MANIFEST-2: Pelabresib + ruxolitinib for the treatment of JAKi-naïve MF

Pelabresib, a bromodomain and extra-terminal motif inhibitor, is currently under investigation in Janus kinase inhibitor (JAKi) naïve patients with myelofibrosis (MF) as part of the phase III MANIFEST-2 trial (NCT04603495).¹

This trial was selected by the MPN Hub Steering Committee  as a top abstract at the 65th American Society of Hematology (ASH) Annual Meeting and Exposition. Rampal presented the latest data from the MANIFEST-2 clinical trial of pelabresib + ruxolitinib for the treatment of JAKi-naïve myelofibrosis. Here, we summarize the key points.

Study design¹

• In this double-blind trial, 430 patients were randomized 1:1 to either the experimental arm, receiving pelabresib 125 mg plus ruxolitinib; or a control arm, receiving placebo plus ruxolitinib, over 21-day cycles.
• The primary endpoint of MANIFEST-2 was ≥35% reduction in spleen volume ≥35% (SVR35) at Week 24.
• Secondary endpoints were Total Symptom Score (TSS) change, ≥50% reduction in TSS (TSS50) rate, and adverse events of any grade.

Key eligibility criteria included:

• patients with JAKi-naïve MF (primary of post-essential thrombocytosis/polycythemia vera);
• Dynamic International Prognostic Scoring System intermediate-1 or above;
• splenomegaly of ≥450 cm³; and
• TSS ≥10.

Results¹

At Week 24, the rate of SVR35, TSS50, and absolute change in symptom scores were recorded. Overall, the rate of SVR35 and TSS50 was higher in the experimental arm, with a higher mean spleen volume reduction (SVR) across the whole cohort (Figures 1 and 2).

SVR35, ≥35% reduction in spleen volume ; TSS50, ≥50% reduction in Total Symptom Score.
*Adapted from Rampal.¹

• The mean SVR for pelabresib + ruxolitinib was −50.6%
• The mean SVR for placebo + ruxolitinib was −30.6%

RUX, ruxolitinib; SVR35, ≥35% reduction in spleen volume ; TSS50, ≥50% reduction in Total Symptom Score.
*Adapted from Rampal.¹

 In each measure of TSS, pelabresib + ruxolitinib resulted in a larger mean change in symptom score from baseline to Week 24 (Figure 3). The highest recorded symptom decrease was observed in itching and pain under the left rib vs night sweats and pain under the left rib in the pelabresib arm vs the placebo arm, respectively.

RUX, ruxolitinib.
*Adapted from Rampal.¹

 Safety¹

Overall, the safety profile was comparable for the pelabresib and ruxolitinib alone groups (Table 1). A decreased incidence of anemia was observed, which is particularly beneficial for the treatment of MF where anemia is common.

Table 1. Treatment-emergent adverse events*

AE, adverse event; SAE, serious adverse event. *Adapted from Rampal.1
Treatment-emergent adverse event, % (unless otherwise specified)	Pelabresib + ruxolitinib (n = 212)	Placebo + ruxolitinib (n = 214)
Any grade AE	96.7	97.2
Grade ≥3 AE	49.1	57.5
SAE	29.7	29.4
Hematologic
Anemia	43.9	55.6
Thrombocytopenia	32.1	23.4
Decreased platelet               count	20.8	15.9
Non-hematologic
Diarrhea	23.1	18.7
Dysgeusia	18.4	3.7
Constipation	18.4	24.3
Nausea	14.2	15.0
Cough	12.7	11.2
Fatigue	11.8	16.8
Dizziness	11.3	8.9
Headache	11.3	10.7
COVID-19	11.3	15.9
Dyspnea	9.0	13.1

Conclusion

Overall, treatment with pelabresib + ruxolitinib resulted in a higher incidence of SVR35 and significantly reduced splenomegaly in JAKi-naïve patients with MF compared with ruxolitinib + placebo. The combination also produced a significantly higher rate of dual SVR35 and TSS50, with a higher rate of improved individual symptom scores. The safety profile was comparable with ruxolitinib monotherapy, with a lower incidence of anemia. The results of MANIFEST-2 highlight pelabresib as a potential treatment option for JAKI-naïve MF for extended investigation in clinical trials.