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Dr John Mascarenhas: Preliminary Data Show Substantial Spleen, Symptom Improvement With Pelabresib, Ruxolitinib Combination in Myelofibrosis


John Mascarenhas, MD, director of the Adult Leukemia Program at The Tisch Cancer Institute at Mount Sinai, spoke on preliminary data findings of the phase 2 MANIFEST study investigating the efficacy and safety profile of pelabresib, ruxolitinib combination therapy in JAK inhibitor-naive patients with myelofibrosis and those with suboptimal response to ruxolitinib monotherapy.

Significant improvement in spleen volume reduction (SVR) and symptom burden observed with pelabresib, ruxolitinib combination therapy in phase 2 data of patients with myelofibrosis, both Janus kinase (JAK) inhibitor-naive and those with suboptimal response to ruxolitinib monotherapy, highlights its potential moving into randomized phase 3 investigations, said John Mascarenhas, MD, director of the Adult Leukemia Program at The Tisch Cancer Institute at Mount Sinai.

Mascarenhas served as lead author of a study presented at the 2022 European Hematology Association (EHA) Congress, titled, “BET inhibitor pelabresib (CPI-0610) combined with ruxolitinib in patients with myelofibrosis — JAK inhibitor-naive or with suboptimal response to ruxolitinib — preliminary data from the MANIFEST study.”


How did efficacy and safety of pelabresib, ruxolitinib combination therapy fare in the phase 2 MANIFEST study of patients with myelofibrosis?

So, what we've seen so far, now this is being presented at EHA2022, the most mature results of this phase 2 study. The 2 cohorts of primary interest are cohort 2, so suboptimal responses of ruxolitinib receiving pelabresib at about 125 milligrams daily, days 1-14 of a 21-day cycle. And cohort 3, the JAK inhibitor-naive patients who received both drugs. Again, pelabresib, 125 milligrams daily, days 1-14 of a 21-day cycle.

What we've seen is phenomenal results in terms of spleen and symptom benefits. So, for example, if you look at cohort 3, the RUX [ruxolitinib] inhibitor-naive patients, we saw a SVR rate of 35% or greater at 68%, and a TSS [total symptom score] response rate of 56%.

If you go backwards and look in time, and compare this to studies of monotherapy, this compares very favorably. Monotherapy JAK inhibitor with ruxolitinib treatment, somewhere between 20%-40% response rates. And here we're seeing nearly 70% response rate in terms of SVR. These responses are deep, they build over time with the drug, and we're seeing responses in terms of anemia responses as well, as well as bone marrow fibrosis reduction—anywhere between 25% to 30% of patients are having at least a one grade reduction of bone marrow fibrosis even within 6 months, and we don't typically see this with ruxolitinib therapy.

What we're seeing in the clinic in many ways is replicating what was seen in the preclinical modeling, and the murine modeling, demonstrating synergy of these 2 drugs together in better modifying aspects of the disease. What I'm hoping for, which is where this is all leading to is the MANIFEST-2 study, which is a randomized phase 3 study in JAK inhibitor-naive patients built off cohort 3 or arm 3 of the MANIFEST phase 2 study in patients who are naive, randomized to ruxolitinib plus pelabresib, ruxolitinib plus placebo, in a double-blinded fashion.

What I’m hoping to see there is an improvement in duration of benefit of ruxolitinib. So, to extend that median, which has been about 3 years in the COMFORT studies (NCT00952289), perhaps even less than in the commercial real-world space, and extend the benefit longer, because we know that patients who discontinue ruxolitinib will have a poor survival that approximates about a year to a year and a half.

So, what I'm really hoping for is that this combination continues to prove that it is superior in terms of spleen and symptom benefit, is less myelosuppressive—so actually, if you look at the anemia curves with the combination, they are not as deep, the nadir of anemia, which is an on target effect of JAK-2 inhibition, is not as deep when the 2 drugs are combined.

In fact, if you look at arm 3 of the combination in JAK inhibitor-naive patients, the grade 3-4 anemia rate was about 34% and thrombocytopenia rate was 12%. So, this drug does not add significant additional myelosuppression and that's notable because many of the drugs that we do give in myelofibrosis are associated with significant mild suppression and then combining that often amplifies.

This drug is a well tolerated drug, you do see about 30% of patients grade 1-2 GI [gastrointestinal] toxicity, so nausea, vomiting, diarrhea, usually the first couple of cycles. It is rarely a reason for discontinuation of the drug, very easy to manage. And I have to say, all in all, we've not seen a concerning safety signal as it relates to infectious complications or other toxicity.

So, the drug in MANIFEST phase 2 has demonstrated whether it's upfront or in salvaging response to ruxolitinib treated patients, both efficacy, safety, and has not only informed but I think provided the real confidence to move into a randomized phase 3 upfront setting trial, which, again, I would say pelabresib was really the first drug to be combined with ruxolitinib in the upfront setting.

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