Encouraging Safety and Tolerability of BET Inhibitor for Myelofibrosis

The phase 1 study found that INCB057643, as monotherapy or in combination with ruxolitinib, was generally well tolerated in patients with relapsed or refractory myelofibrosis (MF), with thrombocytopenia being the most common adverse event. Improvements were observed in spleen volume and symptom burden.

Bromodomain and extra-terminal (BET) proteins are epigenetic reader proteins that transcriptionally regulate the expression of genes involved in MF pathogenesis. A previous phase 1/2 basket trial investigated the oral small-molecule pan-BET inhibitor INCB057643, and the results were promising in patients with MF.¹ The results of that trial led to the current ongoing trial (NCT04279847), which is poised to determine the safety and tolerability of INCB057643 as a monotherapy or combination therapy with ruxolitinib treatment.²

Justin Watts, MD, Miller School of Medicine, University of Miami, Florida, presented the open-label, phase 1, dose-escalation and expansion study.² The dose escalation (n=18) had a 3 + 3 design, started at 4 mg daily, and escalated up to 12 mg daily in continuous 28-day cycles. After the recommended dose for expansion was determined, dose expansion trials began for monotherapy (n=20) and combination therapy (n=23). Patients in the monotherapy expansion group included those with relapsed or refractory MF and essential thrombocythemia. The combination group included patients with chronic or accelerated MF who did not respond well to ruxolitinib alone or patients with MF who were Janus kinase (JAK) inhibitor naive.²

In the monotherapy group, 2 cases of dose-limiting toxicity (DLT) were observed: one for hyperbilirubinemia and one for thrombocytopenia. A single DLT in the combination therapy group was observed with thrombocytopenia. Acute myeloid leukemia transformation occurred in 3 patients; however, 2 of the patients had conditions included in the dose escalation arm and not the dose-expansion study. Treatment-emergent adverse effects were “as expected,” said Dr. Watts, with thrombocytopenia (45.9%) and anemia (24.6%) being the most common in the entire cohort.²

In the monotherapy group, 3 of 7 patients receiving at least 10-mg dosing achieved spleen volume reduction of 35% or more from baseline, and this metric was seen in 5 of 20 patients receiving combination therapy. Almost all patients in the combination group saw spleen reduction. “In combination, there appears to be significant synergy, and we see activity with as little as 4 mg with spleen volume reduction,” said Dr. Watts.²

Patients saw remarkable symptom improvements with INCB057643. The monotherapy group saw a total symptom score reduction of 50% or more (TSS50) in 11 of 20 patients. In the combination therapy group, 12 of 19 patients achieved TSS50, with some patients having all symptoms improved by week 40. The dose expansion trials are still ongoing.²

REFERENCES

1 Falchook G, Rosen S, LoRusso P, et al. Development of 2 bromodomain and extraterminal inhibitors with distinct pharmacokinetic and pharmacodynamic profiles for the treatment of advanced malignancies. Clin Cancer Res. 2020;26(6):1247-1257. doi: 10.1158/1078-0432.CCR-18-4071

2 Watts JM, Hunter AM, Vannuchhi A, et al. 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. Abstract #658. Presented at the ASH Annual Meeting; December 7-10, 2024; San Diego, California.