Myelofibrosis Trial: Combining a BET and JAK Inhibitor Might Be Better Than SOC

For patients who have Janus kinase (JAK) inhibitor–naive myelofibrosis, the combination of pelabresib plus ruxolitinib provides markedly greater benefit compared with ruxolitinib monotherapy. This is according to a primary analysis of the MANIFEST-2 randomized phase 3 trial published in Nature Medicine.

First author for the study Raajit Rampal, MD, PhD, of Memorial Sloan-Kettering Cancer Center in New York City, wrote with colleagues that the combination “is well tolerated, improves signs of underlying myelofibrosis pathobiology and provides substantial clinical benefit over standard-of-care JAK inhibitor monotherapy.”

Monotherapy with a JAK inhibitor such as ruxolitinib is the current standard of care (SOC) for myelofibrosis. Investigators launched the MANIFEST-2 trial to evaluate how the bromodomain and extra-terminal domain (BET) inhibitor pelabresib compares with this standard.

In the trial, patients with JAK inhibitor–naive myelofibrosis were randomized 1:1 to receive either the study combination of pelabresib plus ruxolitinib or an SOC regimen of placebo plus ruxolitinib. They were administered either pelabresib 125 mg once daily for 14 days followed by a 7-day break or placebo, combined with twice daily ruxolitinib dosed at 10 or 15 mg. The trial’s study arm ultimately enrolled 214 patients, and its SOC arm enrolled 216 patients.

The primary end point for the trial, reduction in spleen volume by 35% or more from baseline at week 24, was achieved for 65.9% of patients who received the study combination versus 35.2% of patients who received the SOC regimen (P<0.001).

The results included evidence of symptom improvement with the study combination, with an absolute change in total symptom score (TSS) of –15.99 in the study arm versus –14.05 in the SOC arm (P=0.0545). A reduction in TSS of at least 50% from baseline by week 24 was achieved in 52.3% of patients in the study arm versus 46.3% in the SOC arm.

“Consistent with proinflammatory cytokines analysis, improvements in fibrosis and overall bone marrow morphology were also observed to a greater degree in the pelabresib–ruxolitinib arm than in the ruxolitinib–placebo arm,” Rampal and colleagues mentioned.

The most common treatment-emergent adverse events observed in the trial were thrombocytopenia and anemia. Thrombocytopenia affected 52.8% of patients in the study arm and 37.4% of patients in the SOC arm; grade 3 or worse severity was noted in 13.2% of patients in the study arm and 6.1% of patients in the SOC arm. Anemia affected 44.8% of patients in the study arm and 55.1% of patients in the SOC arm; grade 3 or worse severity was noted in 23.1% of patients in the study arm and 36.5% of patients in the SOC arm.

“Durability of response, survival and correlation with clinical outcomes will be further evaluated with ongoing, long-term follow-up of this study,” noted Rampal and colleagues.