Aptose Biosciences presented clinical data at the 66th American Society of Hematology (ASH) Annual Meeting in San Diego, highlighting the potential of tuspetinib (TUS) as part of a triplet therapy for newly diagnosed acute myeloid leukemia (AML) patients. The TUS+VEN+AZA (tuspetinib+venetoclax+azacitidine) regimen is currently enrolling patients in a clinical trial at U.S. sites.
Tuspetinib's Activity and Safety Profile
Tuspetinib, an oral multi-kinase inhibitor, targets kinases that drive AML cell proliferation. Data from the Phase 1/2 APTIVATE trial (NCT03850574) in relapsed/refractory (R/R) AML patients showed that tuspetinib, both as a single agent and in combination with venetoclax (VEN), demonstrated efficacy across various AML genetic subgroups, including those with adverse mutations in TP53 and RAS genes, and those with mutated or unmutated (wildtype) FLT3 genes.
Rafael Bejar, MD, PhD, Chief Medical Officer at Aptose, stated, "Our extensive dataset with TUS and TUS+VEN support advancement of the TUS+VEN+AZA triplet frontline therapy and we are pleased to now have the TUSCANY triplet clinical trial up and running." He further noted that tuspetinib targets known venetoclax resistance mechanisms, potentially preventing resistance to both agents when used in combination.
Clinical Trial Highlights
Single-agent tuspetinib (n=93 patients) achieved a 60% CR/CRh (complete remission/complete remission with partial hematologic recovery) rate with 80 mg TUS in FLT3-mutated and venetoclax-naive AML patients. In the same group, a 33% CRc (composite complete remission) and 42% ORR (overall response rate) were observed. The study included patients who had failed prior venetoclax therapy and those with mutated or unmutated FLT3. Tuspetinib, administered orally once daily, achieved CR/CRh responses at various dose levels (40, 80, 120, and 160 mg) without dose-limiting toxicities (DLTs). The safety profile was favorable, with no DLTs through 160 mg per day, no drug-related discontinuations, no QTc prolongation, no differentiation syndrome, and no deaths.
In combination therapy (n=79 patients), 40% ORR was achieved with 80 mg TUS + 400 mg VEN in FLT3-mutated patients. Among these, 83% (5/6) had failed prior-VEN treatment, and 50% (3/6) had failed both prior-VEN and FLT3 inhibitor treatment. The TUS+VEN combination showed activity across diverse R/R AML populations with adverse mutations in VEN-naive, prior-VEN, FLT3WT, FLT3MUT, and prior-FLT3i patients. The combination also demonstrated favorable safety and tolerability, with no new or unexpected safety signals, no drug-related CPK elevations, no differentiation syndrome, and no deaths.
Addressing Unmet Needs in AML
AML is a heterogeneous hematologic malignancy with significant unmet needs, particularly in patients ineligible for intensive chemotherapy. The TUS+VEN+AZA triplet aims to provide a more effective and mutation-agnostic standard of care for these patients. Tuspetinib's ability to target venetoclax resistance mechanisms and its broad activity across AML subtypes position it as a promising agent in combination therapies.
