Momelotinib Combo is Safe and Helps Ease Symptoms in Myelofibrosis

Treatment with nuvisertib in combination with Ojjaara (momelotinib) is safe and generated meaningful improvements in symptom burden, spleen volume, and anemia outcomes in patients with relapsed or refractory myelofibrosis previously treated with at least one JAK inhibitor, according to data from a phase 1/2 study presented at the 2025 ASH Annual Meeting and Exposition.

Across evaluable patients with relapsed or refractory disease receiving nuvisertib at 360 milligrams (mg) twice daily or higher (18 patients), the combination appeared well tolerated and produced a 58% total symptom score reduction of at least 50% at any time, with an absolute reduction in all 7 individual symptoms; at week 24, this rate was 42%. There was a spleen volume reduction of at least 25% in 50% of patients at both week 24 and at any given time. Moreover, there was a 56% anemia response rate. These outcomes consisted of 3 major responses and 6 minor responses.

Notably, Dr. John O. Mascarenhas explained that this is the first combination study using momelotinib in myelofibrosis, saying: “This is the preliminary data from the phase 1/2 study of nuvisertib… in combination with momelotinib, which has shown clinical responses in patients with relapsed or refractory myelofibrosis.”

Mascarenhas is a professor of medicine at the Icahn School of Medicine at Mount Sinai, director of the Center of Excellence for Blood Cancers and Myeloid Disorders, a member of The Tisch Cancer Institute, and director of the Adult Leukemia Program, and is a clinical investigator for the Myeloproliferative Disorders Program.

Understanding the Scientific Rationale for this Combination Therapy

During the presentation, Mascarenhas explained that targeting both the PIM1 and JAK-mediated pathways may address circumstances that contribute to persistent symptom burden, spleen progression, and cytopenias in patients with myelofibrosis. It is for this reason that nuvisertib, an oral selective PIM1 inhibitor, was combined with momelotinib, an already FDA-approved JAK1 JAK2 and ACVR1 inhibitor, with demonstrated activity and improvement in anemia for those with myelofibrosis. Nuvisertib also previously demonstrated single-agent activity in relapsed or refractory disease.

It was based on these complementary mechanisms that investigators aimed to better understand this dual inhibition approach.

“We thought a combination strategy with momelotinib and nuvisertib, which have differing mechanisms of action and minimal overlapping toxicities, would be advantageous and worth evaluating in myelofibrosis,” Mascarenhas stated.

With this in mind, the global phase 1/2 study was launched and enrolled patients with primary post–polycythemia vera or post–essential thrombocythemia myelofibrosis who previously received a JAK inhibitor other than momelotinib.

During treatment, nuvisertib was escalated from 240 mg to 720 mg twice daily in combination with momelotinib 200 mg once daily. The primary end point of the study was safety and tolerability, while secondary end points included spleen volume reduction, total symptom score reduction, overall survival, bone marrow fibrosis changes, and pharmacokinetics.

Safety and Early Efficacy of Nuvisertib Plus Momelotinib

The combination demonstrated a favorable safety profile throughout dose escalation, according to Mascarenhas. Across dose cohorts of nuvisertib 240 mg, 360 mg, 480 mg, and 720 mg twice daily combined with momelotinib 200 mg once daily, one dose-limiting toxicity of grade 4 thrombocytopenia without bleeding occurred, and the maximum tolerated dose was not reached. Three patients required dose modifications for gastrointestinal side effects, and enrollment is ongoing.

The most common nonhematologic treatment-emergent side effects were grade 1/2 diarrhea 78% nausea 50% vomiting 28% fatigue 22% and decreased appetite 22%; isolated grade 3 events occurred with nausea and vomiting, and no grade 3 or 4 events occurred with diarrhea, fatigue, decreased appetite, or increased creatinine. Additional nonhematologic events occurring in at least 20% of patients included grade 2 urinary tract infections in 4 patients.

Hematologic toxicity was limited, with decreased platelet counts observed in a small subset; 2 patients experienced grade 2 and 2 experienced grade 3/4 thrombocytopenia.

“In general, this is a really well tolerated combination. There was no new safety signal found with the combination that we did not see with the monotherapy,” Mascarenhas explained.

Clinical Benefit and Ongoing Development in Myelofibrosis

Among patients treated with nuvisertib 360 mg twice daily or higher (12 patients), clinically meaningful symptom and spleen responses were observed, and symptom improvement was sustained. Deep reductions across all symptom domains were demonstrated, including fatigue, night sweats, early satiety, abdominal discomfort, pain under the left ribs, and bone pain. Individual symptom analysis demonstrated reductions across all symptoms, including normalization of fatigue scores toward levels seen in non-myelofibrosis populations.

The combination maintained platelet stability and produced clinically significant improvements in hemoglobin. Moreover, early platelet declines resolved quickly, returning to stable trajectories during therapy. These findings align with prior nuvisertib monotherapy results, where the agent demonstrated non-myelosuppressive activity and allowed ongoing hemoglobin and platelet stability.

The combination produced sustained clinical benefit, with 12 patients remaining on treatment at the time of analysis, although discontinuations occurred in 3 patients due to side effects, two by patient withdrawal, and one by physician decision to pursue stem cell transplantation. Moreover, increases in anti-inflammatory adiponectin and decreases in the pro-inflammatory alarmin EN-RAGE correlated with the degree of symptom improvement observed.

“Overall, these preliminary data support ongoing clinical development of nuvisertib in combination with momelotinib for myelofibrosis,” Mascarenhas concluded.

Reference

1. “Preliminary data from the Phase I/II study of nuvisertib, an oral investigational selective PIM1 inhibitor, in combination with momelotinib showed clinical responses in patients with relapsed/refractory myelofibrosis,” byDr. John O. Mascarenhas. Blood.

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