Nuvisertib Combo Improves Safety in JAK-Pretreated R/R Myelofibrosis

Nuvisertib combined with momelotinib achieved a spleen volume reduction of 25% at week 24 and any given time in 50% of patients with relapsed/refractory myelofibrosis.

Results from a phase 1/2 trial shared at the 2025 American Society of Hematology (ASH) Annual Meeting and Exposition demonstrated safer outcomes with nuvisertib (TP-3654) plus momelotinib (Ojjaara), as well as improved symptom burden, anemia outcomes, and spleen volume, in patients with relapsed/refractory myelofibrosis following treatment with at least 1 JAK inhibitor.

Across evaluable patients with relapsed/refractory disease receiving nuvisertib at 360 mg twice daily or higher (n = 18), the combination appeared well tolerated and produced a 58% total symptom score reduction of at least 50% (TSS50) 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% (SVR25) 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/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. Key eligibility criteria included having a DIPSS intermediate-1 or intermediate-2 score, or high-risk disease; a platelet count of 50×10⁹/L or greater; hemoglobin less than 10 g/dL; splenomegaly of 450 cm³ or greater; and quantifiable baseline symptoms per MF-SAF v4.0.

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, TTS reduction, overall survival, bone marrow fibrosis changes, and pharmacokinetics.

The median age for patients treated (n = 18) was 75 years (range, 51-82), 50% were male, the median spleen volume was 1370 cm³ (614-4250), median spleen length was 8 cm (3-20), and median TSS was 29 (9-37). At baseline, the median platelet count was 196×10⁹/L (range, 81-601×10⁹/L), with 83% of patients having counts of at least 100×10⁹/L and 17% having counts below 100×10⁹/L. The median hemoglobin was 9.1 g/dL (7.9-10.1 g/dL), and 56% of patients required transfusion. Among disease characteristics, 44% had primary myelofibrosis, 17% had post-polycythemia vera myelofibrosis, and 39% had post-essential thrombocythemia myelofibrosis. According to the DIPSS, 6% were intermediate-1 risk, 61% intermediate-2 risk, and 33% high risk.

Mutational analysis showed JAK2 V617F in 61%, calreticulin in 17%, MPL variants in 22%, and triple-negative disease in 6%, with 61% harboring high molecular risk mutations defined as ASXL1, SRSF2, EZH2, IDH1/2, or U2AF1. All patients had received at least one prior JAK inhibitor, including 17% who had received two or more, and the duration of prior therapy was less than 6 months in 11%, 6 to 12 months in 17%, and at least 12 months in 72%.

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 (16.7%) required dose modifications for gastrointestinal adverse effects (AEs), and enrollment is ongoing.

The most common non-hematologic treatment-emergent AEs 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 non-hematologic 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 didn't see with the monotherapy,” Mascarenhas explained.

Clinical Benefit and Ongoing Development in Myelofibrosis

Among patients treated with nuvisertib 360 mg twice daily or higher (n = 12), 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, as explained by Mascarenhas.

The combination produced sustained clinical benefit, with 12 patients remaining on treatment at the time of analysis, though discontinuations occurred in 3 patients due to AEs, 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

Mascarenhas J, Scandura J, Gupta V, et al. 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. Blood. 2025;146(suppl 1): 482. doi.org/10.1182/blood-2025-482