February 2017 Vol 10, Special Issue: Payers’ Perspectives In Oncology: ASH 2016 Highlights - Myelofibrosis
Phoebe Starr

San Diego, CA—The investigational drug pacritinib, a JAK1/JAK2 inhibitor, achieved benefits in patients with myelofibrosis, including a significant reduction in the spleen volume compared with the best available therapy that included the JAK1/JAK2 inhibitor ruxolitinib (Jakafi), according to the phase 3 PERSIST-2 clinical trial. The results were presented by John O. Mascarenhas, MD, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York City, at the 2016 American Society of Hematology (ASH) meeting.

The PERSIST-2 study enrolled patients with myelofibrosis associated with thrombocytopenia, a known risk factor for death and complications. Although the study results suggest that pacritinib is beneficial for these patients, the FDA put studies of pacritinib on hold in February 2016, because of cardiac and hemorrhagic concerns, as well as excess deaths in the phase 3 PERSIST-1 study. The PERSIST-2 results were not known at that time.

At the ASH meeting experts emphasized that myelofibrosis associated with thrombocytopenia is a potentially fatal disease, with few good treatment options, and the safety of pacritinib shown in PERSIST-2 is reasonable.

Encouraging Efficacy

“PERSIST-2 is the only randomized trial to date in patients with myelofibrosis and thrombocytopenia and prior JAK2 inhibitor exposure. This study is intriguing. Pacritinib did improve symptoms and spleen volume, but it remains to be seen what the FDA will do,” said ASH Secretary Stephanie J. Lee, MD, MPH, Professor of Medicine, Univer­sity of Washington, Seattle, during a premeeting webinar, where this study was singled out as important.

In the PERSIST-2 study, 221 patients (of a planned 311 patients) were randomized to pacritinib 400 mg once daily, pacritinib 200 mg twice daily, or best available therapy, which included the JAK1/JAK2 inhibitor ruxolitinib. Ruxo­litinib is indicated for intermediate- or high-risk myelofibrosis but not for thrombocytopenia (platelet counts <100,000 µL). However, up to 33% of patients with myelofibrosis have low platelet counts.

Overall, 18.1% of patients who received either dose of pacritinib achieved a spleen volume reduction from baseline at 24 weeks versus 2% of patients who received best available therapy (P = .001). This primary end point was achieved in 14% of the 75 patients who received once-daily pacritinib and in 21.6% of patients who received twice-daily pacritinib, both of which were significantly (P = .001) superior to the best available therapy. Furthermore, 25% of patients who received pacritinib had ≥50% total symptom score reduction versus 14% of patients who received best available therapy. There was no significant difference in the overall survival across the treatment arms.

Safety Profile

Death rate was the same (at 14%) among patients who received pacritinib 400 mg once daily and in patients who received best available therapy, but was lower (9%) among patients who received pacritinib 200 mg twice daily.

The most common treatment-emergent adverse events were gastrointestinal and hematologic, and these generally occurred less frequently with twice-daily pacritinib than with once-daily pacritinib. Grade 3 or 4 cardiac adverse events occurred in 7% of patients who received once-daily pacritinib, in 13% of patients who received twice-daily pacritinib, and in 3% of patients who received the best available therapy; grade 3 or 4 bleeding occurred in 14%, 7%, and 7% of patients, respectively.

“The safety profile remains reasonable, given the fact that we are treating patients with low platelet counts who are already at risk for both bleeding and cardiac events,” said Dr Mascarenhas.

“I think the FDA needs to revisit their decision to put this drug on clinical hold. Pacritinib is good for patients with low platelet counts and has many of the benefits seen with prior therapies,” said Selina M. Luger, MD, Director, Leukemia Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, a session co-moderator at ASH.

In the original phase 3 study, the drug looked like it had some toxicity, added Dr Luger.

“I think you have to realize that these patients have a disease…[that] is much more toxic than what we have seen with this drug. I would not give this drug to a healthy individual, but we need to learn how to minimize those toxicities in these sick patients,” she said.

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