AUTHORS
Nikolai Podoltsev Podoltsev, MD, PhD, Gabriel Mannis I, MD2, Justin Watts, MD3, Deepa Jeyakumar, MD4, Pankit Vachhani, MD5, Uma Borate, MBBS, MSc6, Brian A Jonas, MD, PhD7, Eric Tam, MD, MBA8, Harry Erba, MD, PhD9, Yuling Shi10, Donna Haney11, William Rice, PhD12, Rafael Bejar, MD, PhD13, Naval Daver, MD14
AFFILIATIONS
1 Yale School of Medicine, New Haven, Connecticut, United States
2 Stanford Cancer Center, Palo Alto, California, United States
3 Miller School of Medicine, Miami, California, United States
4 UC Irvine Health, Irvine, California, United States
5 University of Alabama at Birmingham, Birmingham, California, United States
6 The James Cancer Hospital and Solove Research Institute, Columbus, Ohio, United States
7 UC Davis Comprehensive Cancer Center, Sacramento, California, United States
8 USC Norris Comprehensive Cancer Center, Los Angeles, California, United States
9 Duke Cancer Institute, Durham, North Carolina, United States
10 Aptose BioSciences, Del Mar, California, United States
11 Aptose BioSciences, Del Mar, California, United States
12 Aptose BioSciences, Del Mar, California, United States
13 Aptose BioSciences, Del Mar, California, United States
14 MD Andesrson, Houston, Texas, United States
ABSTRACT
BACKGROUND
The combination of venetoclax (VEN) with azacitidine (AZA) improves response rates and overall survival in newly diagnosed AML patients ineligible for intensive induction chemotherapy. However, long-term outcomes remain poor, particularly in cases harboring adverse FLT3-ITD, RAS, or TP53 mutations that drive VEN resistance and early relapse. As VEN resistance carries a dismal prognosis, the addition of a well-tolerated, broadly active, targeted agent to AZA/VEN is needed to enhance response rates, increase survival, and prevent 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 TUS indirectly inhibits MCL1 expression. In earlier HM-FLTI-101 studies with relapsed/refractory (R/R) AML patients, TUS monotherapy (93 pts) and TUS in combination with VEN (79 pts) produced objective responses in pts with diverse mutations, supporting evaluation of TUS with AZA/VEN in the current TUSCANY frontline cohort.
OBJECTIVES
To evaluate the safety, tolerability, response rates, MRD status, and PK of TUS at four dose levels in combination with AZA and VEN in newly diagnosed AML pts ineligible for induction chemotherapy (NCT03850574).
METHODS
TUSCANY evaluates TUS with standard-dose AZA (75 mg/m² daily for 7 days) and VEN (400 mg daily for 21 or 28 days) in each 28-day cycle in pts with previously untreated AML ineligible for intensive chemotherapy, regardless of genotype. TUS is administered at 40, 80, 120, or 160 mg once daily in a dose-exploration design, followed by expansion of active dose levels. Safety, response rates, PK of TUS and VEN, and MRD status are assessed.
RESULTS
Demographics: As of 06 July 2026, 34 pts with newly diagnosed AML received TUS in combination with VEN and AZA at 40 mg (n=4), 80 mg (n=12), 120 mg (n=5), and 160 mg (n=13). Median age was 76 years (range 63–82), with 20 (58.8%) aged 75–84 years. ECOG performance status was 0 (32.4%), 1 (44.1%), and 2 (23.5%). Ten pts (29.4%) were FLT3-mutated (7 [20.6%] FLT3-ITD) and 24 (70.6%) FLT3-wild-type; 11 (32.4%) had TP53 mutation and/or complex karyotype (CK) and 2 (5.9%) NRAS/KRAS mutations.
Safety: TEAEs were reported in 33 pts (97.1%), most frequently (≥25%) decreased neutrophil (76.5%), platelet (67.6%), and white blood cell counts (64.7%), anemia (58.8%), diarrhea (50.0%), constipation (41.2%), nausea (38.2%), hypokalemia (29.4%), and vomiting and hypophosphatemia (each 26.5%). SAEs occurred in 21 pts (61.8%), most commonly febrile neutropenia (17.6%) and pneumonia (11.8%). TEAEs led to TUS termination in 3 pts (8.8%). Two dose-limiting toxicities were reported, both at the 160 mg TUS dose level (Grade 3 reversible myositis and Grade 4 prolonged neutropenia extending to Day 42 of Cycle 1); no DLTs occurred at 40, 80, or 120 mg. No treatment-related deaths were reported.
Pharmacokinetics: TUS exposure increased with dose and reached steady state by ~Day 15, with a flat concentration-time profile at steady state. Plasma TUS and VEN with AZA were consistent with each agent alone, indicating no meaningful PK interaction and supporting the triplet without dose adjustment.
Responses: Among 33 evaluable pts, overall response rate was 81.8% (27/33) and composite complete remission (CRc) was achieved in 25 pts (75.8%), with CR/CRh in 23 (69.7%) and CR in 19 (57.6%). CRc rates by dose were 75.0% (3/4) at 40 mg, 75.0% (9/12) at 80 mg, 75.0% (3/4) at 120 mg, and 76.9% (10/13) at 160 mg. Responses occurred irrespective of FLT3 status: all 9 evaluable FLT3-mutated pts achieved CRc (100%), as did 16 of 24 FLT3-wild-type pts (66.7%). Among pts with TP53 mutation and/or CK (n=11), CRc was 63.6%, compared with 81.8% (18/22) in pts without TP53/CK. CRc was achieved in 2/2 NRAS/KRAS-mutated pts and 4/5 NPM1-mutated pts. MRD negativity by central flow cytometry was observed in 20 of 25 CRc responders (80.0%).
CONCLUSIONS
TUS with standard-dose VEN/AZA has been well tolerated in older, treatment-naive AML pts ineligible for intensive chemotherapy, with a manageable safety profile, minimal discontinuation, and no treatment-related deaths. The triplet produced high response rates across dose levels and molecular subgroups, including FLT3, TP53/CK, and RAS, with MRD-negative remissions in most CRc responders. Additional enrollment and longer follow-up will be presented.
DISCLOSURES
Nikolai Podoltsev Podoltsev, MD, PhD: No relevant conflicts of interest to declare.