Phase 1 Safety and Efficacy of Tuspetinib Plus Venetoclax Combination Therapy in Study Participants with Relapsed or Refractory Acute Myeloid Leukemia (AML) Support Exploration of Triplet Combination Therapy of Tuspetinib Plus Venetoclax and Azacitid

INTRODUCTION: Combination therapy with a hypomethylating agent (HMA) and venetoclax (VEN) has improved response rates and overall survival of newly diagnosed AML patients. However, long-term outcomes remain poor, particularly in those with adverse clones harboring FLT3-ITD, RAS, or TP53 mutations. Since the emergence of VEN resistance is associated with a dismal prognosis, addition of a well-tolerated and active agent to the HMA/VEN combination is needed to improve response rates, increase survival, and prevent emergence of resistant AML clones. Tuspetinib (TUS) is a potent once daily oral kinase inhibitor of SYK, FLT3, JAK1/2, RSK1/2, mutant KIT, and TAK1-TAB1 kinases that mediate dysregulated cellular proliferation in AML. Development of TUS as a combination agent with HMA/VEN is supported by early phase safety and efficacy results in R/R AML, both as a monotherapy and in combination with VEN. AIMS: To assess the safety, tolerability, and pharmacokinetics (PK) of TUS and TUS/VEN to support selection of appropriate doses for monotherapy and combination (doublet and triplet) therapy. METHODS: TUS was administered to study participants (pts) with R/R AML as a single agent in dose escalation, exploration, and expansion (20-200 mg once daily dose levels), and at once daily dose levels of 40 and 80 mg in combination with VEN (400 mg once daily dose). Cycles were planned to be 28 days, with a C1D15 marrow assessment in the combination arm. RESULTS: As of July 02, 2024, 93 pts have been treated with TUS monotherapy: pts were mostly Asian (47.3%) and White (41.9%) with a median age of 63 years (range 18-84 years). No TUS-related non-hematologic SAEs, QTc prolongation, differentiation syndrome, deaths, or discontinuations were observed. Clinical responses with TUS were observed across the 40-160 mg dose levels including the recommended Phase 2 dose of 80 mg (n=19, CRc=26.3%) among all evaluable pts. Clinical response was superior in VEN-naïve (n=30, CRc=30.0%) vs prior-VEN treated pts (n=35, CRc=5.7%), with CR/CRh=35.7% (n=14) for VEN-naïve pts receiving 80 mg TUS. Among pts with FLT3 mutated (FLT3-MUT) treated with TUS 80 mg, CRc=37.5% (n=8), with 33.3% (n=3) in prior-FLT3i exposed. Dose cohorts higher than 80 mg TUS had a greater proportion of prior-VEN treated pts, which likely impacted their response rate, motivating study of the TUS/VEN combination. Seventy-nine pts were treated with TUS/VEN combination therapy: pts were largely White (77.2%) with a median age of 69 years (range 31-86 years); with 73.4% having wild-type FLT3 (FLT3-WT). Participants received a mean of 2.3 prior lines of therapy (range 1-7); 74.7% were prior-VEN treated. The most frequent TEAEs were those typically associated with VEN, including febrile neutropenia (26.6%; lower than expected for a VEN-containing regimen in R/R AML), nausea (26.6%), and pneumonia (22.8%). Objective responses were observed (overall CRc=18.5%) in pts receiving 80 mg TUS/400 mg VEN: FLT3-WT (n=49, CRc=16.3%); FLT3-MUT (n=15, CRc=26.7%), including pts with prior-FLT3i treatment (n=13, CRc=30.8%); prior-VEN treated (n=48, CRc=18.8%); and VEN-naïve (n=17, CRc=17.6%) pts. One response (n=14; 7.1%) was observed at 40 mg TUS/400 mg VEN. PK data showed no clinically meaningful interactions between TUS and VEN. Available data from the frontline triplet study will be presented at the meeting. CONCLUSIONS: Tuspetinib as monotherapy and in combination with VEN has been well- tolerated with objective responses among diverse AML patient groups including those with FLT3-WT and mutated TP53 or RAS, and in prior-VEN and prior-FLT3i treated pts. These safety and efficacy results support the upcoming combination of TUS/VEN plus azacitidine as a triplet in newly diagnosed AML pts ineligible for intensive chemotherapy, independent of FLT3 mutation status.