(P 320) PEAK STUDY: A PHASE 3 RANDOMIZED, OPEN-LABEL, MULTICENTER CLINICAL STUDY OF BEZUCLASTINIB (CGT9486) AND SUNITINIB VERSUS SUNITINIB IN PATIENTS WITH GASTROINTESTINAL STROMAL TUMORS

Objective: Peak is a randomized Phase 3 study evaluating the efficacy and safety of bezuclastinib in combination with sunitinib versus sunitinib as second-line treatment in adult patients with imatinib-resistant or intolerant gastrointestinal stromal tumors (GIST). KIT mutations are activating mutations in up to 80% of GIST patients. Despite current treatments, relapse occurs due to secondary resistance mutations in the ATP-binding domain (exons 13, 14) or activation loop (exons 17, 18). Subsequent lines of therapy are effective against subsets of resistance mutations but are often unable to inhibit the full spectrum of tumors within an individual patient. Bezuclastinib (formerly PLX9486), targeting KIT exons 17, and 18 resistance mutations, combined with sunitinib, targeting KIT exons 9, 11, 13, and 14 mutations, may inhibit a broader spectrum of secondary KIT mutations in GIST than sunitinib alone. Bezuclastinib was safely administered as both monotherapy and in combination with sunitinib in 46 patients with relapsed and/or refractory GIST in a Phase 1/2 clinical study and led to a decrease in mutations harboring KIT exon 17, detected in ctDNA, that temporally correlated with a reduction in tumor burden. Patients with a median of 3 prior lines of therapy treated with combination bezuclastinib and sunitinib (n=15) experienced a 12-month median PFS and 80% clinical benefit rate, suggesting simultaneously targeting a broader range of KIT mutations was associated with clinical activity and an acceptable safety profile; thus, warranting further evaluation in a randomized clinical trial.

Methods: Peak is an open-label, multi-part (Parts 1a: n~20, Part 1b: n~18, Part 2: n~388 patients), randomized, multi-center clinical study of bezuclastinib plus sunitinib versus sunitinib alone in adult patients (≥ 18 years of age) with histologically confirmed locally advanced, metastatic and/or unresectable GIST. Key inclusion criteria: patients with >1 measurable lesion per modified Response Evaluation Criteria in Solid Tumors v1.1, Eastern Cooperative Oncology Group Performance Status 0 to 2, clinically acceptable chemistry/hematology local laboratory values, and have received prior imatinib therapy. Key exclusion criteria: known PDGFR driving mutations or known succinate dehydrogenase deficiency, clinically significant cardiac disease, major surgery within 4 weeks of the first dose of study drug, and GI abnormalities that could preclude adequate absorption. Other exclusion criteria include use of strong CYP3A4 inhibitors or inducers, or sunitinib within 3 weeks (Parts 1a and 1b); participants entering Part 2 may not have been treated with sunitinib previously. Ascending dose levels of reformulated bezuclastinib (starting at 300mg QD) in patients who have received any number of prior lines of therapy, including imatinib, will be assessed in Part 1a. Each cohort will include > 3 patients with the option to expand based on Sponsor or Independent Data Monitoring Committee review. Once a dose level has been selected, > 9 additional patients will be enrolled to confirm the recommended dose of bezuclastinib for Part 2. Part 1b will randomize (1:1) patients who received > 2 prior lines to 2 weeks of bezuclastinib or sunitinib as a single agent. All patients will then receive the combination of bezuclastinib and sunitinib; potential pharmacokinetic (PK) interaction between sunitinib and bezuclastinib will be assessed. Utilizing a 1:1 randomization, Part 2 will evaluate the efficacy and safety of the recommended dose of bezuclastinib from Part 1a in combination with sunitinib (37.5 mg daily) versus sunitinib (37. 5 mg daily) alone and enroll patients with documented disease progression on or intolerance to imatinib. Efficacy will be assessed based on PFS as the primary endpoint, a blinded independent central review will be used to determine progression events and response.

Results: Peak is actively enrolling (NCT05208047).

Conclusion: There remains a high unmet need for more effective and better tolerated second- and later-line treatments for patients with GIST. Phase 1/2 bezuclastinib data in advanced solid tumors, including GIST, were encouraging and support further clinical investigation of co-targeting the complementary conformational states of the same kinase with bezuclastinib and sunitinib. The Peak Study aims to assess the efficacy and safety of bezuclastinib in combination with sunitinib as second-line treatment in adult patients with imatinib-resistant, or intolerant, GIST.