Dr Watts on the Investigation of INCB057643 in Advanced Myelofibrosis and MPN

Justin M. Watts, MD, associate professor of medicine, Division of Hematology, chief, Leukemia Section, University of Miami Sylvester Comprehensive Cancer Center, discusses the design of a phase 1 trial (NCT04279847) investigating INCB057643 in patients with advanced myelofibrosis and other myeloid neoplasms, and highlights how this agent could address unmet needs in patients with relapsed/refractory myeloproliferative neoplasms (MPNs).

INCB057643 is an oral small molecule BET inhibitor that most selectively targets BRD-4, he begins. The agent is being evaluated in a phase 1 dose-escalation and -expansion study of patients with advanced myelofibrosis, including those with relapsed/refractory myelofibrosis and patients who are suboptimal responders to ruxolitinib (Jakafi), Watts details. Patients in the former group received the BET inhibitor as a monotherapy; those in the latter cohort received the agent as an add-on therapy, he explains.

Findings from the study were reported at the 2024 ASCO Annual Meeting, and demonstrated that INCB057643 when used as a monotherapy (n = 28) or in combination with ruxolitinib (n = 16), was generally well tolerated at doses ranging from 4 mg to 10 mg.

The maximum tolerated dose of the agent was established at 10 mg per day, Watts continues. INCB057643 monotherapy is currently being evaluated in a dose-expansion phase, with the combination regimen being assessed in the dose escalation phase at 8 mg, he reports. Watts notes that 8 mg is likely to be the optimal dose of INCB057643 when administered alongside ruxolitinib. During the dose expansion phases, different dosing of the BET inhibitor is permitted based on a patient's platelet count, Watts says. This cohort includes both patients with myelofibrosis and those with essential thrombocythemia who have progressed on standard therapy, he states.

Initially, the dose escalation phase of the trial included a cohort of patients with myelodysplastic syndromes (MDS) and MDS/MPN overlap syndrome, Watts expands. However, the study’s focus has since shifted exclusively to patients with advanced myelofibrosis due to the significant unmet needs present in this patient population, Watts says. Many patients with advanced myelofibrosis have progressed on multiple lines of therapy or are completely intolerant or refractory to JAK inhibition, he explains. Accordingly, enhancing their response to therapy, reducing toxicities, decreasing spleen size beyond what can be achieved with ruxolitinib alone, and concurrently addressing anemia could benefit these patients, Watts concludes.