the strategic sequencing of targeted therapies in GIST, suggesting that ripretinib prior to sunitinib may prolong PFS.