Dr Watts on the Potential Advantages of INCB057643 in Advanced Myelofibrosis

"We think 1 advantage of the drug is that it can be given continuously… This may be the reason why we see such good symptom responses. We’ll [have to] see if we’re correct in terms of [labeling INCB057643] as best in class."

Justin M. Watts, MD, associate professor of medicine, Division of Hematology, chief, Leukemia Section, University of Miami Sylvester Comprehensive Cancer Center, discusses the potential advantages of the oral small molecule BET inhibitor INCB057643 vs other agents in this drug class in patients with advanced myelofibrosis and other advanced myeloproliferative neoplasms (MPNs).

ongoing phase 1 dose-escalation/expansion study

 highlighted the tolerability and clinical activity of INCB057643, a BET inhibitor, both as monotherapy and in combination with ruxolitinib (Jakafi). Across both arms, the treatment was generally well tolerated at doses of 4 mg to 10 mg, with no fatal treatment-related adverse effects (AEs) reported. Grade 3 or higher treatment-emergent AEs (TEAEs) were observed in 61.4% of patients, and 25.0% experienced serious TEAEs. Both treatment arms demonstrated improvements in spleen volume and symptom burden, suggesting clinical benefit.

One key advantage of INCB057643 is its ability to be administered continuously without planned dose holds, although dose adjustments or temporary holds can be made if AEs occur, Watts begins. Continuous exposure to the BET inhibitor appears critical for maintaining symptom responses, as interruption could lead to rebounds in MYC and cytokine levels, he notes. This sustained exposure may contribute to the consistent reduction in symptom burden observed, although the effect on spleen volume appears more stable over time, Watts explains.

These results reinforce the potential of INCB057643 as an active agent in this drug class, with ongoing evaluation needed to confirm whether it represents a best-in-class BET inhibitor, he says. The findings also underscore the promise of this approach for delivering meaningful benefits in patients with conditions characterized by elevated MYC and cytokine activity, Watts concludes.

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Justin M. Watts, MD, discusses the potential advantages of the oral small molecule BET inhibitor INCB057643 in advanced myelofibrosis.

Dr Watts on the Final Results of the 2102-HEM-101 Trial in IDH1-Mutated AML

Justin M. Watts, MD, associate professor, medicine, Division of Hematology, chief, Leukemia Section, University of Miami Sylvester Comprehensive Cancer Center, 

discusses the final 5-year results from the phase 2 2102-HEM-101 trial

 (NCT02719574) in the cohort of patients with 

-mutated acute myeloid leukemia (AML) who were treated with olutasidenib (Rezlidhia).

This pivotal phase 2 trial enrolled 153 patients with relapsed or refractory 

-mutant AML who had progressed after standard therapies, often following multiple lines of treatment, Watts begins. The median number of prior therapies in this population was 2, including chemotherapy, hypomethylating agents, venetoclax (Venclexta), or previous transplants, Watts says. These patients received single-agent olutasidenib, administered as a single 150-mg pill twice daily, he reports. The treatment was notably well tolerated, and previously reported data showed a complete remission (CR)/CR with partial hematologic recovery (CRh) rate of 35% and an overall response rate (ORR) of 48% among efficacy-evaluable patients (n = 147), Watts explains.

A notable finding was the duration of response (DOR) among responders, especially those who achieved CR/CRh, he continues. For these patients, the median DOR was 25.3 months (range, 1.8-54.6), which is exceptional for relapsed/refractory AML treated with a single-agent targeted therapy, according to Watts. The 5-year follow-up data reaffirmed these findings, Watts states. The median overall survival (OS) for all patients was 11.6 months (range, 0.2-57.1), but this number was skewed by the poor outcomes in the non-responders (n = 78), who had a median OS of just 3.9 months (range, 0.2-32.6), Watts says. However, patients who respondedhad a median OS of approximately 3 years, he adds. For those who achieved CR/CRh, the median OS was not reached (range, 6.3-57.1+ months), with the OS curve indicating that more than 50% of these patients were still alive at the 5-year mark, Watts explains.

These results provide substantial confidence in using olutasidenib for patients with AML with 

 mutations, Watts emphasizes. If a patient responds to this treatment, there is a strong likelihood of a prolonged remission and significantly extended survival, Watts concludes.

Justin M. Watts, MD, discusses the final 5-year results of the 2102-HEM-101 trial of olutasidenib in patients with IDH1-mutated acute myeloid leukemia.

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 

 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 

, 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.

Justin M. Watts, MD, discusses the design and purpose of a phase 1 trial evaluating INCB057643 in myelofibrosis and other advanced myeloid neoplasms.

Justin M. Watts, MD, discusses the safety profile and tolerability of INCB057643 in patients with 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.

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.

Justin M. Watts, MD

Articles

Dr Watts on the Potential Advantages of INCB057643 in Advanced Myelofibrosis

Dr Watts on the Final Results of the 2102-HEM-101 Trial in IDH1-Mutated AML

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

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