BMS-986158 in combination with JAKi: An early analysis of disease modification in myelofibrosis

BMS-986158 is a selective oral bromodomain and extra-terminal motif inhibitor currently under evaluation in combination with the Janus kinase inhibitors (JAKi) ruxolitinib or fedratinib in patients with treatment-naïve (TN) and relapsed/refractory (R/R) myelofibrosis (MF), as part of the phase 1b/2 CA011-023 (NCT04817007) study.

JAKi are the current standard of care for MF. The use of bromodomain and extra-terminal motif inhibitor in combination has been shown to reduce proinflammatory signals and disease burden preclinically – a key differentiator from the standard of care in MF.

During the 65th American Society of Hematology (ASH) Annual Meeting, Lee-Hoflich, et al. presented an analysis of the early disease-modifying properties of BMS-986158 in combination with JAKi. Here, we summarize the key points.

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Design¹

A summary of the trial design and key eligibility criteria are provided in Figure 1.

BID, twice a day; DIPSS, Dynamic International Prognostic Scoring System; ECOG PS, Eastern Cooperative Oncology Group performance status; FED, fedratinib; Int, intermediate; MF, myelofibrosis; QD, daily; RP2D, recommended phase II dose; RUX, ruxolitinib.
*Adapted from Lee-Hoflich, et al.¹

 In this analysis, exploratory measures of disease modification included:

• measurement of longitudinal JAK2 VAF;
• evaluation of the bone marrow microenvironment;
• megakaryocyte cluster density; and
• modulation of circulatory cytokines and growth factors.

Results¹

• In total, 80% of patients with TN MF (n = 10) and 57% of patients with R/R MF (n = 7) experienced a ≥20% JAK2^v617F VAF reduction.
• Most patients reached persistent JAK2^v617F VAF reduction at 48 weeks.
• A reduction in fibrosis was observed in both TN and R/R MF, positively associated with an increasing dose level of BMS-986158.
• Overall, 45% of patients with TN MF and 20% with R/R MF achieved a Grade ≥1 bone marrow fibrosis (BMF) reduction, associated positively with increased dose levels.

A summary of Grade ≥1 BMF reductions for TN and R/R patients are outlined in Tables 1 and 2, respectively.

Table 1. Bone marrow fibrosis reduction in patients with treatment-naïve myelofibrosis*

BID, twice daily; MF, myelofibrosis; QD, daily; RUX, ruxolitinib. *Adapted from Lee-Hoflich, et al.1
BMS-986158 QD + RUX 15 mg BID, % (unless otherwise specified)	Grade ≥1 reduction	Stabilized (maintained at MF 1 or MF 2)	Progressed (increased MF score or at highest grade MF 3)
2.0 mg	0	100	0
3.0 mg	50	25	25
3.75 mg	100	0	0

Table 2. Bone marrow fibrosis reduction in patients with relapsed/refractory myelofibrosis*

BID, twice daily; FED, fedratinib; MF, myelofibrosis; QD, daily. *Adapted from Lee-Hoflich, et al.1
BMS-986158 QD + FED 400 mg, % (unless otherwise specified)	Grade ≥1 reduction	Stabilized (maintained at MF 1 or MF 2)	Progressed (increased MF score or at highest grade MF 3)
0.5 mg	0	0	100
0.75 mg	0	25	75
1.0 mg	50	50	0

Conclusion

Data from this biomarker analysis highlights potential disease-modifying properties of combination BMS-986158 + JAKi in both TN and R/R MF. In this small cohort, most patients reached ≥20% JAK2^v617F VAF reduction, as the dose levels increased. This suggests that this combination could be a feasible treatment option for further clinical trials.