Dr Watts on the Safety of the BET Inhibitor INCB057643 in Myelofibrosis

Justin M. Watts, MD, associate professor of medicine, Division of Hematology, chief, Leukemia Section, University of Miami Sylvester Comprehensive Cancer Center, discusses the safety profile and tolerability of INCB057643, based on findings from a phase 1 trial (NCT04279847) investigating the safety, tolerability, and preliminary efficacy of the novel BET inhibitor in patients with myelofibrosis and other advanced myeloid neoplasms.

The ongoing, open-label, dose-escalation and -expansion study is evaluating INCB057643 as monotherapy and in combination with ruxolitinib (Jakafi). INCB057643 monotherapy is being investigated in patients with relapsed/refractory myelofibrosis, essential thrombocythemia, myelodysplastic syndrome (MDS), or MDS/myeloproliferative neoplasm (MPN) overlap syndromes. INCB057643 plus ruxolitinib is being evaluated in patients with advanced chronic- or accelerated-phased myelofibrosis who had a suboptimal response to ruxolitinib alone, or those with JAK inhibitor–naive myelofibrosis.

Findings presented at the 2024 ASCO Annual Meeting showed that in patients with myelofibrosis and other MPNs treated with INCB057643 alone (n = 28) and in combination with ruxolitinib (n = 16), grade 3 or higher treatment-emergent adverse effects (TEAEs) occurred in 61.4% of patients, and 25.0% experienced serious TEAEs. TEAEs led to treatment discontinuation in 6 total patients, including 5 receiving monotherapy. Thrombocytopenia was the most common TEAE (59.1%), and it was the most common TEAE that led to discontinuation (n = 5).

Additionally, 2 dose-limiting toxicities (DLTs) were reported in patients receiving INCB057643 monotherapy, including 1 patient with myelofibrosis who experienced hyperbilirubinemia and another patients with MDS/MPN who had thrombocytopenia. In the combination cohort, 1 DLT was reported in a patient with myelofibrosis who experienced thrombocytopenia.

Treatment with INCB057643 demonstrated a broad therapeutic window, making it a potentially more flexible treatment option compared to some other BET inhibitors, Watts explains. Dose adjustments based on individual patient needs, especially concerning platelet counts, were a focal point, he adds. Watts explains that most instances of thrombocytopenia were manageable, allowing patients to continue with treatment without severe complications.

The 2 DLTs reported in the monotherapy arm were observed in patients receiving 12 mg of INCB057643 per day, and 10 mg daily was established as the optimal therapeutic dose Watts continues. He also explains that anemia, which is often a concern with this class of drugs, occurred in 27.3% of patients.

Importantly, Watts mentions that no significant cases of neutropenia were observed, and gastrointestinal toxicity was less common than expected with few instances of diarrhea reported, and nausea remained mild at grade 1 or 2. Additionally, dysgeusia was reported in 22.7% of patients but was deemed manageable.