Acute Myeloid Leukemia Drug Candidate XY0206 Achieves 45.7% Complete Remission Rate, 60% in FLT3-Mutated Patients

Chinese researchers found a 45.7% complete remission rate in a clinical trial of XY0206, a drug candidate for acute myeloid leukemia (AML). The rate reached 60.0% among patients with FLT3 mutations.

On the 1st (local time), according to the American Society for Clinical Investigation journal Journal of Clinical Investigation (JCI), a research team led by Wang Hong and Cheng Tao at the Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences, published a study analyzing XY0206's antileukemic effects.

The results showed that XY0206 blocked the STAT5, AKT and ERK signaling pathways through kinase inhibition centered on FLT3. It maintained antileukemic activity in models of FLT3-ITD mutations, the F691L “gatekeeper” mutation, microenvironment-induced resistance and acquired resistance.

AML is the most common acute leukemia in adults. About 30% of newly diagnosed patients have FLT3 gene mutations, most commonly internal tandem duplication (FLT3-ITD) and tyrosine kinase domain point mutations (FLT3-TKD).

These mutations activate FLT3 independently of its ligand, stimulating STAT5, PI3K/AKT and RAS/MAPK/ERK signaling. Persistent signaling promotes leukemia cell proliferation and survival, worsens prognosis and leads to treatment resistance.

Existing FLT3 inhibitors, including midostaurin, quizartinib and gilteritinib, have improved treatment outcomes, but the development of resistance has been identified as a limitation. Many next-generation inhibitor candidates have also remained in early development or failed to advance into clinical trials.

XY0206 is a structurally optimized derivative of sunitinib, an inhibitor approved for several solid tumors. The researchers said XY0206 binds directly to FLT3, blocks downstream signaling and induces apoptosis in FLT3-ITD AML cells.

In primary AML blasts and xenograft models, XY0206 showed greater antileukemic activity than gilteritinib and was well tolerated.

In a phase 1/2 trial of XY0206 monotherapy in 35 patients with relapsed or refractory (R/R) AML (NCT04471064), the overall composite complete remission rate (CRc) was 45.7%. The rate was higher, at 60.0%, among patients with FLT3-ITD mutations.

Three of eight patients with R/R AML who had previously received an FLT3 inhibitor also achieved complete remission.

The researchers said the findings support further clinical evaluation of XY0206 in patients whose sensitivity to existing FLT3 inhibitors has decreased.