Early-Stage PIM-1 Kinase Inhibitors Explored in Myelofibrosis

In recent years, the landscape of myelofibrosis treatment has evolved significantly, with 4 JAK inhibitors currently approved for myelofibrosis. Unfortunately, many patients experience disease progression, marked by the enlargement of the spleen or the recurrence of symptoms. Nuvisertib, formerly known as TP-3654, is a novel oral PIM-1 kinase inhibitor currently being evaluated in phase 1 and 2 clinical trials.

During his presentation at the 7th Annual Baptist Health Miami Cancer Institute Immunotherapies Summit for Hematologic Malignancies, Firas El Chaer, MD, shared his insights on the development of PIM-1 kinase inhibitors.

“Identifying new targets and new molecules that address new pathways in myelofibrosis is of prime importance,” El Chaer, chief of Leukemia and medical director of infusion services at Baptist Health Miami Cancer Institute, told Targeted Oncology in an interview.

Phase 1/2 Trial

Findings from a phase 1/2 trial (NCT04176) presented at the 2025 American Society of Hematology Annual Meeting and Exposition demonstrated that the agent was well tolerated and displayed no dose-limiting toxicities (DLTs) with promising efficacy signals.¹

In the trial, nuvisertib was tested across multiple dose levels, with a promising dosage of 720 mg administered twice daily. Specifically, 77 patients were given the 480-mg dose (n =1) or the 720 mg dose (n = 15) daily or 360 mg (n = 11), 480 mg (n = 24) or 720 mg (n = 26) twice daily.

This dosage is expected to achieve sustained total symptom score reductions and durable symptom improvement. Additionally, there has been a notable reduction in spleen volume among patients with relapsed or refractory myelofibrosis.

Regarding adverse effects (AEs), the most common grade 1 treatment-emergent adverse effects (TEAEs) that occurred in at least 10% of patients were diarrhea (53.2%; n = 41), nausea (40.3%; n = 31), and vomiting (29.9%; n = 23). Common grade 2 TEAEs that occurred in patients were the similar, occurring at rates of 20.8% (n = 16), 16.9% (n = 13), 10.4% (n = 8), and 10.4% for nausea, diarrhea, vomiting, and fatigue, respectively. Finally, common grade 3 TEAEs experienced by patients were diarrhea, increased blood bilirubin levels, and asthenia, which occurred at respective rates of 5.2% (n = 4), 3.9% (n = 3), and 2.6% (n = 2), respectively.

Common grade 3 hematologic TEAEs from the trial were decreased platelet counts and anemia, occurring at respective rates of 16.9% (n = 13) and 13% (n = 10).

One of the advantages of PIM-1 kinase inhibition is its potential to modulate the cytokine profile in patients. El Chaer noted that, unlike many JAK inhibitors, nuvisertib may not only prevent the worsening of anemia and thrombocytopenia but could also improve these conditions. This is particularly significant for patients who often struggle with constitutional symptoms associated with myelofibrosis, as these symptoms can complicate treatment options.

Safety and Efficacy Trial

Findings from a phase 1/2 safety and efficacy trial (NCT04176198) evaluating nuvisertib and momelotinib (Ojjaara),2 showed the combination was well tolerated in patients with myelofibrosis who were previously treated with a JAK inhibitor.

For patients receiving the 720 milligram twice daily dose of nuvisertib monotherapy, 20% achieved a spleen volume reduction of at least 25%. Furthermore, 45% of patients at this same dosage experienced a reduction in their total symptom score of at least 50%. These symptom improvements were notably durable, with some lasting up to 100 weeks.

In group receving the combination, clinical activity was even more pronounced. Half of the evaluable patients achieved a spleen volume reduction of at least 25% at week 24, and 58% reached a total symptom score reduction of at least 50% at any point during the study. This combination also showed a 56% anemia response rate, which is particularly significant for myelofibrosis patients who often suffer from low red blood cell counts.

El Chaer highlighted that the trials have primarily enrolled patients categorized as intermediate to high risk, many of whom harbor multiple high molecular risk mutations. This demographic typically faces poorer survival outcomes, making the efficacy and tolerability of nuvisertib even more crucial.

“Although gastrointestinal side effects such as nausea and diarrhea have been reported, they are generally low grade and manageable with standard medications,” El Chaer said.

For community oncologists, nuvisertib represents a novel mechanism of action in the treatment of relapsed refractory myelofibrosis. It offers a new therapeutic option characterized by significant symptom relief, reduced spleen size, and minimal toxicity related to blood cell counts.

As the first PIM-1 kinase inhibitor being tested in this arena, it adds a vital tool to the oncologist's arsenal. In summary, while traditional treatments continue to play a role, the introduction of nuvisertib marks a significant advancement in the fight against myelofibrosis.

“As traditional treatment options face limitations, particularly in patients with relapsed or refractory disease, this novel approach offers hope for improved management,” El Chaer concluded.

REFERENCES

1. Rein L, El Chaer F, Yuda J, et al. Nuvisertib, an oral investigational selective PIM1 kinase inhibitor, showed clinical responses strongly correlating with cytokine modulation in patients with relapsed/refractory myelofibrosis in the ongoing global phase I/II study. Blood. 2025;146(suppl 1):2018. doi:10.1182/blood-2025-2018

2. 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: 10.1182/blood-2025-482