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<0.0001). mPFS was 16.5 months (95% CI, 13.8-19.2) for the combination vs 9.2 months (95% CI, 7.2-11.0) for monotherapy. ORR significantly improved with the combination vs monotherapy (46% vs 26%; risk difference, 20%; 95% CI, 10.6-28.6; P<0.0001). As of Sep 30, 2025, OS data remain immature. Incidence of adverse events (AEs) was similar between arms. Grade (Gr)≥3 AEs were comparable, with no significant increase in common sunitinib-associated AEs. Higher rates of Gr≥3 ALT/AST elevations and anemia were observed with the combination and were manageable with dose modification. ALT/AST elevations led to bezuclastinib dose reductions in 13.2% and discontinuations in 1.5% of patients in the combination arm; all Gr3 hepatic AEs resolved; no Gr4 events occurred. Additional treatment-emergent AEs leading to discontinuation of either drug in >1 patient in the combination arm were neutropenia (2.9%) and diarrhea (1%). No treatment-related AEs led to death in the combination arm. Conclusions: Combined KIT inhibition with bezuclastinib + sunitinib significantly improved mPFS vs sunitinib monotherapy, reducing the risk of progression or death by 50% and increasing ORR from 26% to 46%. The combination was well tolerated with no new safety findings. Clinical trial information: NCT05208047 .