Promising Triplet with Tuspetinib Shows Efficacy in Newly Diagnosed AML

Positive early data from the ongoing phase 1/2 TUSCANY clinical trial (NCT03850574) demonstrated that the triplet therapy of tuspetinib (HM43239), venetoclax (Venclexta), and azacitidine provides a high rate of complete remissions and measurable residual disease (MRD) negativity in patients with newly diagnosed acute myeloid leukemia (AML).¹

Clinical Data from the TUSCANY Trial

The TUSCANY trial is an open-label, multi-center, phase 1/2 dose-escalation and expansion study.² Early data from ten patients across 3 cohorts (40 mg, 80 mg, and 120 mg) of tuspetinib in combination with venetoclax and azacitidine have yielded promising results. A key finding is the achievement of a 100% complete remission (CR/CRh) rate among all subjects treated at the 80 mg and 120 mg dose levels. This high rate of response is particularly notable given the diverse patient population enrolled, which includes those with difficult-to-treat mutations.¹

Beyond achieving high remission rates, the triplet therapy has demonstrated a high rate of MRD negativity. Among the patients who responded to therapy, 78% (n = 7/9) achieved MRD negativity, a crucial endpoint for predicting long-term survival in AML. The data also indicate that complete remissions may be achieved more quickly at the higher 120 mg dose compared to the lower doses, a trend that warrants further investigation as the trial progresses.

“We already have data from 3 different [tuspertinib] dose levels in the TUSCANY trial, and the data continue to strengthen at higher doses of [tupsetinib] and over time. We are building a strong case for [tuspetinib, azacitidine, and venetoclax] as a triplet frontline therapy of choice to address a broad AML population, including subgroups with the most adverse of mutations,” said William G. Rice, PhD, chairman, president, and CEO of Aptose Biosciences in a press release.

AML is an aggressive hematologic malignancy with a poor prognosis, particularly in older patients and those with high-risk genetic mutations such as TP53, RAS, and FLT3-ITD. While standard-of-care treatments have improved outcomes, there remains a significant unmet need for therapies that are both effective and well-tolerated across the broad spectrum of AML patient genotypes. The combination of venetoclax and a hypomethylating agent like azacitidine has become a common frontline approach for patients ineligible for intensive chemotherapy.

Safety and Tolerability

The safety profile of the tuspetinib triplet therapy has been positive date, with no dose-limiting toxicities reported at the completed dose levels. The therapy has been well-tolerated, and no relapses or treatment-related deaths have been reported. One patient at the initial 40 mg dose did not respond, which was attributed to not achieving the tuspetinib exposures previously associated with a response. The favorable safety and tolerability profile is particularly important for newly diagnosed patients with AML, many of whom are older and may have comorbidities.

The early results from the TUSCANY trial present a compelling case for the use of tuspetinib in combination with venetoclax and azacitidine as a frontline therapy for newly diagnosed AML. The high rates of CR/CRh and MRD negativity, combined with its broad-spectrum activity and favorable safety profile, position the regimen as a potential new standard of care. With no relapses reported to date and a trend toward more rapid responses at higher doses, the company is continuing to advance the trial into the 160 mg dose cohort. The maturation of these data and long-term follow-up will be critical to fully assess the durability of these responses and the overall survival benefit.

REFERENCES:

1. Aptose Reports Early Data Demonstrating Tuspetinib Improves Standard of Care Treatment Across Diverse Populations of Newly Diagnosed AML in Phase 1/2 TUSCANY Trial. News release. Aptose Biosciences. August 18, 2025. Accessed August 19, 2025. https://tinyurl.com/mw2pvxcv

2. Clinical Trial to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Tuspetinib (HM43239) in Patients with Relapsed or Refractory Acute Myeloid Leukemia (TUSCANY). ClinicalTrials.gov. Updated December 20, 2025. Accessed August 19, 2025. https://clinicaltrials.gov/study/NCT03850574