Standard-dose ripretinib plus sunitinib versus ripretinib dose escalation in advanced GIST after progression on four prior therapies: Preliminary results of a multicenter cohort study.

11534 Background: Patients with advanced GIST who progress after four lines of therapy, including imatinib, sunitinib, regorafenib, and ripretinib, face limited treatment options. Ripretinib dose escalation is a potential option recommended by NCCN and CSCO guidelines, while combination therapy with TKIs targeting complementary pathways may offer an alternative for patients harboring multiple resistance mutations. This study aims to evaluate the efficacy of ripretinib dose escalation versus combination therapy following progression on standard-dose ripretinib to identify more effective treatment strategies. Methods: This study is a multicenter cohort study designed to evaluate the efficacy and safety of ripretinib dose escalation versus combination therapy with sunitinib in patients with advanced GIST who have progressed after four prior lines of therapy. Eligible patients receive ripretinib dose escalation group (150 mg twice daily) or the combination therapy group (ripretinib 150 mg once daily plus sunitinib 25 mg once daily). The primary endpoint was progression-free survival (PFS). Results: Between September 2023 and December 2025, 30 patients were enrolled (16 in the ripretinib dose escalation group and 14 in the combination group). Primary KIT11 mutation were identified in 17 patients, 62.5%(10/16) in the dose escalation group and 50% (7/14) in the combination group, while KIT 9 mutations were 2 patients both in the combination group . As of December 30, 2025, 5 patients in the ripretinib dose escalation group remained on treatment with stable disease, whereas all patients in the combination group had experienced disease progression; 3 of these showed slow progression and continued therapy. mPFS1 with standard-dose ripretinib was comparable between groups (6.0 months [95% CI: 4.7–7.3] vs. 7.0 months [95% CI: 5.2–8.8]). Following progression, ripretinib dose escalation achieved a mPFS2 of 8.3 months (95% CI: 4.7–12.0), significantly longer than combination therapy (3.1 months [95% CI: 2.0–4.3]) . OS data remain immature. Ripretinib dose escalation demonstrated better tolerability, with no grade ≥3 adverse events reported. In contrast, the combination group experienced higher toxicity, 35.7% discontinued treatment due to severe adverse reactions. Conclusions: Preliminary results indicate that ripretinib dose escalation demonstrated superior efficacy and a more favorable safety profile compared with combination therapy involving sunitinib. These findings support ripretinib dose escalation as the preferred treatment option for patients with advanced GIST who have progressed after four lines of standard therapy. However, the sample size in this study is still small, and further research with a larger sample is needed to validate this conclusion.