Efficacy and safety of nuvisertib in MF: Preliminary phase I/II data

Treatment-emergent toxicities, including cytopenias, present a limitation in the management of myelofibrosis (MF) with emerging combination therapies, highlighting the need for novel approaches. 

Early clinical studies of nuvisertib, an investigational, oral, highly selective PIM1 kinase inhibitor, alone and in combination with ruxolitinib shows reduction in spleen size and bone marrow (BM) fibrosis. During the European Hematology Association (EHA) 2025 Congress, June 12–15, 2025, Milan, IT, Lindsay Rein presented preliminary data from a phase I/II study (NCT04176198) evaluating the efficacy and safety of nuvisertib in patients with primary or secondary MF (N = 77).

In the dose-escalation phase, nuvisertib dose ranged from 480 mg daily to 720 mg twice daily. In the efficacy population (n = 18), the evaluable dose was 720 mg twice daily. The primary endpoint was safety and tolerability, with key secondary endpoints including spleen volume reduction, total symptom score, BM fibrosis change, and pharmacokinetics. 

Key learnings

No DLTs were observed at any dose. The most common AEs were diarrhea, nausea, and vomiting – transient and managed with supportive care. Grade 3/4 diarrhea and nausea were reported in 5.2% and 1.3% of patients, respectively. 

SVR, SVR25, and TSS50 were reported in 67% (12/18), 22.2% (4/18), and 44.4% (8/18) of patients, respectively. Improvement on PGIC was shown in 83.3% (15/18) of patients. Responses were durable, and 33% (25/77) of patients remain on active treatment at ≥12 months.

Mean Hb ≥1.0 g/dL for ≥12 weeks and mean platelet count ≥30 × 10⁹/L for ≥28 days without RBC/platelet transfusion were observed in 24% (6/25) and 26.7% (8/30) of patients, respectively. Grade ≥1 improvement in BM fibrosis was seen in 42.9% (12/28) of patients.

Longitudinal analysis showed symptom reduction correlated with cytokine modulation (p < 0.001) of pro- and anti-inflammatory cytokines (e.g. decreased EN-RAGE and MIP1β and increased adiponectin).

Nuvisertib was well tolerated, with clinical activity including spleen, symptom, and hematological and durable responses in patients with R/R MF. Emerging data support its clinical development as monotherapy and in combination with JAK inhibitors.