BACKGROUND The combination of venetoclax (VEN) with azacitidine (AZA) improves response rates and overall survival in newly diagnosed AML patients. However, overall survival remains poor, particularly in cases harboring adverse FLT3-ITD, RAS, or TP53 mutations that drive VEN resistance and early relapse. The addition of a well-tolerated, broadly active, targeted agent to AZA/VEN is needed to enhance response, increase survival, and decrease therapeutic resistance.

Tuspetinib (TUS) is a potent, once-daily oral kinase inhibitor that targets SYK, FLT3, JAK1/2, RSK1/2 of the RAS/MAPK pathway, and mutant KIT kinases that drive dysregulated proliferation in AML, and has been shown to indirectly inhibit MCL1 expression. In the prior APTIVATE study in relapsed/refractory (R/R) AML, both TUS monotherapy (93 pts) and TUS in combination with VEN (79 pts) produced objective responses in patients with diverse mutations with no dose-limiting toxicities (DLTs) observed at the 40-160 mg dose levels, supporting the combination of TUS with AZA/VEN in the TUSCANY study.

OBJECTIVES To evaluate the safety, tolerability, response rates, measurable residual disease (MRD) status, and pharmacokinetics (PK) of TUS at various dose levels, in combination with VEN (APTIVATE), and in combination with AZA and VEN in newly diagnosed AML patients ineligible for induction chemotherapy (TUSCANY).

METHODS The TUSCANY study investigates TUS in combination with standard doses of AZA (75 mg/m² daily for 7 days) and VEN (400 mg daily for 21 or 28 days) in each 28-day treatment cycle in patients with previously untreated AML, regardless of genotype. TUS is administered at dose levels of 40, 80, 120, and 160 mg daily for 21 or 28 days per cycle in a 3+3 dose-escalation design with 3–6 patients per cohort, followed by expansion of active dose levels. Safety, response rates, PK of VEN and TUS, and MRD status are systematically assessed.

RESULTS Patient Demographics in the TUSCANY Frontline Study: Ten pts, aged 69 to 81 years received TUS (40, 80, or 120 mg once daily) in combination with VEN and AZA. Of these, 1 proceeded to transplant, and 8 remain on treatment. The cohort includes 2 pts with complex karyotypes (CK) and TP53 mutations, 2 with FLT3-ITD, one with RAS mutation, and 5 with myelodysplasia-related mutations.

Safety: Treatment has been well tolerated with no DLTs, no Grade 4 myelosuppression observed past Day 42 in Cycle 1 in the absence of leukemia, and no treatment-related deaths or discontinuations. Grade ≥3 hematologic toxicity was observed in 9 pts (90%), with the most common being decreased platelet count (60%) and white blood cell count (60%). Febrile neutropenia was reported in only one patient. Non-hematologic adverse events were mostly Grade 1–2, with gastrointestinal symptoms such as constipation (50%), nausea (40%), and diarrhea (40%) being most frequent. Serious adverse events (SAEs) occurred in four patients (40%) with none leading to treatment discontinuation or death. Treatment modifications due to TEAEs occurred in 30% of patients for TUS, 40% for VEN, and 30% for AZA.

PK: Plasma concentrations of TUS and VEN with AZA were consistent with levels observed for each agent as monotherapy, suggesting no meaningful PK interaction between them. Mean steady-state trough concentrations of TUS were 0.17 mM (40 mg), 0.34 mM (80 mg), and 0.55 mM (120 mg). Corresponding VEN concentrations were 0.83 mM, 1.31 mM, and 1.78 mM, respectively, supporting the combination of TUS with VEN and AZA without dose adjustment. Additionally, azole antifungal use did not appear to alter TUS exposure.

Responses: CR/CRh rates were 90% across all TUS dose levels: 3 of 4 pts at the lowest dose of 40 mg, 3 of 3 pts at 80 mg, and 3 of 3 pts at 120 mg TUS. CR/CRh occurred in 2/2 (100%) FLT3-ITD pts, 7/8 (87.5%) FLT-WT pts, 1/1 (100%) RAS mutated pts, and 2/2 (100%) mutated TP53/CK pts. Marrow MRD by flow cytometry <0.1% was achieved in 5/9 (56%) of responding pts, including two with TP53-mutation/CK.

CONCLUSIONS TUS has been well-tolerated, both as monotherapy and in combinations with VEN, with objective responses in diverse AML pts including those with FLT3-WT and mutated TP53, RAS, or FLT3. The combination of TUS with standard dosing of VEN/AZA in treatment-naïve AML demonstrates promising safety, tolerability, and efficacy, including MRD-negative remissions in a broad range of mutationally diverse pts. Additional enrollment and follow-up will be presented at the meeting.

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2025
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