Behind MANIFEST-2: Pelabresib Plus Ruxolitinib in Myelofibrosis

Raajit K. Rampal, MD, PhD, hematologic oncologist at Memorial Sloan Kettering Cancer Center, discusses the MANIFEST-2 trial, a phase 3 study comparing ruxolitinib (Jakafi) to pelabresib (CPI-0610) and ruxolitinib combined with placebo.

The trial enrolled untreated patients with symptomatic and enlarged spleens due to myelofibrosis.

Transcription:

0:09 | I presented the phase 3 data for the MANIFEST-2 trial, which was a phase 3 trial that was comparing ruxolitinib and pelabresib, which is a BET inhibitor, vs ruxolitinib and placebo. This was a trial of untreated patients with myelofibrosis who had symptoms and an enlarged spleen. It was a double-blind, placebo-controlled trial, the primary end point being the spleen volume reduction by 35%, as well as the key secondary end points of total symptom score reduction and the proportion of patients who achieved a 50% reduction in their total symptom score.

0:49 | The top-line data from this study demonstrated that as compared with ruxolitinib monotherapy, there was a clear superiority of the combination therapy in terms of reducing the spleen size, which was almost a 2-fold magnitude increase in the proportion of patients whose spleen was reduced in size. I think the significance of that is that, at least historically, it has shown that there is a survival benefit that correlates with spleen volume reduction. That was not what was directly assessed with this trial, but I think that is part of what makes it important.

1:25 | With regards to symptom reduction, there was a numerical benefit in terms of the combination vs single-agent ruxolitinib, although it did not quite reach statistical significance. I think beyond those end points were some other compelling and important data, including reductions in inflammatory cytokines that we are seeing with a combination [that are] not seen quite so much with ruxolitinib alone, better hemoglobin parameters for the combination, more patients had anemia with ruxolitinib alone and better preservation with the combination therapies. [For] bone marrow fibrosis, a greater proportion of patients appeared to have an improvement in their bone marrow fibrosis with combination than what we have seen with ruxolitinib alone. I think those are kind of the key positive takeaways.

2:20 | Importantly, there were not any new adverse event signals from the combination therapy. The 1 thing that if we think about hematologic and non-hematologic toxicity, there was a little bit more thrombocytopenia seen with combination therapy, and in nonhematologic toxicities, that was observed with combination therapy than with ruxolitinib. But again, largely there [were] no new safety signals from the combination therapy over what we have seen with ruxolitinib.