Promising clinical activity and tolerability were demonstrated by INCB057643 monotherapy and in combination with ruxolitinib among patients with relapsed/refractory (R/R) myelofibrosis (MF), according to results from a phase 1 clinical trial. 

These data were presented by Justin Watts, MD, Sylvester Cancer Center, Miami, Florida, at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois.

Previous research has shown INCB057643, a small-molecular BET inhibitor, to have clinical activity and tolerability for patients with MF. Researchers conducted an open-label, dose-escalation/expansion study to evaluate INCB057643 as monotherapy among patients with R/R MF, essential thrombocythemia (ET), myelodysplastic syndrome (MDS), or myeloproliferative neoplasm (MPN), or as or combination therapy with ruxolitinib among patients with MF and suboptimal response to ruxolitinib, or who were Janus kinase inhibitor (JAKi) naïve. 

The primary end point was safety, with secondary end points of spleen volume (SV) response, with at least a 35% reduction from baseline at Week 24 (SVR35), at least 50% reduction in symptom response from baseline (TSS50), and anemia response defined as hemoglobin increase of at least 1.5 g/dL from baseline.  

At enrollment, 18 patients were treated with INCB057643 monotherapy in dose escalation, 20 patients with INCB057643 monotherapy in dose expansion, and 23 patients with INCB057643 plus ruxolitinib in dose escalation. Among all patients, 79% had MF, 8% had MDS or MPN, and 13% had ET. Patients who had monotherapy in the dose escalation had a median INCB057643 exposure of 196 (range, 15 to 812) days, patients in monotherapy dose expansion had a median exposure of 155 (range, 25 to 560), and patients in the combination dose expansion had a median exposure of 176 (range, 25 to 560). 

In terms of safety, the most common treatment-emergent adverse event was thrombocytopenia (46%). Overall, 57% of treatment-emergent adverse events were grade 3 or higher, the most common being thrombocytopenia (26%) and anemia (20%). Approximately 31% of patients experiences serious treatment-emergent adverse events, which included 5% being treatment-related. 

At 24 weeks, 3 of 20 patients treated with INCB057643 monotherapy at any dose achieved SVR35 and 4 of 17 patients treated with INCB057643 plus ruxolitinib. Regarding TSS50, 7 of 19 patients treated with INCB057643 monotherapy at any dose achieved a symptom response and 8 of 16 treated with INCB057643 plus ruxolitinib at any dose. Additionally, 6 of 22 patients treated with INCB057643 monotherapy at any dose achieved an anemia response and 4 of 20 patients treated with INCB057643 plus ruxolitinib. 

“INCB057643 mono or combo with RUX was generally well-tolerated, with no [treatment]-related fatal events. Improvements in anemia, spleen size, and symptom burden were observed with mono and combo,” the researchers concluded. 

Additionally, a dose expansion trial is ongoing, and a phase 3 study is in progress. 

Source:

Watts J, Vannucchi A, Hunter A, et al. Safety and efficacy of bromodomain and extra-terminal (BET) inhibitor INCB057643 in patients (pts) with relapsed or refractory myelofibrosis (r/r-MF) and other advanced myeloid neoplasms: A phase (Ph) 1 study. Presented at 2025 ASCO Annual Meeting. May 30-June 3, 2025; Chicago, IL. Abstract 6574.