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.

6574 Background: BET proteins are epigenetic readers that regulate expression of oncoproteins involved in hematologic malignancies, including MF. The oral, small-molecule BET inhibitor INCB057643 had favorable tolerability and encouraging clinical activity in pts with advanced MF in a previous Ph 1/2 trial. Methods: This ongoing Ph 1, open-label 3+3 dose-escalation/expansion study (NCT04279847) is evaluating INCB057643 monotherapy (mono; part 1; 4 mg→12 mg once daily [qd]) in adults with r/r-MF, essential thrombocythemia (ET), myelodysplastic syndrome (MDS), or MDS/myeloproliferative neoplasm (MPN) overlap syndrome, or combination therapy (combo; part 2; 4 mg qd→part 1 maximum tolerated dose) with ruxolitinib (RUX) in adults with MF and suboptimal response to RUX or who were Janus kinase inhibitor (JAKi) naive. Primary endpoint is safety/tolerability. Secondary endpoints: spleen volume (SV) response (≥35% reduction from baseline [BL; SVR35] at Week [Wk] 24), symptom response (≥50% reduction from BL in MPN-Symptom Assessment Form total symptom score [TSS50] at Wk 24), and anemia response (sustained hemoglobin increase ≥1.5 g/dL from BL [if transfusion (TF) independent at BL] or TF independence [if dependent at BL] for ≥12 wks). Results: As of 9Sep2024, 18 pts were treated in mono dose escalation, 20 in mono dose expansion, and 23 in combo dose escalation. 48 (79%) pts had MF, 5 (8%) MDS or MDS/MPN, and 8 (13%) ET. Median (range) INCB057643 exposure was 196 (15–812) days (d) in mono dose escalation, 155 (14–341) d in mono dose expansion, and 176 (25–560) d in combo dose escalation. The most common treatment (tx)-emergent adverse event (TEAE) was thrombocytopenia (TCP; 46%). Grade ≥3 TEAEs occurred in 57%, most commonly TCP (26%) and anemia (20%). Serious TEAEs occurred in 31%; 3 (5%) were tx related. No fatal events were tx related. 9 TEAEs lead to discontinuation. 2 dose-limiting toxicities occurred with mono (12 mg, TCP, hyperbilirubinemia) and 1 with combo (6 mg, TCP). 3 pts had acute myeloid leukemia transformation (4-mg mono MDS/MPN, 10-mg mono MDS, 4-mg combo MF). Wk 24 SVR35 was achieved by 3/20 evaluable MF pts treated with any mono dose (3/7 receiving ≥10 mg) and by 4/17 treated with any combo dose. Wk 24 TSS50 was achieved by 7/19 evaluable MF pts treated with any mono dose (5/8 receiving ≥10 mg) and by 8/16 treated with any combo dose. Durable anemia response occurred in 6/22 evaluable mono pts (2 TF-dependent at BL) and 4/20 combo pts. Conclusions: INCB057643 mono or combo with RUX was generally well tolerated, with no tx-related fatal events. Improvements in anemia, spleen size, and symptom burden were observed with mono and combo. Dose expansion is ongoing for 6- and 10-mg mono and 4- and 8-mg combo groups (add-on and JAKi naive). A Ph 3 study of INCB057643 mono in advanced post-JAKi MF pts is being initiated. Clinical trial information: NCT04279847 .