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.

El Chaer:Sumitomo Pharma America, Inc.: Consultancy, Research Funding; Sobi: Consultancy; Bristol Meyers Squibb: Consultancy, Research Funding; Geron: Consultancy; AbbVie: Consultancy; CTI Biopharma: Consultancy; MorphoSys: Consultancy; Amgen: Consultancy, Research Funding; ACCC: Consultancy; PharmaEssentia: Consultancy, Research Funding; DAVA Oncology: Consultancy, Other: Travel Grant; Celgene: Research Funding; Sanofi: Research Funding; FibroGen: Research Funding; BioSight: Research Funding; MEI Pharma: Research Funding; Novartis: Research Funding. Rein:Abbvie: Consultancy; PharmaEssentia: Other: Site Principal Investigator for clinical trial, Research Funding; Merck: Other: Site Principal Investigator for clinical trial, Research Funding; Blueprints Medicine: Other: Site Principal Investigator for clinical trial, Research Funding; Geron: Other: Site Principal Investigator for clinical trial, Research Funding; Protagonist: Other: Site Principal Investigator for clinical trial, Research Funding; Incyte: Consultancy, Other: Site Principal Investigator for clinical trial, Research Funding; DAVA Oncology: Other: Speaker, conference participant; Sobi: Consultancy; Cogent Biosciences: Other: Site Principal Investigator for clinical trial, Research Funding; Morphpsys: Consultancy; Novartis: Consultancy, Honoraria, Other: Site Principal Investigator for clinical trial, Research Funding; Sumitomo Dainippon Pharma Oncology: Consultancy, Other: Site Principal Investigator for clinical trial, Research Funding; Karyopharm: Other: Site Principal Investigator for clinical trial, Research Funding; Telios Pharma: Research Funding; Silence Therapeutics: Research Funding. Yuda:Incyte: Research Funding; Amgen: Research Funding; BrightPath Biotherapeutics Co.,Ltd.: Research Funding; Takeda: Research Funding; Mitsubishi Tanabe: Research Funding; AbbVie: Research Funding; Janssen: Research Funding; Novartis: Research Funding; BMS: Research Funding; Daiichi Sankyo: Research Funding; Chugai: Research Funding; Genmab: Research Funding; Sumitomo Pharma: Research Funding; MSD: Research Funding. Shimoda:Takeda: Honoraria, Research Funding; Novartis Pharma KK: Honoraria; Taisho Pharmaceutical Co: Research Funding; Sumitomo Dainippon Pharma Co Ltd: Research Funding; Shinogi & Co Ltd: Research Funding; PharmaEssentia Japan KK: Research Funding; Otsuka Pharmaceutical Co Ltd: Research Funding; Nippon Kayaku Co Ltd: Research Funding; Mochida Pharmaceutical Co Ltd: Research Funding; Kyowa Kirin Co Ltd: Research Funding; Eisai Co Ltd: Research Funding; Daiichi Sankyo Co Ltd: Research Funding; Chugai Pharmaceutical Co Ltd: Research Funding; AbbVie GK: Honoraria, Research Funding; Sierra Oncology: Consultancy. Ichii:Bristol Myers Squibb: Speakers Bureau; Sumitomo Pharma: Speakers Bureau; Janssen Pharmaceutical: Speakers Bureau; Nippon Shinyaku: Speakers Bureau; CHUGAI PHARMACEUTICAL: Speakers Bureau; ONO PHARMACEUTICAL: Speakers Bureau; Takeda Pharmaceutical: Speakers Bureau; PhamaEssentia Japan: Speakers Bureau; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees. McCloskey:BluePrint Health: Speakers Bureau; Incyte: Speakers Bureau; Novartis: Consultancy; Stemline Therapeutics: Speakers Bureau; Blueprint Medicines: Consultancy; Bristol-Myers Squibb/Pfizer: Consultancy; Amgen: Speakers Bureau; Jazz Pharmaceuticals: Speakers Bureau; Takeda: Speakers Bureau; BluPrint Oncology: Honoraria. Scandura:SDP Oncology: Membership on an entity's Board of Directors or advisory committees; Protagonist Therapeutics: Membership on an entity's Board of Directors or advisory committees; Morphic: Consultancy; Medpacto: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Constellation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Calico: Consultancy. Iurlo:GSK: Consultancy, Honoraria; BMS: Consultancy, Honoraria; AOP: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Bose:Pfizer: Research Funding; Ionis Pharmaceuticals: Research Funding; Blueprint: Honoraria, Research Funding; BMS: Honoraria, Research Funding; AbbVie: Honoraria; Cogent: Honoraria, Research Funding; Astellas: Research Funding; CTI Biopharma Corp: Honoraria, Research Funding; Telios: Research Funding; PharmaEssentia: Honoraria; GSK: Honoraria; Disc Medicine: Research Funding; Novartis: Honoraria; MorphSys: Honoraria, Research Funding; Karyopharm: Honoraria; Incyte: Honoraria, Research Funding; Kartos: Honoraria, Research Funding; NS Pharma: Research Funding; Promedior: Research Funding. Lucchesi:BMS: Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; AOP: Consultancy; Novartis: Consultancy, Speakers Bureau; Grifols: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; MorphoSys: Consultancy; Incyte: Speakers Bureau; Pfizer: Speakers Bureau; SOBI: Consultancy, Speakers Bureau; Protagonist: Consultancy. Benevolo:GSK: Honoraria; BMS: Honoraria; Novartis: Honoraria; Janssen: Honoraria. Vachhani:Astex Pharmaceuticals: Research Funding; Karyopharm: Consultancy; Constellation Pharmaceuticals: Research Funding; GlaxoSmith Kline: Consultancy; Amgen: Consultancy, Research Funding; Blueprint Medicines: Consultancy, Research Funding; Cogent Biosciences: Consultancy; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; CTI BioPharma Corp (now Sobi): Consultancy, Research Funding; GenenTech: Consultancy; MorphoSys: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Stemline: Consultancy; Daiichi Sankyo: Consultancy; Abbvie: Consultancy, Research Funding; Takeda: Research Funding; Kartos Therapeutics: Research Funding; Gilead/Forty Seven: Research Funding; Seattle Genetics: Research Funding. Tantravahi:Novartis: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Partnership for Health Analytic Research LLC: Consultancy, Honoraria; CTI Biopharma: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria, Research Funding. Onishi:Kissei: Honoraria; Sanofi: Honoraria; Meiji Seika: Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Nippon Shinyaku: Honoraria; IQVIA: Honoraria; Incyte: Research Funding; JCR pharma: Research Funding; Daiichi Sankyo: Honoraria; Abbvie: Research Funding; Sumitomo: Research Funding; Asteras: Honoraria; Amgen: Honoraria; Shionogi: Research Funding; AsahiKasei: Honoraria; MSD: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Symbio: Honoraria; Pfizer: Honoraria, Research Funding; Kyowa Kirin: Honoraria; Chugai: Honoraria. Patel:Bristol Myers Squibb: Honoraria; Sobi: Honoraria; Sumitomo: Research Funding; Pfizer: Research Funding; AbbVie: Honoraria; Kronos Bio: Research Funding. Bradley:Geron Corporation: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Ribrag:Belgene: Speakers Bureau; Employment: Ended employment in the past 24 months; AstraZeneca: Honoraria; AstraZeneca, Lilly: Membership on an entity's Board of Directors or advisory committees; Astex, GSK: Research Funding; Abbvie, Ipsen: Speakers Bureau; Pegascy: Current Employment. Kabir:Sumitomo Pharma America, Inc.: Current Employment. Ansaldo:Sumitomo Pharma America, Inc.: Current Employment. Seki:Sumitomo Pharma America, Inc.: Current Employment. Loksa:Sumitomo Pharma America, Inc.: Current Employment. Li:Sumitomo Pharma America, Inc.: Current Employment. Foulks:Sumitomo Pharma America, Inc.: Current Employment, Patents & Royalties: WO2014062838 A2. PCT/US2013/065296, WO2020023910A1, WO2019195753A1, WO2019200254A1, US20200297698A1, WO2021102343A1, WO2019195759A1. Shah:Sumitomo Pharma America: Current Employment. Rampal:Kartos: Consultancy; Sumitomo Dainippon: Consultancy; Cogent: Consultancy; Protagonist: Consultancy; Sierra Oncology/GSK: Consultancy; Constellation/MorphoSys: Consultancy, Research Funding; Jubilant: Consultancy; PharmaEssentia: Consultancy; Galecto: Consultancy; Stemline Therapeutics: Consultancy, Research Funding; CTI BioPharma: Consultancy; Zentalis: Consultancy, Research Funding; Servier: Consultancy; Ryvu: Research Funding; Disc Medicine: Consultancy; AbbVie: Consultancy; Karyopharm: Consultancy; Celgene/BMS: Consultancy; Blueprint: Consultancy; Incyte Corporation: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; Novartis: Consultancy; Promedior: Consultancy.