Flonoltinib Maleate Provides Durable Spleen Reduction and Symptom Improvement in Myelofibrosis

Treatment with the triple-target JAK2/FLT3/CDK6 inhibitor flonoltinib maleate produced significant, durable reductions in splenomegaly and improved symptom response for patients with myelofibrosis, according to data from a first-in-human phase 1/2a study (NCT05153343) presented during the 2024 ASH Annual Meeting.1

As of the data cutoff of September 5, 2024, 77.3% of evaluable patients (n = 22) in the overall study population (n = 30) achieved at least a 35% reduction in spleen volume (SVR35) from baseline at 24 weeks. Two patients achieved SVR35 during cycles 22 and 24, respectively. The best spleen response rate in the overall population was 86.7%, and 76.7% of patients experienced at least a 50% reduction in total symptom burden (TSS50). Bone marrow fibrosis improvement was also observed in 26.1% of patients.

Further analysis of results according to study phase showed that 72.7% and 81.8% of evaluable patients in the dose-escalation (n = 15) and -expansion (n = 15) phases, respectively, achieved SVR35 at 24 weeks. The best spleen response rates were 80% and 93.3% in these respective cohorts. TSS50 was achieved by 80.0% of patients in the escalation cohort and 73.3% of patients in the expansion cohort. Bone marrow fibrosis improvement occurred for 16.7% and 36.4% of patients, respectively. One patient who did not complete 24 weeks of treatment did experience improvements in bone marrow fibrosis during cycle 4.

Assessment of blood cell changes during treatment demonstrated that neutrophil levels returned to normal following treatment, and platelet levels were not significantly affected by treatment with flonoltinib maleate.

“Flonoltinib maleate has outstanding efficacy and manageable safety and tolerability,” presenting author Lijuan Chen, PhD, of the Department of Hematology at West China Hospital, Sichuan University, in Chengdu, stated in an oral presentation of the data. “[A] 100-mg daily [dose of the] single agent showed rapid and long-lasting splenomegaly reduction, improved bone marrow fibrosis grade, and [demonstrated] stable [platelet counts] during treatment.”

JAK inhibitors continue to serve as the gold treatment standard in myelofibrosis, with 4 of these agents currently FDA approved for patients with various platelet levels. However, many of these agents target JAK1 or JAK3 in addition to JAK2, resulting in off-target hematologic toxicities. Accordingly, flonoltinib maleate was developed to potentially improve the selectivity of JAK inhibitors, thereby reducing such adverse effects (AEs). Flonoltinib maleate is highly selective for JAK2 with high response, is associated with stable platelet counts during treatment, and may improve bone marrow fibrosis through CDK6 inhibition.

The ensuing phase 1/2a study enrolled patients with primary myelofibrosis, post–essential thrombocytosis myelofibrosis, or post–polycythemia vera myelofibrosis. Patients were required to have intermediate-1, -2, or high-risk disease, a platelet count of at least 50 x 109/L, and measurable splenomegaly.

In the dose-escalation phase, patients received oral flonoltinib maleate at 1 of 6 escalating doses between 25 mg and 325 mg. The agent was administered on day 1, once daily from day 5 to day 21, and then daily on continuous fasting for 14 days. The optimal dose for the expansion phase was determined to be 100 mg daily, which was subsequently administered for 14 days per cycle, for a total of 12 cycles. Treatment continued until disease progression or intolerable toxicity.

The primary end points in the dose-escalation phase were safety and tolerability, dose-limiting toxicities, identification of the maximum tolerated dose, and pharmacokinetic behavior. The therapeutic activity of flonoltinib maleate served as a secondary end point. In the expansion phase, the primary end point was SVR35; best SVR35 and TSS50 were secondary end points.

A total of 31 patients were included in the study. One patient from the dose-escalation phase was excluded from the efficacy analysis due to a diagnosis of essential thrombocytopenia.

In the overall study population, the mean age was 61.6 years (standard deviation [SD], ± 9.38), and 54.8% of patients were male. The mean hemoglobin count was 103.3 g/dL (SD, ± 24.09); 45.2% of patients had counts of 100 g/L or less, and 19.4% of patients had counts of 80 g/L or less. Notably, a greater percentage of patients in the dose-expansion vs -escalation phase had hemoglobin counts of 100 g/L or less (60.0% vs 31.3%) and 80 g/L or less (26.7% vs 12.5%).

Red blood cell transfusion dependence was present in 16.1% of all patients at baseline. The mean platelet count was 278.8 x 109/L (SD, ± 255.96), and 22.6% of patients had counts of 100 x 109/L or lower. The mean white blood cell count was 18.0 x 109/L (SD, ± 17.38). Intermediate-1, -2, or high-risk myelofibrosis occurred in 58.1% of patients, with 83.9% of patients experiencing at least grade 2 myelofibrosis. JAK2 mutations were presented in 61.3% of patients, and 41.9% of patients had prior JAK inhibitor exposure. The mean spleen volume at baseline was 1841.0 cm (SD, ± 1036.87).

Findings from a subgroup analysis of patients with JAK2 V167F mutations (n = 18) showed that 78.6% achieved SVR35 at week 24 vs 80.0% of those who had JAK2 V167F–negative disease (n = 8). TSS50 was achieved by 72.2% and 75.0% of patients in these respective subgroups. Bone marrow fibrosis improvement was experienced by 35.7% and 16.7% of patients, respectively. Notably, JAK2 V167F mutations were only detected starting from dose level 3 in the escalation phase.

Additional analysis of splenomegaly reduction showed that most patients achieved SVR25 within 1 month, and over 80% of patients achieved at least a 25% reduction in spleen volume (SVR25). In the dose-escalation phase, SVR35 was achieved by 60.0% of patients during cycles 1/2, 71.4% of patients during cycle 6, and 72.7% of patients during cycle 12. The rates of SVR25 during these respective cycles were 60.0%, 85.7%, and 81.8%. In the dose-expansion phase, SVR35 was achieved by 85.7% of patients in cycles 1/2, 61.5% of patients during cycle 6, and 81.8% of patients during cycle 12. The rates of SVR25 during these respective cycles were 92.9%, 69.2%, and 90.9%.

Among all enrolled patients, the most common treatment-related AEs (TRAEs) of grade 3 or higher included anemia (50.0% overall; 50.0% in expansion cohort; 50.0% in escalation cohort), thrombocytopenia (29.0%; 43.8%; 13.3%), leukopenia (19.4%; 25%; 13.3%), neutropenia (16.1%; 25.0%; 6.7%), pneumonia (9.7%; 12.5%; 6.7%), decreased fibrinogen levels (6.5%; 6.3%; 6.7%); hypertension (3.2%; 6.3%; 0.0%), abdominal pain (3.2%; 6.3%; 0.0%), abnormal liver function (3.2%; 6.3%; 0.0%), and myelosuppression (3.2%; 0.0%; 6.7%). Anemia-related TRAEs were only reported for patients who were not transfusion dependent at the time of study entry (n = 26).

Based on these results, a phase 2 open-label, multicenter, parallel-group study (NCT06457425) is being conducted in China and will compare the efficacy and safety of flonoltinib maleate with that of ruxolitinib (Jakafi) for patients with intermediate-2 or high-risk myelofibrosis.

Disclosures: Dr Chen did not have any relevant disclosures to report.

Reference

Chen L, Wang Y, Wang J, et al. First-in-human phase I/IIa safety and efficacy of flonoltinib maleate, a new generation of JAK2/FLT3 Inhibitor in myelofibrosis. Blood. 2024;144(suppl 1):486. doi:10.1182/blood-2024-210674