INCB057643, a bromodomain and extra-terminal protein inhibitor, in combination with ruxolitinib in patients with myelofibrosis: A phase 1 study of safety and efficacy

Abstract Background: The pathophysiology of myelofibrosis (MF) and other hematologic malignancies is modulated by the epigenetic reader bromodomain and extra-terminal (BET) protein. Combination therapy with the BET inhibitor INCB057643 and the Janus kinase (JAK) inhibitor ruxolitinib (RUX) has been shown to synergistically reduce levels of various pro-inflammatory cytokines, reduce disease burden, and reverse bone marrow fibrosis in myeloproliferative neoplasm models. Methods:This analysis of an ongoing phase 1, open-label, 3+3 dose-escalation/expansion study (NCT04279847) is evaluating INCB057643 combination therapy (during dose escalation: starting dose 4 mg once daily [qd] up to the maximum tolerated dose of 10 mg qd established with INCB057643 monotherapy; during dose expansion: starting dose 4 mg qd or 8 mg qd given continuously) as add-on to RUX in adults with MF and suboptimal response to RUX or who were JAK inhibitor (JAKi) naive. The INCB057643 starting dose for each patient was selected based on baseline platelet count, and intra-patient dose upward titration was allowed based on protocol-defined criteria (up to 10 mg qd). Safety and tolerability is the primary endpoint; secondary endpoints include spleen volume response (≥35% reduction from baseline [SVR35] at Week 24), symptom response (≥50% reduction from baseline in Myeloproliferative Neoplasm Symptom Assessment Form total symptom score [TSS50] at Week 24), and anemia response (sustained hemoglobin increase ≥1.5 g/dL [if transfusion independent at baseline] or transfusion independence [if dependent at baseline] for ≥12 weeks). Results:As of March 17, 2025,23 patients were treated in dose escalation (all with suboptimal response to RUX; 11 ongoing) and 13 in dose expansion (all ongoing; suboptimal response to RUX, n=9; JAKi-naive, n=4). Median (range) INCB057643 exposure was 334 (85–749) days in dose escalation; in dose expansion, exposure was 112 (12–172) days in suboptimal response to RUX and 27 (19–34) in newly enrolled JAKi-naive patients. All patients were evaluable for safety. Thrombocytopenia (50%, n=18/36) was the most common treatment-emergent adverse event (TEAE). Grade ≥3 TEAEs occurred in 39% (n=14/36) of patients, with the most common (≥20%) being thrombocytopenia (22%, n=8/36) and anemia (22%, n=8/36). Serious TEAEs occurred in 25% (n=9/36) of patients, with 6% (n=2/36; grade 3 hematoma and grade 3 pyrexia) considered related to INCB057643 treatment. Gastrointestinal (17%, n=6/36) and hepatic (alanine aminotransferase increased, 8% [n=3/36]; aspartate aminotransferase increased, 8% [n=3/36]) TEAEs related to INCB057643 treatment were uncommon and manageable (all were grade 1–2). There were no fatal events that were considered related to INCB057643 treatment. One patient experienced a dose-limiting toxicity (6 mg, thrombocytopenia), and 2 patients had leukemic transformation (4 mg and 8 mg; both with suboptimal response to RUX and multiple high-risk factors for leukemic transformation, with 1 in accelerated phase at baseline). Among patients with a Week 24 efficacy assessment (all of which were in the suboptimal response to RUX group), SVR35 was achieved by 5 of 23 (22%) evaluable patients at Week 24 and by 8 of 28 (29%) patients as best overall response (BOR) at any time. SVR25 at Week 24 was reached by 8 of 23 (35%) patients, and 10 of 28 (36%) patients had a BOR of SVR25. At Week 24, 11 of 21 (52%) evaluable patients achieved a TSS50; 20 of 29 (69%) patients had a BOR of TSS50, and 21 of 29 (72%) had TSS30. Durable anemia response lasting ≥12 weeks occurred in 7 of 28 (25%) evaluable patients, regardless of transfusion status at baseline. Conclusions:INCB057643 combination therapy with RUX was generally well tolerated on a continuous dosing schedule, with few treatment-related serious TEAEs and no treatment-related fatal events, and was associated with improvement in spleen size, marked improvement in symptom burden, and anemia responses. Dose expansion is ongoing for the 4- and 8-mg combination in both the add-on therapy group and in JAKi-naive patients.