New Data Support Pelabresib Combination in Untreated Myelofibrosis

The 96-week results from the MANIFEST-2 phase 3 trial show that adding pelabresib to Jakafi (ruxolitinib) can provide stronger, clinically meaningful benefits for people with myelofibrosis who have not yet received a JAK inhibitor, compared with Jakafi alone, according to data presented by Dr. Raajit Rampal of Memorial Sloan Kettering Cancer Center at the 2025 ASH Annual Meeting and Exposition.

The pelabresib plus Jakafi combination demonstrated deep and durable improvements across primary and secondary efficacy end points compared to Jakafi monotherapy.

In patients who were evaluable at week 96 combination therapy was associated with at least a 35% reduction in spleen volume in 91.5% of patients versus 57.5% with Jakafi plus placebo indicating a sustained benefit from previous evaluation at week 24. At week 24 the reduction in spleen volume was 82.9% with the combination versus 41.8% with placebo plus Jakafi. The median duration of spleen response was not reached in the combination arm versus 138.3 weeks in the placebo arm.

In the intent-to-treat population reduction in spleen volume was maintained at week 96 by 45.3% in the pelabresib plus Jakafi arm versus 30.1% in the placebo plus Jakafi arm. At week 24 the reduction in spleen volume for the respective arms were 65.9% and 35.2%.

Patients in the intent-to-treat population receiving pelabresib plus Jakafi experienced a greater and more durable improvement in their total symptom score. The absolute change from baseline in total symptom score was negative 15.07 in the pelabresib plus Jakafi arm versus negative 12.48 in the placebo plus Jakafi arm. The difference in the arms was negative 2.59 which was greater than the negative 1.96 difference at week 24. A reduction in total symptom score from baseline of at least 50% was achieved by 36.9% of patients in the pelabresib plus Jakafi arm versus 28.2% in the placebo plus Jakafi arm.

The rate of achieving both a significant reduction in spleen volume and a significant symptom improvement was more than double in the combination therapy arm: 31.8% of patients in the pelabresib plus Jakafi arm versus 15.7% in the placebo plus Jakafi arm. This maintained the dual response benefit seen at week 24.

The pelabresib plus Jakafi combination demonstrated favorable effects on anemia, a common and challenging complication of myelofibrosis. In the pelabresib plus Jakafi arm the hemoglobin response was 17.8% versus 11.6% in the placebo plus Jakafi arm. Red blood cell transfusions were required up to week 96 in 33.1% of patients in the pelabresib plus Jakafi arm versus 39.9% in the placebo plus Jakafi arm.

Although the study was not statistically powered for survival end points the longer-term follow-up showed numerically fewer deaths and progression-free survival events in the pelabresib plus Jakafi arm.

In the pelabresib plus Jakafi arm there were 28 deaths versus 32 in the placebo plus Jakafi arm. In the pelabresib plus Jakafi arm the number of progression-free survival events was 22 versus 34 in the placebo plus Jakafi arm.

Bone marrow fibrosis was improved in 52.5% of evaluable patients with pelabresib plus Jakafi versus 27.5% with placebo plus Jakafi and there were also greater reductions in bone marrow morphology seen with the combination. Similar reductions in variable allele frequency of JAK2 V617F CALR and MPL were seen in both arms.

Pelabresib Plus Jakafi Shows Favorable Long-Term Safety and Manageable Side Effects 

The long-term safety profile of pelabresib plus Jakafi was comparable to that of placebo plus Jakafi. Treatment-emergent side effects were mainly low grade and remained similar between the arms over the follow-up period.

Any-grade treatment-emergent side effects occurred in 99.5% of patients in the pelabresib plus Jakafi arm versus 98.1% in the placebo plus Jakafi arm. Grade 3 or higher treatment-emergent side effects occurred in 67.5% of patients in the pelabresib plus Jakafi arm versus 70.1% in the placebo plus Jakafi arm.

Externally and independently adjudicated cases of leukemic transformation were reported in both arms. The frequency was noted to be in line with what is historically seen in myelofibrosis and an early imbalance between the arms decreased over time.

Study Design Supports Robust Evaluation of Combination in Myelofibrosis 

The MANIFEST-2 study is a double-blind randomized phase 3 trial designed to assess the efficacy and safety of combining pelabresib with Jakafi in patients with myelofibrosis who have not previously been treated with a Janus kinase inhibitor.

Standard-of-care treatment with Janus kinase inhibitor monotherapy improves splenomegaly and symptom burden but provides responses of limited depth and durability. There is a significant need for new combination strategies that can address the underlying biology of the disease and improve long-term clinical outcomes.

Patients were randomized to receive either pelabresib or a placebo once daily in combination with Jakafi administered twice daily.

The data cut off for this analysis was March 2, 2025, with a median follow-up period of 115.9 weeks.

At the cut off approximately half of the patients in both arms remained on their assigned treatment. A total of 56.5% of patients in the pelabresib plus Jakafi arm and 59.3% in the placebo plus Jakafi arm completed 96 weeks of the assigned treatment.

The most common reasons for treatment discontinuation included side effects, physician decision, withdrawal of consent, and protocol-defined disease progression.

The findings strongly suggest that the pelabresib plus Jakafi combination provides clinically meaningful benefits over the standard of care for Janus kinase inhibitor–naive patients with myelofibrosis.

“The week 96 results from the phase 3 MANIFEST-2 trial of pelabresib and Jakafi versus placebo and Jakafi constitute the longest follow-up to date of a randomized combination trial in Janus kinase inhibitor-naive patients with myelofibrosis” concluded Rampal.

Reference

1. "Durable efficacy and long-term safety with pelabresib plus ruxolitinib in JAK inhibitor-naive myelofibrosis: 96-week results from the phase III MANIFEST-2 study," by Dr. Raajit Rampal. Blood.

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