Primary results of the phase 3 peak study of bezuclastinib + sunitinib vs sunitinib monotherapy in advanced gastrointestinal stromal tumors (GIST).

11500 Background: GIST, the most common mesenchymal malignancy of the gastrointestinal tract, is commonly driven by activating KIT mutations. Despite therapeutic advances, treating advanced GIST with KIT tyrosine kinase inhibitors (TKIs) remains challenging due to emergence of heterogeneous resistance mutations inadequately addressed by current approved therapies. Bezuclastinib, an oral, selective type 1 TKI, in combination with sunitinib, a type 2 TKI, inhibits common primary and secondary resistance mutations in advanced KIT -mutant GIST. The Peak study evaluated efficacy and safety of bezuclastinib + sunitinib vs standard second-line sunitinib monotherapy in patients with advanced GIST who received prior imatinib therapy. Methods: Peak was a multipart study: dose confirmation (Part 1a), 2 drug-drug interaction (DDI) assessments (Part 1b; DDI substudy), and a randomized phase 3 (Part 2; abstract focus). Patients were randomized 1:1 to bezuclastinib 600 mg once daily (QD) + sunitinib 37.5 mg QD (n=204) or sunitinib 37.5 mg QD (n=209). Primary endpoint was blinded independent central review (BICR)-assessed median progression-free survival (mPFS). Key secondary endpoints were objective response rate (ORR) per BICR and overall survival (OS). Crossover to combination was permitted at BICR-confirmed progression. Results: Patients (N=413) were randomized to either bezuclastinib + sunitinib or sunitinib monotherapy; median (range) age, 63 (30-88) years; 59.6% and 14.0% had activating KIT mutations in exons 11 only and 9 only, respectively. The combination significantly improved mPFS (HR, 0.50; 95% CI, 0.39-0.65; P