Safety and Efficacy of Bromodomain and Extra-Terminal Inhibitor INCB057643 in Patients with Relapsed or Refractory Myelofibrosis and Other Advanced Myeloid Neoplasms: A Phase 1 Study

Introduction: Bromodomain and extra-terminal (BET) proteins are epigenetic readers that regulate expression of critical oncoproteins involved in the pathophysiology of hematologic malignancies, including myelofibrosis (MF). In a previous phase 1/2 clinical trial, INCB057643 (an oral, small-molecule BET inhibitor) evaluated as monotherapy or combination (combo) with the Janus kinase (JAK)1/JAK2 inhibitor ruxolitinib (RUX) showed favorable tolerability and encouraging clinical activity in patients (pts) with advanced MF.

Methods: This ongoing phase 1, open-label 3+3 dose-escalation/expansion study (NCT04279847) is evaluating INCB057643 as monotherapy (part 1; 4 mg→12 mg once daily [qd]) in adults with relapsed/refractory MF, essential thrombocythemia (ET), myelodysplastic syndromes (MDS), or MDS/myeloproliferative neoplasm (MPN) overlap syndromes, or as combo therapy (part 2; 4 mg qd→part 1 maximum tolerated dose) with RUX in adults with MF who have suboptimal response to RUX. Primary endpoints are safety/tolerability, including dose-limiting toxicities (DLTs). Secondary endpoints include spleen volume (SV) response (≥35% reduction from baseline [BL] in SV [SVR35] at Week 24), symptom response (≥50% reduction from BL in MPN-Symptom Assessment Form total symptom score [TSS50] at Week 24), and anemia response (hemoglobin increase ≥1.5 g/dL from BL [if transfusion independent at BL] or achieving transfusion independence [if dependent at BL] for ≥12 weeks).

Results: Among pts treated with ≥1 dose of INCB057643 as of March 29, 2024, 18 were treated in part 1 monotherapy dose escalation (median [range] age, 71 [50–79] years), 10 in part 1 monotherapy dose expansion (68 [50–79] years), and 16 in part 2 combo therapy dose escalation (71 [50–76] years; median [range] RUX dose, 22.4 [10.0–47.2] mg/day). Overall, 37 (84.1%) pts had MF, 5 (11.4%) had MDS or MDS/MPN, and 2 (4.5%) had ET. Median (range) duration of INCB057643 exposure was 195.5 (15–654) days (d) in the monotherapy dose-escalation cohort, 139.0 (14–183) d in the monotherapy dose-expansion cohort, and 194.0 (85–402) d in the combo therapy dose-escalation cohort.

The most common treatment-emergent adverse events (TEAEs, >25.0%) overall were thrombocytopenia (59.1%), nausea (29.5%), and anemia (27.3%). Grade ≥3 TEAEs occurred in 61.4% overall, with thrombocytopenia or platelet count decrease (36.4%) and anemia (20.5%) the most common. Serious TEAEs occurred in 25.0% overall. There were 2 treatment-related serious TEAEs, 6 TEAEs leading to discontinuation, and no treatment-related fatal events. Two DLTs occurred with monotherapy (12 mg, thrombocytopenia, hyperbilirubinemia) and 1 with combo therapy (6 mg, thrombocytopenia). One pt with MDS/MPN experienced acute myeloid leukemia transformation. No clear/consistent clinically significant cardiotoxicity signals were identified.

Among evaluable monotherapy MF pts, Week 24 SVR35 was achieved by 3/16 pts treated with any dose (3/7 receiving ≥10 mg); improvements in SV at any time during the treatment period were observed in 13/19 pts treated with any dose. Among evaluable pts receiving combo therapy, Week 24 SVR35 was achieved by 3/12 pts treated with any combo dose; improvements in SV at any time during the treatment period were observed in 13/16 treated with any combo dose.

Of the evaluable pts receiving monotherapy, Week 24 TSS50 was achieved by 5/14 pts treated with any dose (5/7 receiving ≥10 mg); of 19 pts treated at any dose, 12 achieved best response of TSS50 during the treatment period. Among evaluable pts receiving combo therapy, Week 24 TSS50 was achieved by 6/11 pts treated with any combo dose; of 15 pts treated at any dose, 10 achieved best response of TSS50 during the treatment period.

Among 19 and 14 evaluable pts receiving monotherapy or combo therapy who were not transfusion dependent at BL, 3 each had anemia response. Lastly, 2/6 evaluable pts who were transfusion dependent at BL achieved transfusion independence (both received monotherapy).

Conclusions: Treatment with INCB057643 monotherapy or in combo with RUX was generally well tolerated, with no treatment-related fatal events. Improvements in anemia, spleen size, and symptom burden were observed in pts receiving monotherapy and combo therapy. Dose expansion is ongoing for 6 mg and 10 mg monotherapy; ongoing dose escalation for combo therapy is expected to be completed, with data presentation at ASH 2024.