Nuvisertib (TP-3654), an Investigational Selective PIM1 Kinase Inhibitor, Showed Durable Clinical Response and Sustained Hematological Improvement in Relapsed/Refractory Myelofibrosis Patients

Background: PIM1 expression is upregulated in hematologic malignancies including myelofibrosis (MF). In preclinical models, PIM1 knockout (KO) was shown to prevent MF progression without affecting platelet (PLT) counts, whereas pan-PIM KO caused decreased PLT counts (Dutta A, 2021; An N, 2013). Cytopenias due to disease pathogenesis and/or treatment-emergent are major limitations of MF treatment leading to poor prognosis. TP-3654, an oral investigational highly selective PIM1 kinase inhibitor, alone and in combination with ruxolitinib, showed spleen size and bone marrow (BM) fibrosis reduction and normalization or increase of blood counts in murine MF models.

Methods: This global phase 1/2 study evaluates safety and efficacy of Nuvisertib (TP-3654) monotherapy in patients (pts) with MF (NCT04176198, Arm 1). Key eligibility includes primary or secondary MF; previously treated with or ineligible for JAK inhibitor; DIPSS intermediate 1, 2 or high-risk MF; PLT ≥25x10⁹/L; splenomegaly (≥450 cm³ by imaging); and ≥2 measurable symptoms per MFSAF v4. The study aims to identify the RP2D of TP-3654 monotherapy and assess safety, clinical activity (spleen volume reduction [SVR], total symptom score [TSS] reduction), PK and PD markers (cytokine, BM fibrosis).

Results: As of 10 June 2024, 65 pts enrolled in 5 dose levels from 480 mg QD to 720 mg BID. At baseline (BL), median age 73 years (range 50, 85), spleen volume 1936 cm³ (range 270, 7719), TSS 23 (range 4, 62), hemoglobin (Hgb) 9.7 g/dL (range 5.6, 15.2; 52% pts were <10 g/dL; 29% pts required transfusion), PLT 85x10⁹/L (range 24, 816; 55% pts were <100x10⁹/L; 17% pts were <50x10⁹/L). 35% pts with both anemia and low PLT counts; 26% pts had high molecular risk (HMR) mutation; and 95% pts received ≥1 prior JAK inhibitor. Median treatment duration was 15 weeks (wks) (range 2.6, 147), 33 (51%) pts continue treatment. No DLT occurred. Treatment-related adverse events (TRAEs) occurring in ≥20% pts were Gr 1/2 nausea, vomiting, and diarrhea. Gr ≥3 TRAE occurring in ≥3 pts included PLT count decreased (n=4; 3 pts had BL Gr 2 and 1 pt Gr 1 PLT count decreased). Mean Hgb and PLT counts remained stable throughout the 24-wk treatment. In pts treated with 720 mg QD or BID dose for ≥12 wks, ≥25% SVR was observed in 5 of 16 pts (31% SVR25 response) and ≥50% reduction in TSS in 8 of 16 pts (50% TSS50 response) at any time. At Wk 24, ≥50% reduction was observed in bone pain, early satiety, pain under left rib, and night sweats; fatigue showed 48.4% reduction. TSS50 responses were durable for ≥12 wks and showed strong correlation with cytokines reduction (ENRAGE, PAI1, MIP1B etc.). In pts with BL Hgb <10 g/dL, 6 of 18 (33%) evaluable pts showed Hgb response [≥1.0 g/dL Hgb increase sustained for ≥12 wks without transfusion, including 3 pts with ≥1.5 g/dL Hgb increase]. Hgb responses were also observed in pts with BL Hgb ≥10 g/dL. In pts with BL PLT <100×10⁹/L, 7 of 22 (32%) pts showed PLT response [≥30×10⁹/L increase maintained ≥4 wks] and PLT counts recovered to ≥100×10⁹/L in all responders. 6 of 18 (33%) evaluable pts (assessments at BL and at ≥Wk 24) showed ≥1 Gr reduction in BM fibrosis; of whom all pts showed SVR25 or TSS50 responses, 3 pts showed Hgb and PLT responses, and 5 pts continuing treatment for ≥1 year.

Conclusions: TP-3654 monotherapy was well tolerated with no DLTs. Preliminary data of TP-3654 in relapsed/refractory MF pts showed clinical activity including SVR25, symptom improvement correlating with cytokines reduction, BM fibrosis reduction, and Hgb and PLT responses. Current monotherapy and preclinical data support the development of TP-3654 in combination with JAK inhibitors ruxolitinib and momelotinib (NCT04176198, Arms 2 and 3, respectively); enrollment ongoing in all 3 arms.