eltanexor (KPT-8602) / Ono Pharma, Karyopharm, Antengene - LARVOL DELTA

UBTF tandem duplications generate a nuclear export signal motif that drives an XPO1 dependency in leukemia (ASH 2025) - "Disrupting this axis, genetically (NES-M) orpharmacologically (eltanexor), impairs chromatin targeting, induces differentiation, and suppressesleukemogenesis. These findings nominate XPO1 as a dependency in UBTF-TD AML and support clinicalevaluation of XPO1 inhibitors in this subtype."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • CD33 • CD34 • ITGAM • KIT • KMT2A • MEIS1 • NPM1 • PTPRC • XPO1

Targeting β-catenin nuclear export and protein degradation in high-risk acute lymphoblastic leukemia (ASH 2025) - "The combination of Selinexorwith GSK3B inhibition (LY2090314) or PSMB8/PSMB9 inhibition (Zetomipzomib/ONX0914) resulted insynergistic nuclear β-catenin accumulation in reporter cells...The identification of β-catenin as an XPO1 cargo protein and thenucleus as a shelter from protein degradation provide a mechanistic rationale for combining XPO1inhibition (selinexor, eltanexor) with GSK3B or immunoproteasome inhibition, which will support thedesign of forthcoming in vivo studies, including xenograft-based preclinical efficacy models in patient-derived B- and T-ALL xenografts. These findings identify β-catenin as a previously unrecognized and functionally significantcargo protein of XPO1 in B- and T-ALL... These findings identify β-catenin as a previously unrecognized and functionally significantcargo protein of XPO1 in B- and T-ALL. Our finding supports a promising combinatorial strategy for thetreatment of r/r ALL by co-targeting nuclear export and β-catenin protein..."

IO biomarker • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Leukemia • Multiple Myeloma • T Acute Lymphoblastic Leukemia • Targeted Protein Degradation • PSMB8 • PSMB9 • XPO1

Therapeutic horizons in targeting XPO1 with small inhibitor molecules: Recent achievements, synthetic strategies, opportunities, challenges, and future perspectives. (PubMed, Bioorg Chem) - "The FDA approval of Selinexor marked a major milestone followed by second-generation compounds such as Eltanexor and Verdinexor. This review highlights the therapeutic applications, biological roles, the mechanisms of inhibition, recent preclinical and clinical achievements, and emerging opportunities in anticancer and antiviral therapeutics mediated by XPO1 inhibition. Specifically, this review emphasizes the detailed adopted chemical strategies for the development of XPO1 small molecule inhibitors and their emerging inhibition mechanisms, aiming to support future XPO1 inhibitor design."

Journal • Review • Oncology

Eltanexor (KPT-8602) With Inqovi (Decitabine-Cedazuridine) in High-Risk Myelodysplastic Syndromes (clinicaltrials.gov) - P1/2 | N=3 | Terminated | Sponsor: National Cancer Institute (NCI) | Completed ➔ Terminated; Drug company withdrew support.

Trial termination • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

Altered RNA Export in SF3B1 Mutants Increases Sensitivity to Nuclear Export Inhibition (ASH 2023) - "Previous findings from a phase 2 clinical trial of the XPO1 inhibitor selinexor in patients with high-risk myelodysplastic syndrome (MDS) relapsed or refractory to hypomethylating agents (HMA) revealed increased activity in patients with SF3B1 mutations...Using the Bliss independence model to calculate synergy, we identifed two drugs that greatly synergized with eltanexor specifically in the SF3B1 mutant cell lines: venetoclax (a BCL2 inhibitor), and navitoclax (a BCL2/BCL-XL inhibitor)...Our findings may also contribute to the development of potentially synergistic therapeutic combinations. In this regard, recent human data have shown that venetoclax can overcome the poor prognosis of spliceosomal mutant AML patients (Senapati et al, Blood 2023); therefore, combining eltanexor with venetoclax could represent a promising SF3B1-specific therapy."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • BCL2L1 • SF3B1 • SIK1 • XPO1

Phenotypic Drug Response Profiling Identifies Asparaginase-Based Synergistic Combinations for Very High Risk Acute Lymphoblastic Leukaemia (ASH 2023) - "Eight clinically relevant agents with promising sensitizing activity as identified by decreased area-under-the-curve with addition of ASNase were identified (SEL, selinexor; ELTA, eltanexor; VEN, venetoclax; BZM, bortezomib; navitoclax; carfilzomib; mitoxantrone, birinapant). We validated combinations of ASNase with the 8 selected drugs plus 4 drugs used in induction therapy (prednisolone, dexamethasone, vincristine and daunorubicin) using a 4x4 drug matrix in 15 high-risk ALL PDX samples...Our results identify XPO1 inhibitors as a new class of drugs with promising anti-leukaemic activity in BCP-ALL. Co-culture based DRP shows promise in identifying alternative novel sensitive synergistic combinations ex-vivo with decreased toxicity for patients who have an inadequate response to standard therapy."

Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • XPO1

Application of a Phenotype-Based Predictive Analytic in a Phase Ib Study of Selinexor and Venetoclax in Patients with Relapsed or Refractory Acute Myeloid Leukemia (ASH 2024) - P1 | "After a median follow up of 3.02 (range, 0.62-15.4) months, median event free survival was 2.4 (95% CI : 1.9-12.1) months and median overall survival was 6.4 (95% CI : 2.5-12.1) months.Using commercially available, fresh remnant AML samples (n=12), ex vivo blast reductions with SEL and eltanexor (ELTA) showed SINE activity on our PA platform. Second-generation SINE compound ELTA with VEN could further improve outcomes in an ongoing study (NCT06399640) and provide a more tolerable SINE regimen to overcome VEN resistant AML. Analysis is ongoing to establish a flow-based PA for selection of participants in future AML clinical trials."

Clinical • IO biomarker • P1 data • Acute Myelogenous Leukemia • Anemia • Anorexia • Cardiovascular • Fatigue • Febrile Neutropenia • Heart Failure • Neutropenia • Pulmonary Disease • Thrombocytopenia • FLT3 • IDH2 • MCL1 • MYC • NPM1 • NRAS • TP53

The XPO1-FOXC1-HOX Functional Axis Opens New Therapeutic Avenues to Treat DEK-NUP214 AML Patients (ASH 2023) - "The two XPO1 inhibitors (Selinexor and Eltanexor) included in our drug panel were within the four top-ranked compounds. This study offers valuable insights into the molecular and pathological mechanisms underlying t(6; 9)-AML, revealing a functional interaction between DEK-NUP214, XPO1 and FOXC1, and providing evidence to consider XPO1 inhibition as a potential new avenue to treat these patients."

Clinical • IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • DEK • FLT3 • FOXC1 • KMT2A • NUP214 • SESN1

Mechanisms and Therapeutic Strategies to Reverse TET2 Mutant Clonal Hematopoiesis and the Risk of MDS, AML, and Atherosclerotic Cardiovascular Disease (ASH 2023) - "In summary, this study proposes eltanexor treatment as a novel therapeutic approach to specifically target TET2-mutant cells in individuals with CHIP and sheds light on the underlying mechanisms of the pro-inflammatory slant of TET2-mutant macrophages. These findings offer potential new avenues for precise therapies in humans with CHIP and associated cardiovascular risks from atherosclerosis."

Acute Myelogenous Leukemia • Atherosclerosis • Cardiovascular • Hematological Malignancies • Myelodysplastic Syndrome • Oncology • ATF3 • IL1B • TET2

Pharmacologic Inhibition of XPO1 By Selinexor Improves Late-Stage Erythropoiesis in Severely Affected β0-Thalassemia/Hemoglobin E (ASH 2023) - "Nine compounds with known XPO1 inhibitory effect including five synthetic (KPT-185, KPT-276, KPT-330 or selinexor, KPT-335 or verdinexor and KPT-8602 or eltanexor) and four natural active compounds (curcumin, oridonin, piperlongumine and plumbagin) were evaluated in patient-derived HSPCs (n=1) for their potency and efficacy. Therefore, repurposing of selinexor to improve ineffective erythropoiesis in β-thalassemia is compelling. Moreover, combination treatments of selinexor with HbF inducers and/or SMAD2/3 blockers could be further validated to possibly achieve greater therapeutic benefits for β-thalassemia treatments."

IO biomarker • Beta-Thalassemia • Genetic Disorders • Hematological Malignancies • Multiple Myeloma • Myelofibrosis • Oncology • CD34 • GATA1 • SMAD2 • TFRC

KPT-8602 Induced Hematopoietic Differentiation in U2AF1S34F Mutant Cells and Myelodysplastic Syndromes Bone Marrow Stem and Progenitor Cells (ASH 2023) - "Collectively, these findings suggest that KPT-8602 promotes myeloid and erythroid differentiation and further validates the use of KPT-8602 as a therapeutic strategy for MDS. Future studies will fully elucidate the specific mechanisms by which KPT-8602 acts in the context of splicing factor mutations, and other commonly found MDS mutation types."

Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • ASXL1 • BCOR • CSF2 • ITGAM • PPM1D • SF3B1 • TET2 • TFRC • TP53 • U2AF1

A CRISPR/Cas9 pipeline in patient-derived xenograft models in vivo identifies attractive therapeutic targets (AACR-NCI-EORTC 2025) - "For example, XPO1 emerged as major dropout gene in the KO experiments, and treatment with the selective XPO1 inhibitor Eltanexor significantly reduced leukemia burden in most PDX models in vivo, underscoring the predictive power of our approach. Our study highlights XPO1 and HDAC3 as interesting dependency genes in acute leukemia.ConclusionWe conclude that inhibitors of XPO1 and HDAC3 warrant evaluation in clinical trials in leukemia patients and that our pipeline provides a powerful framework to investigate additional genes and therapeutic targets in the future."

IO biomarker • Late-breaking abstract • Preclinical • Hematological Malignancies • Leukemia • Oncology • BCL2 • HDAC3

Targeting serine metabolism vulnerability in omipalisib-resistant acute myeloid leukemia with phosphoglycerate dehydrogenase inhibitors. (PubMed, Biomed Pharmacother) - "Furthermore, we found that, like OCI-AML cells, the exportin 1 (XPO1) inhibitors selinexor and eltanexor significantly induced cell cycle arrest and reduced PHGDH expression in OCI-AML3-OR cells. Therefore, treatment with PHGDH inhibitors could be a therapeutic strategy for refractory AML to PI3K/mTOR inhibitors. Relevant clinical trials are warranted."

IO biomarker • Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • PHGDH • XPO1

PROLONGED XPO1 INHIBITION BY ELTANEXOR INDUCES DIFFERENTIATION IN PATIENTS WITH NPM1-MUTATED AML (SIE 2025) - "UPN01, a 72-year-old female, had NPM1-mutated AML with IDH2, FLT3 (N676L), and NRAS mutations, relapsing after intensive chemotherapy and venetoclax plus azacitidine. UPN02, a 77-year-old male, had NPM1-mutated AML with a FLT3-ITD (allelic ratio 1.2 at screening) and a WT1 truncating mutation, relapsing after azacitidine and gilteritinib...Importantly, no safety signals were identified in the first two patients enrolled in the study. Analysis of transcriptomic data is currently ongoing."

Clinical • IO biomarker • Acute Myelogenous Leukemia • Heart Failure • Renal Disease • FLT3 • IDH2 • NPM1 • NRAS • WT1

Inhibition of XPO1 by selinexor enhances terminal erythroid maturation through modulation of HSP70 trafficking in severe β0-thalassemia/HbE. (PubMed, PLoS One) - "In this study, we screened nine XPO1 inhibitors, including the natural compounds curcumin, piperlongumine, plumbagin, and oridonin, as well as the synthetic agents KPT-185, KPT-276, selinexor, verdinexor, and eltanexor, in erythroid progenitors from patients with severe β0-thalassemia/HbE to identify the most effective inducer of TEM and to investigate the downstream molecular mechanisms involved...Combination treatments with hydroxyurea (a γ-globin inducer) and SIS3 (a SMAD3 inhibitor) confirmed selinexor's dominant effect...These findings suggest that cytoplasmic HSP70 trafficking may contribute to erythroid maturation in severe β0-thalassemia/HbE, implicating regulatory pathways beyond nuclear GATA1 stabilization. Collectively, our findings highlight the therapeutic potential of repurposing selinexor to enhance erythroid maturation in β-thalassemia and suggest that cytoplasmic HSP70 trafficking warrants further investigation as a contributor to terminal erythroid..."

Journal • Beta-Thalassemia • Genetic Disorders • Hematological Disorders • GATA1 • SMAD3 • XPO1

A Phase 1b Study of Selinexor and Venetoclax in Patients With Relapsed or Refractory Acute Myeloid Leukemia (SOHO 2025) - P1 | "Introduction: Our preclinical studies showed synergistic antileukemia activity of selinexor (SEL), a selective inhibitor of nuclear export (SINE), combined with venetoclax (VEN), with potential to overcome VEN resistance by reducing MCL1. SEL-VEN was feasible in a heavily pretreated AML cohort, with no new toxicity signal. Two patients experienced durable CR, confirming SEL-VEN activity. The second-generation SINE eltanexor with VEN (NCT06399640) could provide a more tolerable SINE regimen to overcome VEN-resistant AML."

Clinical • P1 data • Acute Myelogenous Leukemia • Oncology • FLT3 • IDH2 • MCL1 • NPM1 • NRAS • TP53

RNA processing kinase inhibitors and epigenetic inhibitors in combination with oncology drugs or investigational agents in multi-cell type patient-derived tumor cell line spheroids. (PubMed, Cancer Chemother Pharmacol) - "These findings may provide guidance for development of clinical trial combination regimens including cirtuvivint, CC-671 or iadademstat. Full data sets are available on PubChem."

IO biomarker • Journal • Preclinical • Oncology • Targeted Protein Degradation • KRAS

XPO1 inhibition in KRAS-mutant cancers: time for clinical trials but how? (PubMed, Transl Lung Cancer Res) - No abstract available

IO biomarker • Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Multitargeted Reduction of Inflammation and Atherosclerosis in Tet2 -deficient CHIP via XPO1 Inhibition and Atf3 restoration. (PubMed, bioRxiv) - "Here, we show that the XPO1 nuclear export inhibitor eltanexor significantly reduces atherosclerotic plaque formation in a mouse model of Tet2 -mutant CHIP...Tet2 loss diminished ATF3 binding to the regulatory loci of inflammatory mediators, which was restored upon XPO1 inhibition. These results provide new insights into drivers of heightened inflammation in TET2 -mutant CHIP and highlight a novel therapeutic strategy for intervention."

IO biomarker • Journal • Atherosclerosis • Cardiovascular • Hematological Disorders • Hematological Malignancies • Inflammation • ATF3 • TET2

Targeted inhibition of exportin-1 enhances anticancer efficacy and augments therapeutic outcomes in pancreatic ductal adenocarcinoma by modulation of LAMC2/KRAS/ERK1/2/AKT signaling network via hsa-miR-193b-3p (ESMO-GI 2025) - "Our study highlights role of XPO1 in modulating DNA damage, oncogenic ncRNAs, and LAMC2/KRAS/ERK1/2/AKT signaling cascade via miR-193b-3p in PDAC tumorigenesis. Altogether, XPO1 inhibition may serve as a potential therapy in PDAC."

Clinical • IO biomarker • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • KRAS • LAMC2 • MIR193B • SOX21-AS1 • XPO1

The XPO1 inhibitor Eltanexor modulates the Wnt/β-catenin signaling pathway to reduce colorectal cancer tumorigenesis. (PubMed, Cancer Res Commun) - "Drug sensitivity assays using organoids from Apcmin/+ mice tumors show increased sensitivity to Eltanexor compared to wild-type organoids. Collectively, these findings highlight XPO1 as a potent target for CRC chemoprevention."

IO biomarker • Journal • Colorectal Cancer • Oncology • Solid Tumor • FOXO3 • XPO1

RNA processing kinase inhibitors and epigenetic inhibitors in combination with oncology drugs or investigational agents in multi-cell type patient-derived tumor cell line spheroids. (PubMed, Res Sq) - "We investigated the activity of two CLK inhibitors, cirtuvivint and CC-671, and the LSD1 inhibitor iadademstat alone and in combination with anticancer drugs or investigational agents...These agents included the XPO1 inhibitor, eltanexor, and the KRAS G12D specific inhibitor MRTX-1133 which had activity in tumor lines harboring the KRAS G12D mutation. LSD1 inhibition was effective with ubiquitin proteasome pathway inhibitors. The full data sets are available on PubChem."

IO biomarker • Journal • Preclinical • Oncology • Targeted Protein Degradation • KRAS

Targeting EP300 in diffuse large b-cell lymphoma: efficacy of A485 and synergistic effects with XPO1 inhibition. (PubMed, BMC Cancer) - "Our study elucidated that EP300 inhibition, especially in combination with XPO1 blockade, could serve as a promising therapeutic strategy for the treatment of DLBCL."

IO biomarker • Journal • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • E2F1 • EP300

Eltanexor (KPT-8602) With Inqovi (Decitabine-Cedazuridine) in High-Risk Myelodysplastic Syndromes (clinicaltrials.gov) - P1/2 | N=3 | Completed | Sponsor: National Cancer Institute (NCI) | Recruiting ➔ Completed | N=80 ➔ 3 | Trial completion date: Jul 2027 ➔ Mar 2025 | Trial primary completion date: Apr 2027 ➔ Mar 2025

Enrollment change • Trial completion • Trial completion date • Trial primary completion date • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

Clinical Significance of XPO1 High Expression in Diffuse Large B-Cell Lymphoma and Its Mechanism (PubMed, Zhongguo Shi Yan Xue Ye Xue Za Zhi) - "Cell proliferation, apoptosis, and cell cycle assays were performed to explore the effect of XPO1 inhibitor (KPT-8602) and XPO1 knockdown...Inhibiting the function of XPO1 or reducing its expression can significantly decrease the expression of MYBL1 XPO1 is highly expressed in DLBCL, which is associated with poor prognosis. The oncogenic roles of the new XPO1/MYBL1 signaling are identified in DLBCL and XPO1 inhibitor may be a potential option for newly-diagnosed DLBCL patients."

IO biomarker • Journal • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • MYBL1 • XPO1