INCB057643 combined with ruxolitinib tablets/ruxolitinib can improve symptoms in patients with myelofibrosis

INCB057643 (Incyte Corp) as monotherapy or in combination with Ruxolitinib in relapsed/refractory myelofibrosis Good improvements in anemia, spleen size, and symptom burden were achieved in patients with pan>RRMF), essential thrombocythemia (ET), myelodysplastic syndrome (MDS), or MDS/myeloproliferative neoplasms (MPN) overlap syndrome. Data from the ongoing LIMBER Phase 1 trial (NCT04279847) will be released in 2025.

INCB057643 is an oral small molecule targeting bromodomain and exo-terminal (BET) proteins that affects and regulates gene expression and helps drive cancer progression. In MF, BET inhibitors have shown promising anticancer potential in preliminary clinical trials; however, they appear to be less effective as single treatments. Therefore, researchers are studying the clinical benefits of INCB057643 in combination with Janus kinase (JAK) inhibitors, a cornerstone of MF treatment.

LIMBER is a Phase 1, open-label, dose-escalation study evaluating INCB057643 as monotherapy in escalating doses of 4 to 12 mg daily (Part 1) or in combination with ruxolitinib once daily in escalating doses of 4 mg to the maximum tolerated dose in Part 1 (Part 2). The primary endpoints are safety and tolerability, and key secondary endpoints include spleen volume (SV) response (≥35% reduction from baseline [BL; SVR35] at week 24), symptom response (MPN Symptom Assessment Form total symptom score at week 24 [ TSS50] ≥50% reduction compared to BL) and an anemic reaction (sustained hemoglobin increase ≥1.5 g/dL from BL [if BL is transfusion-independent (TF)] or TF-independent [if BL is TF-dependent], lasting ≥12 weeks).

Among trial participants,48 (79%) had MF, 5 (8%) had MDS or MDS/MPN, and 8 (13%) had ET. Eighteen people were treated in the single-agent dose-escalation group, and 20 people were treated in the single-agent dose-expansion group. 23 people were treated in the combined dose escalation group. The median (range) exposure to INCB057643 was 196 (15-812) days for single-agent dose escalation, 155 (14-341) days for single-agent dose escalation, and 176 (25-560) days for combined dose escalation.

At At 24 weeks, 3 of 20 evaluable MF patients treated with any single treatment dose achieved SVR35 (three of 7 patients treated with ≥10 mg), and 4 of 17 patients treated with any combination dose achieved SVR35. At week 24, 7 of 19 evaluable MF patients treated with any monotherapy dose achieved TSS50 (5 of 8 patients treated with ≥10 mg), and 8 of 16 patients treated with any combination dose achieved TSS50. Six of 22 evaluable patients with monotherapy achieved a durable anemic response (2 TF dependent on BL), while 4 of 20 patients treated with combination therapy achieved an anemic response.

The most common treatment-emergent adverse event (TEAE) in 46% of the population was thrombocytopenia, 26% of which were grade 3 or higher. Grade 3 or above anemia occurred in 20% of patients. Thirty-one percent of patients experienced serious TEAEs, 5% of which were treatment-related. Researchers reported no fatal TEAEs, and only nine resulted in discontinuation.

Two dose-limiting toxicities (DLTs) were observed in the monotherapy group: one due to thrombocytopenia and the other to hyperbilirubinemia. One DLT occurred in the 6 mg combination treatment group. In addition, 3 patients developed acute myeloid leukemia transformation: 1 received 4 mg monotherapy in the setting of MDS/MPN, 1 received 10 mg MDS monotherapy and 1 received 4 mg MF combination therapy.

Preliminary study results showBET inhibitor combinations have the potential to improve clinical outcomes for patients. Continued research is needed to further elucidate the position of INCB057643 in the MF treatment paradigm.

Reference materials:https://www.jakavi.com/