Positive Results from Prospective, Randomized, Phase 3 Registrational Trial of Pelabresib + Ruxolitinib for JAK Inhibitor-Naive Myelofibrosis

Using a combination of pelabresib and ruxolitinib provides a substantial clinical benefit over standard-of-care JAK inhibitors alone for treating myelofibrosis, according to outcomes from a randomized phase 3 trial. Recently published in Nature Medicine, the data marks a consequential step forward in this difficult-to-treat condition.

Background

“The mainstay of therapy for myelofibrosis have been JAK inhibitors, but they don’t work for everyone,” says Aaron Gerds, MD, a hematologist/oncologist at Cleveland Clinic Cancer Institute. “Roughly one third of patients can achieve a 35% reduction in spleen volume on the currently available JAK inhibitors. These therapies also have limited depth and durability of response. There is a lot more we need to do in terms of making inroads in endpoints such as reducing symptom burden for these patients.”

JAK inhibitors improve hepatosplenomegaly symptoms, but they do not provide actual disease modification. “These therapies don’t resolve genetic mutations or bone marrow morphology of the underlying disease,” says Dr. Gerds. “We need to get deeper inside these diseases and root them out in a meaningful way. That’s why we’re targeting complementary avenues to JAK signaling pathways.”

Data from the phase 2 trial MANIFEST demonstrated that patients achieved durable improvements in splenomegaly and symptom burden when treated with the bromodomain and extraterminal domain (BET) inhibitor pelabresib along with the JAK inhibitor ruxolitinib.

Study design

Building on this study, researchers launched MANIFEST-2, a global, phase 3, randomized, double-blind active control study. Four hundred thirty patients with a confirmed diagnosis of myelofibrosis and no previous JAK inhibitor treatment were randomized to either receive pelabresib and ruxolitinib or ruxolitinib plus placebo. One hundred fifty-four patients were in the pelabresib/placebo arm and 160 patients were in the pelabresib/ruxolitinib arm. (Two patients in each arm did not receive study treatment, and 54 patients in the placebo arm discontinued study treatment.)

Key findings

The primary endpoint was reduction in spleen volume by 35% or more. At week 24, 65.9% of patients in the pelebresib/ruxolitinib arm achieved a spleen volume reduction of 35% or more, compared to 35.2% in the ruxolitinib/placebo arm. Additionally, 18.8% of patients in the pelabresib/ruxolitinib arm achieved an improvement of at least one grade of bone marrow morphology, compared to 11.2% in the ruxolitinib/placebo arm.

There was no additive toxicity with the combination therapy compared to the single agent.

Patients receiving the combination therapy had more frequent improvements in pro-inflammatory cytokines, including TNF, IL-6 and IL-8, which are markers associated with a poor prognosis. Patients in the ruxolitinib/placebo arm were more likely to experience increases in IL-8, which is correlated with lower overall survival.

The study also evaluated patients’ hemoglobin levels. Of the patients who experienced anemia at the start of the study, 27.6% of the pelabresib/ruxolitinib group needed blood transfusions during the first 24 weeks of treatment, compared to 37.5% of patients in the ruxolitinib/placebo group.

Next steps

Researchers are awaiting long-term follow-up results from the trial to determine the durability of the response to this combination therapy. This data will help inform decisions about drug combinations and sequencing. The researchers are also closely watching other BET inhibitors in development.

“We’re entering a brave new frontier with this disease, thanks to more effective medications,” says Dr. Gerds. “Meanwhile, we need to dig deeper to identify markers such as allele burden and changes in fibrosis score, which may be markers of disease modification.”