(P 412) SARC044: A PHASE II TRIAL OF BEZUCLASTINIB IN COMBINATION WITH SUNITINIB IN PATIENTS WITH GIST WHO PROGRESSED ON SUNITINIB MONOTHERAPY

Objective: Gastrointestinal stromal tumor (GIST) is the most common sarcoma subtype and the most common mesenchymal malignancy of the GI tract. About 80% of GISTs are driven by primary mutations in the receptor tyrosine kinase KIT, leading to ligand-independent activation of oncogenic signaling through PI3K/AKT/mTOR and RAS/RAF/MAPK pathways. Tyrosine kinase inhibitors (TKIs) revolutionized GIST management and dramatically improved patient outcomes, however treatment resistance arises from additional KIT mutations in the ATP-binding pocket (AP) encoded by exons 13-14, and in the activation loop (AL) encoded by exons 17-18. No single approved TKI broadly suppresses the spectrum of resistant clones, and TKI combinations have been limited by toxicity from overlapping VEGFR inhibition. The type I TKI bezuclastinib (CGT9486, formerly PLX9486) inhibits KIT AL resistance mutations, does not inhibit VEGFR, and has complimentary activity with sunitinib (inhibitor of KIT AP resistance mutations). Part 2e of the first-in-human study (PLX121-01) evaluated the bezuclastinib + sunitinib combination in 15 patients with GIST, demonstrating a median progression-free survival (mPFS) of 12.1 months (11.6 months in patients with prior sunitinib exposure), suggesting activity in advanced GIST. The ongoing Phase III Peak study (NCT05208047) evaluates the combination versus sunitinib alone in second-line. SARC044 (NCT06208748) investigates bezuclastinib + sunitinib in patients with sunitinib-resistant, KIT-mutant GIST, and incorporates robust correlatives to determine mechanisms of treatment resistance and response.

Methods: SARC044 is a multi-center, open label, single-arm phase II trial enrolling up to 40 adult patients with KIT exon 9 or 11-mutant GIST resistant to imatinib and sunitinib monotherapy. After TKI washout (baseline), patients initiate bezuclastinib 600 mg daily for 2 weeks, then add sunitinib 37.5 mg daily; the combination is administered continuously (28-day cycles) until mRECISTv1.1 progression or unmanageable toxicity (Figure 1). Response evaluations (RE) are performed every 8 weeks through 15 months on study, then every 12 weeks. Treatment beyond mRECISTv1.1 progression is permitted in patients with clinical benefit in the opinion of the investigator. All patients have circulating tumor DNA (ctDNA) collected at baseline, cycle 1 day 15 (C1D15, after 2 weeks of bezuclastinib alone), C2D1 (after 2 weeks on combination), C3D1 (RE#1), and progression. Targeted exome sequencing of ctDNA will track primary/resistant KIT mutation dynamics across therapy. Twenty patients will have 18FDG PET/CT performed at baseline, C1D15, and C2D1 with biopsy of a resistant tumor guided by C2D1 PET/CT. Targeted exome sequencing, allele-specific and long-read PCR (to detect AP+AL mutation phasing), and immunoblotting (to evaluate KIT and downstream pathway activation) will be performed on tissue. EORTC QLQ-C30 surveys will collect patient-reported outcomes (PRO) at baseline, on treatment, and at progression. The primary endpoint is mPFS and secondary endpoints include overall survival (OS) at 1 and 2 years, clinical benefit rate (CBR) at 16 weeks (complete response + partial response + stable disease), adverse event rate, PRO, and KIT mutation profile in ctDNA and tissue. At a one-sided 5% significance level, a sample size of 35 evaluable patients achieves 83% power in a one-sample log-rank test to detect a mPFS of 6.5 months when the mPFS of the historic control group is 4 months. Expected accrual is 12 months across 4 sites in the United States with ~36 mo to study completion.

Results: N/A, No results for this abstract type

Conclusion: N/A, No conclusion for this abstract type.