Cytokine Modulation Correlates Strongly with Symptom Improvement in Patients with Myelofibrosis Treated with Nuvisertib (TP-3654), an Investigational Selective PIM1 Kinase Inhibitor

Background: PIM1 expression is upregulated in myelofibrosis (MF) and has been shown to modulate cytokine induced PI3K/AKT and JAK/STAT pathways. Clinical features of MF are partly attributed to circulating cytokines, a subset of which have been shown to correlate with poor prognosis. Nuvisertib (TP-3654), an oral investigational highly selective PIM1 kinase inhibitor, is being evaluated in a phase 1/2 study in patients (pts) with relapsed/refractory MF. In preclinical murine MF models, TP-3654 alone and in combination with ruxolitinib, showed reduced spleen size, bone marrow (BM) fibrosis and, importantly, cytokine response genes.

Methods: Data were collected from the ongoing global phase 1/2 study evaluating the safety and efficacy of TP-3654 monotherapy in pts with MF (NCT04176198, Arm 1). Key eligibility included primary or secondary MF; previously treated with or ineligible for JAK inhibitor treatment; DIPSS intermediate 1, 2 or high-risk MF; platelet ≥25x10⁹/L; splenomegaly (≥450 cm³ by imaging); and ≥2 measurable symptoms per MFSAF v4. We conducted a comprehensive analysis of 64 cytokine changes in plasma from pts treated with TP-3654 after ≤4-week (wk) intervals to Wk 12, and 8-wk intervals past Wk 96. Individual cytokine longitudinal analysis and a modified Kaplan-Meier (KM) assessment was conducted to predict symptom score improvement.

Results: As of June 10, 2024, 65 pts were enrolled in 5 dose levels. At baseline, 52% of pts were anemic (Hgb <10 g/dL), 55% had low platelet counts (<100x10⁹/L), 35% had both anemia and thrombocytopenia, and26% had high molecular risk mutations. In pts treated with 720 mg QD or BID dose levels for ≥12 weeks, ≥25% spleen volume reduction (SVR) was observed in 31% of pts (SVR25 response) and ≥50% reduction in symptoms in 50% of pts (TSS50 response) at any time. The observed overall TSS50 response, as well as each individual symptom domain, were durable for ≥12 wks and showed a strong correlation with cytokine changes. Longitudinal analyses showed significant (p <0.0001) decreases in pro-inflammatory cytokines IL-18, MIP1β and PAI, among others, and an increase of the anti-inflammatory adipokine, adiponectin. Cytokine changes were observed within 1 day of TP-3654 treatment and continued past Wk 48, showing early- and long-term pharmacodynamic modulation.

A modified KM analysis showed changes in ENRAGE, PAI1, MIP1β and adiponectin levels at multiple timepoints, significant (p <0.0001) predicting Wk 12 and Wk 24 TSS50 response probability. Additionally, individual symptom improvement at Wk 12 and Wk 24 were linked to cytokine changes, such as fatigue and itching for ENRAGE, and fatigue, satiety and SVR for adiponectin. Individual cytokine-related symptoms analyzed at Wk 12 (baseline individual score ≥3 per MFSAF v4) were linked to cytokine changes: fatigue for IL1RA, EGFR, and CD40L; night sweats for TNF-RI, TIMP1, EPO and CD40L; and itching for MIP1β and MCP1; and similar correlations observed at Wk 24. In addition, 6 of 18 (33%) evaluable pts showed ≥1 grade reduction in BM fibrosis correlating with 3 of 6 (50%) showing anemia and platelet response, and 5 of 6 (83%) were on active treatment for ≥1 year. Reductions in TSS, spleen volume, inflammatory cytokines and BM fibrosis with hematological responses in those evaluable pts suggest potential disease modification.

Conclusions: The preliminary data of TP-3654 in relapsed/refractory MF pts showed promising clinical activity, including SVR, TSS improvement, and correlating cytokine modulation. ENRAGE and adiponectin levels were significant predictors of SVR, TSS50 responses and specific symptom improvement for fatigue, itching and satiety. Translational studies are ongoing to further explore potential disease modification activity of TP-3654.

Rein:Incyte: Consultancy, Other: Site Principal Investigator for clinical trial, Research Funding; DAVA Oncology: Other: Speaker, conference participant; Sumitomo Dainippon Pharma Oncology: Consultancy, Other: Site Principal Investigator for clinical trial, Research Funding; Novartis: Consultancy, Honoraria, Other: Site Principal Investigator for clinical trial, Research Funding; Morphpsys: Consultancy; Cogent Biosciences: Other: Site Principal Investigator for clinical trial, Research Funding; Protagonist: Other: Site Principal Investigator for clinical trial, Research Funding; Geron: Other: Site Principal Investigator for clinical trial, Research Funding; Blueprints Medicine: Other: Site Principal Investigator for clinical trial, Research Funding; Merck: Other: Site Principal Investigator for clinical trial, Research Funding; PharmaEssentia: 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; Sobi: Consultancy; Abbvie: Consultancy. El Chaer:CTI Biopharma: Consultancy; AbbVie: Consultancy; Sumitomo Pharma America, Inc.: Consultancy, Research Funding; MorphoSys: Consultancy; Amgen: Consultancy, Research Funding; ACCC: Consultancy; PharmaEssentia: Consultancy, Research Funding; Geron: Consultancy; Bristol Meyers Squibb: Consultancy, Research Funding; Sobi: Consultancy; 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. Yuda:Janssen: Research Funding; Incyte: Research Funding; BMS: Research Funding; Takeda: Research Funding; MSD: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Daiichi Sankyo: Research Funding; Chugai: Research Funding; Mitsubishi Tanabe: Research Funding; BrightPath Biotherapeutics Co.,Ltd.: Research Funding; Sumitomo Pharma: Research Funding; Genmab: Research Funding; Amgen: 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. Rampal:Constellation/MorphoSys: Consultancy, Research Funding; Zentalis: Consultancy, Research Funding; Servier: Consultancy; Sumitomo Dainippon: Consultancy; Cogent: Consultancy; Protagonist: Consultancy; Stemline Therapeutics: Consultancy, Research Funding; Galecto: Consultancy; Karyopharm: Consultancy; Ryvu: Research Funding; Jazz Pharmaceuticals: Consultancy; Kartos: Consultancy; Sierra Oncology/GSK: Consultancy; Jubilant: Consultancy; Disc Medicine: Consultancy; CTI BioPharma: Consultancy; PharmaEssentia: Consultancy; Incyte Corporation: Consultancy, Research Funding; AbbVie: Consultancy; Blueprint: Consultancy; Celgene/BMS: Consultancy; Novartis: Consultancy; Promedior: Consultancy. 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. 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. 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. Iurlo:AOP: Consultancy, Honoraria; BMS: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Bose:Blueprint: Honoraria, Research Funding; Disc Medicine: Research Funding; MorphSys: Honoraria, Research Funding; GSK: Honoraria; Novartis: Honoraria; BMS: Honoraria, Research Funding; AbbVie: Honoraria; Telios: Research Funding; Astellas: Research Funding; Ionis Pharmaceuticals: Research Funding; Pfizer: Research Funding; Kartos: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Karyopharm: Honoraria; Cogent: Honoraria, Research Funding; PharmaEssentia: Honoraria; CTI Biopharma Corp: Honoraria, Research Funding; NS Pharma: Research Funding; Promedior: Research Funding. Lucchesi:AOP: Consultancy; Sanofi: Consultancy, Speakers Bureau; BMS: Speakers Bureau; 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:BMS: Honoraria; Janssen: Honoraria; GSK: Honoraria; Novartis: Honoraria. Vachhani:Amgen: Consultancy, Research Funding; GenenTech: Consultancy; MorphoSys: Consultancy; GlaxoSmith Kline: Consultancy; Karyopharm: Consultancy; Gilead/Forty Seven: Research Funding; Kartos Therapeutics: Research Funding; Takeda: Research Funding; Constellation Pharmaceuticals: Research Funding; Cogent Biosciences: Consultancy; Astex Pharmaceuticals: Research Funding; Stemline: Consultancy; Pfizer: Consultancy; Seattle Genetics: Research Funding; Daiichi Sankyo: Consultancy; Abbvie: Consultancy, Research Funding; CTI BioPharma Corp (now Sobi): Consultancy, Research Funding; Novartis: Consultancy; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Blueprint Medicines: Consultancy, Research Funding. Tantravahi:Morphosys: Consultancy, Honoraria; CTI Biopharma: Consultancy, Honoraria; Partnership for Health Analytic Research LLC: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria, Research Funding. Onishi:JCR pharma: Research Funding; Abbvie: Research Funding; Sumitomo: Research Funding; Meiji Seika: Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Incyte: Research Funding; Shionogi: Research Funding; AsahiKasei: Honoraria; Kyowa Kirin: Honoraria; Chugai: Honoraria; MSD: Honoraria; Kissei: Honoraria; Amgen: Honoraria; Asteras: Honoraria; Sanofi: Honoraria; Daiichi Sankyo: Honoraria; IQVIA: Honoraria; Symbio: Honoraria; Nippon Shinyaku: Honoraria. Kiladjian:Abbvie: Consultancy; Incyte: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; AOP Orphan: Honoraria, Speakers Bureau; PharmaEssentia: Honoraria; Novartis: Consultancy; GSK: Consultancy. 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. Patel:Pfizer: Research Funding; Sumitomo: Research Funding; AbbVie: Honoraria; Bristol Myers Squibb: Honoraria; Sobi: Honoraria; Kronos Bio: Research Funding. 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; Pegascy: Current Employment; Abbvie, Ipsen: Speakers Bureau. Kabir:Sumitomo Pharma America, Inc.: Current Employment. Seki:Sumitomo Pharma America, Inc.: Current Employment. Ansaldo:Sumitomo Pharma America, Inc.: Current Employment. Guffanti:Sumitomo Pharma America,inc.: Current Employment. Lee:Sumitomo Pharma America,inc.: Current Employment. Warner: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. Mesa:AbbVie: Consultancy, Honoraria, Research Funding; Blueprint: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; CTI: Consultancy, Honoraria; Genentech: Consultancy, Honoraria, Research Funding; Geron: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Incyte: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Sierra: Consultancy, Honoraria, Research Funding; Telios: Consultancy, Honoraria; MorphoSys: Consultancy, Research Funding.