INCB057643 ± Ruxolitinib Shows Early Tolerability, Efficacy in Advanced Myelofibrosis

Justin M. Watts, MD

INCB057643 has shown encouraging clinical activity and favorable tolerability as both a single agent and add-on to ruxolitinib (Jakafi) in patients with advanced myelofibrosis, and may address unmet needs for those with other advanced myeloproliferative neoplasms (MPNs)/myelodysplastic syndrome (MDS)—particularly those with relapsed/refractory disease or a suboptimal response to JAK inhibitors, according to Justin M. Watts, MD.¹

At the 2024 ASCO Annual Meeting, results from an ongoing phase 1 dose-escalation/expansion study (NCT04279847) demonstrated that treatment with INCB057643 as a monotherapy (n = 28) and in combination with ruxolitinib (n = 16) was generally well tolerated at doses ranging from 4 mg to 10 mg, with no fatal treatment-related effects observed. Grade 3 or higher treatment-emergent adverse effects (TEAEs) occurred in 61.4% of patients across both arms, and 25.0% experienced serious TEAEs. The most common TEAE observed was thrombocytopenia (59.1%), and 5 patients discontinued treatment due to this TEAE. Notably, 2 dose-limiting toxicities (DLTs) were reported in patients receiving INCB057643 monotherapy at 12 mg, and 1 DLT was observed in the combination arm at the 6-mg dose.

Improvements in spleen volume and symptom burden were observed in both treatment arms. At week 24, spleen volume reduction of at least 35% (SVR35) was achieved by 3 of the 7 evaluable patients treated with 10 mg of INCB057643 or greater, and 3 of the 12 evaluable patients treated with the combination. Additionally, 5 of 14 evaluable patients who received the monotherapy and 5 of 7 evaluable patients who received the monotherapy at 10 mg or greater achieved a reduction in tumor symptom score of at least 50% from baseline (TSS50) at week 24. TSS50 was achieved by 6 of the 11 evaluable patients in the combination arm.

“There’s a subset [of patients] that do extremely well with the monotherapy. Combination therapy cohorts are still evolving, and dose escalation is ongoing,” said Watts, who is an associate professor of medicine in the Division of Hematology and chief of the Leukemia Section at the University of Miami Sylvester Comprehensive Cancer Center in Miami, Florida. “We’re excited to see where this trial heads.”

In an interview with OncLive®, Watts provided background on the phase 1 trial of INCB057643, including its rationale and the patient population being enrolled; highlighted key efficacy and safety findings; and discussed the agent’s potential advantages both alone and as an alternative to first-line ruxolitinib in patients with myelofibrosis.

OncLive: What was the rationale for conducting this phase 1 trial of INCB057643?

Watts: INCB057643 is an oral small molecule BET inhibitor that most selectively targets BRD-4. We’re studying [the agent] in a phase 1 dose-escalation and -expansion study in patients with advanced myelofibrosis. [This includes those with] relapsed/refractory myelofibrosis, in which case we’re using monotherapy with the BET inhibitor, or suboptimal responders to ruxolitinib [Jakafi], where it’s [being used as] an add-on therapy. Those are the 2 different parts of the study.

Part 1 is now in dose expansion, and the maximum tolerated dose [MTD] was [established at] 10 mg a day. Part 2, [which is investigating] the combination therapy with ruxolitinib, is in dose escalation at 8 mg, which is probably going to be the right dose. In the expansion phases, we do allow different dosing of the BET inhibitor based on a patient’s platelet count. For example, on the monotherapy dose-expansion [portion, INCB057643] could be [administered at] 6 mg or 10 mg daily depending on their starting platelets. That cohort includes both patients [with myelofibrosis] and those [with essential thrombocythemia] who have progressed on standard therapy.

How might this study address unmet needs in patients with relapsed/refractory MPNs?

As part of the dose escalation, the trial did [originally] have a cohort that enrolled patients with MDS and MDS/MPN overlap syndrome. Now it’s exclusively focused on advanced myelofibrosis. There’s a big unmet need in both groups. Patients may have [progressed on] multiple lines or may just be completely intolerant or refractory to JAK inhibition, so it [would be] nice to have an active single agent there. [Additionally], the suboptimal responders to ruxolitinib often aren’t doing that well. If we can deepen that response, improve their symptoms and spleen size on top of what ruxolitinib already did, and improve the anemia, we’d really be helping the patient.

What initial efficacy findings from the study were presented at the 2024 ASCO Annual Meeting?

We’re looking at three different efficacy end points: SVR 35 at 24 weeks, TSS50, and anemia improvement. We’ve seen activity in all 3 [areas]—especially in symptom improvement. In terms of SVR35 with the monotherapy, when we hit the most active dose level of 10 mg, we see [over] 40% of patients hitting that SVR35 end point at week 24. These are patients who already progressed on JAK inhibitors. When we looked at the combination therapy, we saw improvement in spleen volume and SVR35 that was closer to [25%] with the addition of the BET inhibitor [across doses]. There’s a clearer dose-response relationship with the monotherapy, [indicating that] 6-mg to 10-mg [doses are needed to achieve] SVR. It [may be] less important with the combination therapy because [INCB057643 is] synergizing with the ruxolitinib, and there are many patient-specific factors that may play into that. If you look at the waterfall plots, most patients experienced some reduction, and many also had SVR25. Approximately 45% [of patients] achieved SVR35 across the 2 parts.

For symptom improvement, we saw more robust responses, with over 50% of patients having TSS50 at week 24 in either arm. When you look at TSS50, at any time, 75% of patients had significant symptom improvement on the study; that was [comparable] with both the monotherapy and combination therapy.

When we look at anemia—and a true anemia response where the hemoglobin improves by 1.5 g for at least 12 weeks, [which] is one of the toughest to achieve—we saw that in 3 patients on both arms. It was probably a more significant hemoglobin improvement with the monotherapy, [but] the mean hemoglobin in all patients improved over time, and 2 out of 6 patients who were transfusion dependent at baseline on the study achieved complete transfusion independence. Those 2 patients who were both on monotherapy had a very robust improvement in their hemoglobin. Those patients tend to be triple responders [in that they] have [improvement] in their spleen volume, symptoms, and hemoglobin.

What should be known about the safety profile of this inhibitor?

It’s well tolerated, and it’s got a nice therapeutic window. It’s broader than some BET inhibitors, and it’s flexible in a way that we’re able to adjust the dosing also based on the patient’s platelet count. That’s the real biomarker there; the specific drug-related toxicity that we are aware of and watch for is the platelet count. We will want some reduction if it’s high, but if they’re starting off too low, we’ll use a lower dose. Approximately 60% of patients will develop thrombocytopenia to some degree on the study. Some of that may be drug related vs disease related, but it’s manageable. At the doses we use, it’s not enough to [cause] significant grade 3/4 thrombocytopenia; it’s manageable, it’s grade 1/2 and we can adjust the dose so patients don’t bleed. There were 2 DLTs for thrombocytopenia at 12 mg daily monotherapy; they resolved, but 1 was for the bilirubin and 1 for the platelets. That’s why we just declared 10 mg as the MTD, because we’re already seeing so much activity with just that dose.

We don’t see much anemia. There can be anemia from the disease, but in general, we see more anemia improvement than worsening or stable hemoglobin with the combination therapy. We don’t see neutropenia, and we have not seen much gastrointestinal toxicity, which is notable with this class of therapy. [There was] no diarrhea and minimal, low-grade nausea. Approximately 20% to 30% of patients had dysgeusia, but it is very manageable. It’s been a very well-tolerated drug and is easy to work with at these doses of 4 mg to 10 mg.

What are some of the ongoing next steps for this research?

The monotherapy is [currently being evaluated] in a dose expansion, and the combination therapy is finishing dose escalation and then going into dose expansion. The monotherapy dose expansion includes patients with essential thrombocytopenia now, which is an interesting population to study with a BET inhibitor given their effects on platelets. We tried to be broad with this phase 1 escalation/expansion part of the study to evaluate as many different types of MPNs/myelofibrosis as we could. We still have a cohesive plan and path forward. Ultimately, given the landscape, this may proceed to multiple phase 2 or 3 studies in the future for different populations. A randomized phase 3 study in the front line of high-risk patients in that population is probably 1 place we want to look to see how [INCB057643] compares with ruxolitinib alone. Since we’ve already seen [the results of adding INCB057643] to] ruxolitinib, where it’s a little harder to get the responses optimized, we’d just [administer] both drugs out the gate.

What are some of the potential advantages of INCB057643 compared with other BET inhibitors in the space?

We think 1 advantage of the drug is that it can be given continuously. You don’t have to stop it or hold for AEs. We can adjust the dose, but it’s given every day. Of course, it can be held if needed, but there’s no planned dose holds. This may be the reason why we see such good symptom responses. A patient needs continuous exposure to the BET inhibitor to maintain those system responses and not have them rebound. When they’re off the inhibitor, MYC and other cytokines are going back up. The spleen responsiveness may be a bit more stable; it’s not going to grow overnight. It’s certainly an active class of drugs and an active molecule. We’ll see if we’re correct in terms of [labeling INCB057643] as best in class.

Reference

Watts JM, Vannucchi AM, Hunter A, et al. Bromodomain and extra-terminal (BET) inhibitor INCB057643 in patients with relapsed or refractory myelofibrosis (MF) and other advanced myeloid neoplasms: A phase 1 study. J Clin Oncol. 2024;42(suppl 16):6576. doi:10.1200/JCO.2024.42.16_suppl.6576