Safety and efficacy of bromodomain and extra-terminal protein inhibitor INCB057643 monotherapy in patients with relapsed or refractory myelofibrosis and other advanced myeloid neoplasms: A phase 1 study

Abstract Background: Bromodomain and extra-terminal (BET) proteins are epigenetic readers that regulate expression of oncoproteins (such as NF-κB, c-Myc, and members of the BCL-2 family) involved in the pathophysiology of hematologic malignancies, including myelofibrosis (MF). The BET inhibitor INCB057643 has been shown to reduce levels of various pro-inflammatory cytokines, disease burden, and bone marrow fibrosis in myeloproliferative neoplasm (MPN) models. Methods:This analysis of an ongoing phase 1, open-label, 3+3 dose-escalation/expansion study (NCT04279847) is evaluating INCB057643 monotherapy (during dose escalation: starting dose 4 mg→12 mg once daily [qd]; during dose expansion: starting dose 6 mg qd or 10 mg qd given continuously) in adults with relapsed/refractory MF, myelodysplastic syndrome (MDS), or MDS/MPN overlap syndrome. The INCB057643 starting dose for each patient (pt) was selected based on their baseline platelet count, and intra-pt dose upward titration was allowed based on protocol-defined criteria (up to 10 mg qd). The primary endpoint is safety and tolerability. Secondary endpoints include spleen volume response (≥35% reduction from baseline [SVR35] at Wk24), symptom response (≥50% reduction from baseline in Myeloproliferative Neoplasm Symptom Assessment Form total symptom score [TSS50] at Wk24), and anemia response (sustained hemoglobin increase ≥1.5 g/dL [if transfusion independent (TI) at baseline] or TI [if dependent (TD) at baseline] for ≥12 wk). Histopathologic bone marrow assessments were performed for megakaryocytes (CD61+) and erythroid precursors (CD71+). Bone marrow response was defined as reduced megakaryocytes and increased erythroid precursors from baseline based on gross analysis of cell counts. Plasma proteomic analysis was performed to assess cytokine levels and disease biomarkers. Results:As of March 17, 2025,18 pts (MF, n=13; MDS or MDS/MPN, n=5; 2 ongoing) were treated in dose escalation, and 20 with MF were treated in dose expansion with INCB057643 doses of 6 or 10 mg qd (13 ongoing). Median (range) INCB057643 exposure in pts with MF was 195.5 (15–1001) days for dose escalation and 151.0 (14–530) days in dose expansion. The most common treatment-emergent adverse event (TEAE) was thrombocytopenia (45%, n=17/38; grade ≥3: 26%, n=10). Grade ≥3 TEAEs occurred in 68% (n=26/38) of pts, and serious TEAEs occurred in 34% (n=13/38; 1 [3%] was considered related to treatment). Gastrointestinal (39% [n=15/38]) and hepatic (hyperbilirubinemia, 5% [n=2/38]; alanine aminotransferase increased, 5% [n=2/38]; aspartate aminotransferase increased, 3% [n=1/38]) TEAEs related to INCB057643 treatment were uncommon and all grade 1/2. No treatment-related fatal events were observed. There were 2 dose-limiting toxicities, both in the 12-mg dose cohort (thrombocytopenia and hyperbilirubinemia). Leukemic transformation occurred in 2 pts (pt with MDS/MPN in the 4-mg dose cohort; pt with MDS in the 10-mg dose cohort). Wk24 SVR35 was achieved by 4/26 (15%) evaluable pts with MF overall, including 4/9 (44%) receiving INCB057643 at a dose ≥10 mg. SVR35 as best overall response (BOR) at any time was achieved by 4/30 (13%) pts. SVR25 at Wk24 was reached by 7/26 (27%) pts, and 10/30 (33%) pts had a BOR of SVR25. TSS50 was achieved by 8/23 (35%) evaluable pts at Wk24, including 5/9 (56%) receiving INCB057643 at a dose ≥10 mg. TSS50 and TSS30 as BOR was achieved by 14/28 (50%) and 22/28 (79%) pts, respectively. Durable anemia response lasting ≥12 wk was observed in 9/31 (29%) evaluable pts with MF, MDS/MPN, or MDS. TI was achieved by 2/4 (50%) pts who were TD at baseline (both with MF). Bone marrow response was observed at doses ≥6 mg qd, with the best response recorded at 10 mg qd. Maximal reduction in disease-specific plasma proteomic markers, including proinflammatory cytokines, was observed at the 10-mg qd dose. Conclusions:INCB057643 monotherapy was generally well tolerated on a continuous dosing schedule, with few treatment-related serious TEAEs and no treatment-related fatal events. Improvement in spleen size, marked improvement in symptom burden, and anemia response were observed with monotherapy. Dose expansion is ongoing for the 6- and 10-mg INCB057643 dose cohorts in pts with MF. A phase 3 study is being initiated to investigate INCB057643 monotherapy in pts with advanced MF following JAK inhibitor treatment.