BMS-986158 With JAKi Shows a Manageable Safety Profile in Myelofibrosis

Haifa Kathrin Al-Ali, MD

The combination of BMS-986158, a potent bromodomain and extra-terminal motift (BET) inhibitor, with a Janus kinase (JAK) inhibitor, either ruxolitinib (Jakafi) or fedratinib (Inrebic), was manageable in regard to safety when used for the treatment of patients with intermediate- or high-risk myelofibrosis (MF), according to updated findings from the phase 1/2 CA011-023 study (NCT04817007).¹

In the phase 1/2 study, part 1A of the trial is a dose-escalation phase where BMS-986158 was given in combination with ruxolitinib in patients with MF who were ruxolitinib-naive. In part 1B, patients with relapsed, refractory, or intolerant disease prior to treatment with ruxolitinib were treated with BMS-986158 and fedratinib. For parts 1A and 1B, the planned doses were BMS-986158 2, 3, and 3.75 mg every day (QD) following a schedule of 5 days on and 2 days off and ruxolitinib at 15 mg twice a day, and BMS-986158 0.5, 0.75, and 1.25 mg QD 5 days on and 2 days off and fedratinib 400 mg QD.

Investigators evaluated the primary end points of safety, tolerability, and the determination of a maximum tolerated dose in the dose-escalation phase, as well as the secondary end point of spleen volume reduction (SVR) from baseline. A total of 23 patients were treated as of September 2, 2022, including 11 patients in part 1A and 12 in part 1B. In part 1A, the median age of patients was 67 years (range, 36-81) and in part 1B the median age was 69 years (range, 37-77).

Safety findings showed that any grade treatment-related adverse events (TRAEs) were observed in 9 (82%) and 9 (75%) patients in parts 1A and 1B of the study, and grade 3/4 TRAEs included thrombocytopenia (n = 5, 45%), neutropenia, hypertension, and anemia (n = 1 each, 9%) in part 1A and thrombocytopenia, anemia (n = 5 each, 42%), diarrhea, and blood bilirubin increase (n = 1 each, 8%) in part 1B. Two patients had dose-limiting toxicities (DLTs) in part 1A while 3 had DLTs in part 1B.

Among all evaluable patients in part 1A, SVR was observed at week 12. These responses continued to deepen at week 24. A total of 83% of patients who received BMS-986158 at doses of 2 or 3 mg and ruxolitinib met SVR35 at week 12, and all patients (n = 6) met SVR35 at week 24. This compared with 0 patients meeting SVR35 at week 15 in part 1B among those given BMS-986158 at a dose of 0.5 or 0.75 mg and fedratinib, but 1 of 3 patients in this group (33%) met SVR35 at week 24.

Based on these findings, the trial will conduct a dose-expansion phase using the recommended phase 2 dose of BMS-986158 and ruxolitinib (part 2A) or BMS-986158 with or without fedratinib (part 2B).

In an interview with Targeted Oncology^TM, Haifa Kathrin Al-Ali, MD, professor of translational oncology and head of the Krukenberg Cancer Center at the University Hospital of Halle (Saale) in Germany, discussed findings from the phase 1/2 CA011-023 study of BMS-986158 combined with ruxolitinib or fedratinib in MF.

Red blood cells: © vipman4 - stock.adobe.com

Targeted Oncology: Can you discuss the research you were a part of at the 2023 American Society of Hematology Annual Meeting and the rationale behind it?

Al-Ali: The abstract is about the use of a BET inhibitor called BMS-986158 in combination with JAK inhibitors in first- or second-line of treatment in patients with myelofibrosis. The rationale for this phase 1/2 trial is that although JAK inhibitors have changed the landscape of the treatment of patients with myelofibrosis, they do have some limitations. Mainly, [they have] the issue of loss of response progress of the disease. We know that BET inhibition is an epigenetic approach to modulate gene expression. The rationale is to combine 2 different pathways of action with the hope to improve the response and durability and then the whole outcome of the patient.

What can you discuss regarding the methods, design, and inclusion in the trial?

The trial is a phase 1/2 trial. Phase 1 is the dose-escalation phase which has 2 arms with the first-line treatment of patients with no JAK inhibitor therapy previously. They will have the combination of ruxolitinib plus escalating doses of the BET inhibitor. The second arm [includes] patients who have failed ruxolitinib treatment or are intolerant, and they are treated with the combination of the JAK inhibitor fedratinib and the BET inhibitor in escalating doses. If the dose-escalation phase finishes, then the dose-expansion phase 2 will start.

Can you discuss safety and tolerability in this trial?

In the dose-escalation phase, the main objectives are safety and tolerability. For safety overall, we could say that both the first-line and second-line combinations seem reasonable and tolerable, although there are some adverse events, mainly thrombocytopenia, as expected, from the mechanism of action of both drugs. Yet this was manageable with no bleeding and no discontinuation in part A. In the first-line part or the second-line treatment, there was only 1 patient that was discontinued because of thrombocytopenia. There were some [gastrointestinal] adverse events, but the majority were not severe, and in most of the cases, did not lead to discontinuation of treatment.

In the phase 1 trial data, we showed that the 2 and 3 mg dosing of the BET inhibitor 5 days in a week, 2 days off, to be an optimal dosing for the phase 2 part of the trial. For the second-line treatment with fedratinib, it seems likely that the 1 mg dosing 5 days on, 2 days off, or even the alternative of 5 days and 2 days off, or 3 weeks on and 1 week off, seems to be the most promising dose for the expansion phase.

How was thrombocytopenia managed in both regimens?

For both regimens, the most important was dose modification, dose reduction, and even dose discontinuation depending on the severity of the adverse event. As I said, all adverse events were reversible and manageable with the dose reductions of both the JAK inhibitor, as well as the BET inhibitor.

Could you explain the significance of the observed spleen volume reductions in response rates at week 12 and week 24?

It is very promising with most of the patients reaching the 12[-week] and 24[-week] estimation and evaluation. Their responses were high, more than 80% of patients, but I always stress at this point, we are speaking about phase 1 data. We have more patients. This is an observation which is interesting and promising, but I think we have to wait longer to have more solid data regarding efficacy.

Do you think these results are comparable with other treatments in myelofibrosis?

It's much too early at this stage of the trial to make final conclusions, but it seems promising to have a combination of a JAK inhibitor with a BET inhibitor in the treatment of myelofibrosis. Whether the right thing is to do this from the very beginning in the first-line setting, or at the second part of this trial in the second-line setting, this needs to still be evaluated because we have a lot of large data from other BET inhibitors in the first-line setting. Particularly for patients with suboptimal response in the second-line treatment options, with available data, the most promising approach is in hoping to get the sustainable outcome for our patients.

Are there any other efficacy findings that you'd like to highlight?

There is some observational data that I think is very important. When looking at the data, we have some evidence that in some of these few patients, there was a regression of bone marrow fibrosis, and there are reductions of the JAK allele burden that were observed. Again, I think this is much too preliminary to make final conclusions.

What are the next steps for studying this combination?

Part 2 of the first-line treatment is already open and enrolling. The second-line treatment with fedratinib and the BET inhibitor with a dose of 1 mg is most likely to be looked at in part 2 of the trial, which will open. Patients are continually being enrolled and treated, so we will have more data on safety, including symptom response because in this early stage. We cannot say anything about total symptom improvement, which is a very important aspect for patients with myelofibrosis. These data will be presented in the second part of the trial.

What are some of the biggest challenges remaining in the treatment of myelofibrosis? How do you think targeted therapies like this could help address them?

This is an exciting time for patients with myelofibrosis because we have so many options. Today, we could not say what is the best option for what patients at what time point of the disease. We can only find these answers if we try to include patients as much as possible in all these different trials. I think that in the next few years, we will identify subgroups of patients that are more likely to benefit from 1 combination compared with another group of patients for whom it might be better to use another combination. I think it is an exciting time for patients because of all these new options and possibilities.

REFERENCE:

Ayala R, Lopez N, Abulafia AS, et al. S213: BMS-986158, a potent BET inhibitor, as monotherapy and in combination with ruxolitinib or fedratinib in intermediate- or high-risk myelofibrosis (mf): results from a phase 1/2 study. Hemasphere. 2023;7(Suppl ):e4785165. Published 2023 Aug 8. doi:10.1097/01.HS9.0000967764.47851.65