Novel targeted therapies for R/R MF: PIM1 kinase inhibition

During the MPN Hub Steering Committee meeting, Francesco Passamonti, Università degli Studi di Milano, Milan, IT, chaired a discussion on novel targeted therapies for relapsed/refractory (R/R) myelofibrosis (MF), with a focus on PIM1 kinase inhibition. This discussion also featured Tiziano Barbui, Haifa Kathrin Al-Ali, Steffen Koschmieder, Jean-Jacques Kiladjian, Aaron Gerds, and Laura Michaelis.

Passamonti provided an overview of the mechanism of action of PIM1 kinase inhibitors, before presenting results from a phase I/II trial of nuvisertib, a first-in-class selective PIM1 kinase inhibitor, in patients with R/R MF.

Presentation

• Janus kinase inhibitors (JAKi) are the current standard of care for patients with MF; however, therapies with novel mechanisms of action could provide alternative treatment options for patients who are either ineligible for or R/R following treatment with JAKi.¹

• PIM1 kinases are downstream targets of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway (Figure 1).^2,3

• Nuvisertib, an investigational, oral, PIM1 kinase inhibitor, has been granted orphan drug and fast track designations by the U.S. Food and Drug Administration (FDA) for the indication of MF.⁴ Its safety and efficacy as monotherapy and in combination with JAKi therapy (ruxolitinib or momelotinib) is currently being assessed in patients with R/R MF in an ongoing, open-label, multicenter, phase Ib/II trial (NCT04176198) (Figure 2).⁵

• Initial results from the nuvisertib monotherapy arm (Arm 1) showed promising preliminary efficacy and a favorable safety profile in patients with R/R MF (N = 77):⁶

  • Spleen volume reduction (SVR) was observed in 67% of 18 patients, with 22.2% of patients achieving an SVR ≥25%.

  • Total symptom score (TSS) reduction was reported in 61.1% of 18 patients, with 44.4% of patients achieving a TSS reduction ≥50%.

  • Mean hemoglobin improvement ≥1.0 g/dL for ≥12 weeks without red blood cell transfusion was demonstrated in 24% of patients.

  • Mean platelet improvement ≥30 × 10⁹/L for ≥28 days without platelet transfusion was observed in 26.7% of patients.

  • Improvement in bone marrow fibrosis ≥1 grade was observed in 42.9% of patients.

  • Significant modulation (p < 0.001) of pro- and anti-inflammatory cytokines (e.g. decreased EN-RAGE and MIP-1β, and increased adiponectin) was demonstrated in a longitudinal analysis.

  • Nuvisertib was well tolerated, with no dose-limiting toxicities reported.​

Discussion

• Suboptimal response in the phase Ib/II trial of nuvisertib in patients with R/R MF was defined as inadequate control of symptoms and spleen and/or requiring red blood cell transfusions; Arm 1 included patients who were R/R to or ineligible for JAKi therapy, while Arms 2 and 3 included patients with a suboptimal response to JAKi therapy. 

• The baseline characteristics indicate that patients in Arm 1 had advanced, high-risk MF with a significant disease burden: 

  • Median spleen volume was 1,936 cm³.

  • Median spleen length was 23 cm.

  • Median TSS was 23.

  • 30% of patients were transfusion-dependent.

  • 77% were Dynamic International Prognostic Scoring System (DIPSS) intermediate-2 to high risk.

  • 41% had a high molecular risk.

• Given that both PIM1 kinase inhibitors and JAKi can be associated with thrombocytopenia, the inclusion criteria for Arms 2 and 3 require a platelet count ≥50 × 10⁹/L.

• Monitoring PIM1 kinase activity in patients receiving JAKi to identify patients with elevated kinase activity could help inform treatment selection.

• Nuvisertib and JAKi have a potentially synergistic effect in patients with MF, with nuvisertib targeting PIM1 kinase downstream of the JAK/STAT pathway; therefore, nuvisertib in combination with JAKi could be particularly beneficial in patients treated with JAKi monotherapy who remain symptomatic. 

• There was recognition that these insights were based on a limited number of patients, and that long-term follow-up data would be necessary to understand the potential clinical impact. 

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