vactosertib (TEW-7197) / National OncoVenture, Theragen Etex, Ewha Womans University, Medpacto - LARVOL DELTA

Targeting TGFBR1 with the Investigational Inhibitor TP-6379 Improves Hematopoiesis in Low-Risk MDS Ex Vivo. (PubMed, Cells) - "Primary low-risk MDS bone marrow mononuclear cells (BM-MNCs) were analyzed in vitro for hematopoietic restoration by an ALK4/ALK5 inhibitor (Vactosertib), an ALK2 inhibitor (TP-0184/Itacnosertib) and an ALK5/TGFBR1-specific inhibitor (TP-6379). Similar results were obtained with K562 cells, with or without the knock-in (KI) mutation in SF3B1, with strong sensitivity to rhS100A9 that was overcome by TP-6379. Hence, directly targeting TGFBR1/ALK5 with TP-6379 restores healthy hematopoiesis in low-risk MDS preclinical models."

Journal • Preclinical • Hematological Disorders • Hematological Malignancies • Inflammation • Myelodysplastic Syndrome • Oncology • S100A9 • SF3B1 • TGFB1 • TGFBR1

MedPacto has received approval from Korea’s Ministry of Food and Drug Safety to modify its ongoing multinational phase 1/2 trial of Vactosertib monotherapy in recurrent, refractory or progressive osteosarcoma (TipRanks) - "The study, conducted in Korea and the U.S. across multiple cancer centers, aims to evaluate safety, tolerability, pharmacokinetics and antitumor activity in adolescent and adult patients. The approved change allows exploratory comparison between 200 mg BID and 300 mg BID dosing to determine the optimal regimen, using a 3+3 dose-escalation in phase 1 and Simon’s two-stage design in phase 2."

Clinical protocol • Osteosarcoma

MedPacto has applied to the U.S. Food and Drug Administration for approval of changes to its U.S. Phase 1/2 clinical trial of Vactosertib monotherapy in adolescents and adults with relapsed, refractory, or progressive osteosarcoma (TipRanks) - "The open-label, multicenter trial, conducted with Case Western Reserve University and UH Rainbow Babies and Children’s Hospital, aims to refine dosing while assessing safety, tolerability, pharmacokinetics, and antitumor activity. The company seeks to compare 200 mg BID and 300 mg BID dosing to identify an optimal regimen, with Phase 1 focused on determining maximum tolerated and recommended Phase 2 doses and Phase 2 evaluating objective response rates and biomarker relationships."

Clinical protocol • Osteosarcoma

Vactosertib plus pembrolizumab in patients with non-microsatellite instability-high metastatic colorectal or gastric cancer: a multicenter, phase Ib/IIa study. (PubMed, Nat Commun) - P1/2 | "No objective responses were observed in mGC. Vactosertib plus pembrolizumab showed clinical activity in non-MSI-high mCRC, particularly in patients without liver metastases."

Journal • MSI-H • P1/2 data • Colorectal Cancer • Dermatology • Gastric Cancer • Microsatellite Instability • Oncology • Pruritus • Solid Tumor • MSI

Overcoming TGFβ-mediated immunosuppression to enhance B7-H3 CAR-T cell therapy in Group 3 Medulloblastoma (ISPNO 2026) - "Pharmacological inhibition of TGFβ signalling was tested using the selective TGFBRI inhibitors Vactosertib and LY3200882.Robust TGFβ pathway activation was observed across preclinical models and patient samples, with significantly higher pSMAD3 levels in Group 3 tumours compared with other medulloblastoma subgroups (SHH n=71, Group 3 n=63, Group 4 n=71, WNT n=15). Drug treatment protected CAR-T effector function (cytokine release and proliferation) upon repeated tumour and TGFβ challenge. In vivo studies are evaluating efficacy, safety, feasibility, and pharmacokinetic and pharmacodynamic profiles.These findings provide an initial preclinical rationale for combining TGFβ pathway inhibition with anti-B7H3 CAR T-cell therapy in G3 medulloblastoma."

CAR T-Cell Therapy • IO biomarker • Brain Cancer • Medulloblastoma • Solid Tumor • CD276 • SMAD3 • TGFB1

Natural Killer (NK) Cells in Combination With Interleukin-2 (IL-2) and Transforming Growth Factor Beta (TGFbeta) Receptor I Inhibitor Vactosertib in Cancer (clinicaltrials.gov) - P1 | N=12 | Suspended | Sponsor: David Wald | Trial completion date: Jun 2026 ➔ Jun 2027 | Trial primary completion date: Dec 2025 ➔ Dec 2026

Trial completion date • Trial primary completion date • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Chronic Lymphocytic Leukemia • Chronic Myeloid Leukemia • Colon Cancer • Colorectal Cancer • Esophageal Adenocarcinoma • Esophageal Cancer • Gastric Cancer • Hematological Malignancies • Hodgkin Lymphoma • Leukemia • Lymphoma • Multiple Myeloma • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Oncology • Rectal Adenocarcinoma • Solid Tumor

Vactosertib enhances radiotherapy efficacy by modulating radiation-induced tumor microenvironment remodeling in breast cancer. (PubMed, Radiol Oncol) - "These findings suggest that Vactosertib may enhance the therapeutic efficacy of RT by modulating radiation-induced inflammatory and fibrotic changes in the TME, supporting its potential as a rational combination strategy to improve RT outcomes in breast cancer."

Biomarker • Journal • Breast Cancer • Fibrosis • Immunology • Oncology • Solid Tumor • CD8 • TGFB1

Targeting Tumor Macrophage TGF-β Signaling Overcomes Immunotherapy Resistance in Hepatocellular Carcinoma (EACR 2026) - P2 | "Our study establishes TGF-β signaling in TAMs as a key mechanism of ICB resistance in HCC. The TAM-homing nanoparticle platform provides a powerful tool for dissecting macrophage-specific mechanisms and represents a versatile strategy for developing precision immunotherapies that target specific cellular niches within the immunosuppressive TME."

Hepatocellular Cancer • Oncology • Solid Tumor • TGFB1 • TGFBR1

WITHDRAWN: Phase I/II study of vactosertib, a selective TGF-β receptor I inhibitor, in adolescents and adults with recurrent or refractory osteosarcoma: Safety, pharmacokinetics, and preliminary antitumor activity. (ASCO 2026) - P1/2 | "Clinical Trial Registration Number: NCT05588648 Abstract withdrawn."

Clinical • P1/2 data • PK/PD data • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • TGFB1

Vactosertib Reverses ABCG2-Mediated Multidrug Resistance Through Dual Inhibition of Drug Efflux and Transporter Expression. (PubMed, Exp Cell Res) - "Similar re-sensitizing effects of mitoxantrone were also observed in colony formation and multicellular tumor spheroid assays. In addition to functional inhibition, vactosertib reduced the expression levels in both ABCG2 mRNA and protein without altering membrane localization, suggesting transcriptional downregulation. As a result, these findings indicate that vactosertib reverses ABCG2-mediated MDR through dual effects on inhibiting ABCG2 function and downregulating and the expression of ABCG2, supporting its potency as a chemo sensitizing agent in ABCG2-mediated MDR cancer models."

Journal • Oncology • ABCG2

CASE1223: Oral TGF-beta Receptor I Inhibitor Vactosertib in SOC Chemoradiotherapy for Esophageal Adenocarcinoma (clinicaltrials.gov) - P2 | N=30 | Suspended | Sponsor: Melissa Lumish | Recruiting ➔ Suspended

Trial suspension • Esophageal Adenocarcinoma • Esophageal Cancer • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Oncology • Solid Tumor

Targeting tumor macrophage TGF-β signaling overcomes immunotherapy resistance in hepatocellular carcinoma (AACR 2026) - P2 | "Our study establishes TGF-β signaling in TAMs as a key mechanism of ICB resistance in HCC. The TAM-homing nanoparticle platform provides a powerful tool for dissecting macrophage-specific mechanisms and represents a versatile strategy for developing precision immunotherapies that target specific cellular niches within the immunosuppressive TME."

Hepatocellular Cancer • Oncology • Solid Tumor • TGFB1 • TGFBR1

Engineering durable tumor immunity with a virus-tumor hybrid antigen dendritic cell vaccine (AACR 2026) - "Combination therapy with either anti-PD-1 immune checkpoint blockade or the ALK5 (TGF-β type I receptor) inhibitor Vactosertib further augmented therapeutic efficacy in therapy-resistant tumor models. Collectively, these findings highlight the clinical potential of PROTEXI as an innovative DC vaccine platform that leverages the widespread prevalence of Spike-specific CD4⁺ T-cell immunity to enhance cancer vaccine efficacy—offering a promising therapeutic strategy for patients with advanced, immune-cold tumors."

IO biomarker • Oncology • CD4 • CD8 • CD80 • IL12A • PRAME • TGFB1 • TGFBR1

Rewiring the immune-excluded tumor microenvironment: Vactosertib/anti-PD-1/VEGF inhibitor triplet therapy reinstates antitumor immunity in CRC (AACR 2026) - "BALB/c mice bearing tumors were treated with the FDA-approved pan-VEGFR inhibitor fruquintinib (Fru), an anti-PD-1 antibody, and/or Vac. Triple blockade using Vac, an anti-PD-1 inhibitor, and a VEGFR inhibitor achieved superior antitumor efficacy and broad immune activation compared to all other dual combination therapies in PD-1-resistant CRC. These results suggest that TGF-β inhibition is essential for overcoming treatment resistance in an immunosuppressive TME, supporting the clinical evaluation of this triple combination in refractory CRC."

Biomarker • Tumor microenvironment • Colorectal Cancer • Oncology • Solid Tumor • CD4 • CD8 • IFNG • TGFB1

Targeting HCC tumor microenvironment interactions using an advanced HCC patient-derived on-chip model (AACR 2026) - "The screen revealed that SoC drugs sorafenib and lenvatinib reduced culture viability and induced profound changes in vascular bed organization, while atorvastatin decreased viability without affecting vascular structures...Tocilizumab, galunisertib, and vactosertib lowered IL6 levels, whereas halofuginone increased IL6. These findings highlight the utility of the PDChip model in visualizing drug-induced responses at both molecular and morphological levels, providing detailed insights into drug effects on specific cellular compartments within the HCC TME. This platform enabled a detailed evaluation of drug-induced responses in the tumor and associated microenvironment, highlighting their importance in preclinical research for understanding diseases and developing new drugs."

Biomarker • Clinical • Metastases • Tumor microenvironment • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor • IL6

Oral TGF-beta receptor1 inhibitor vactosertib promotes osteosarcoma regression by targeting tumor proliferation and enhancing anti-tumor immunity (AACR 2024) - "Vactosertib increased immune effectors (e.g., IFNγ+CD8+ cells and NK cells) and inhibited immune suppressors (e.g., M2-like TAM, MDSC) in the OS TME. Our results suggest that inhibition of TGF-β1 signaling is an effective therapeutic strategy against OS through a multi-pronged approach that targets tumor intrinsic and extrinsic factors to achieve optimal immune-effector functions and maximal clinical response."

Oncology • Osteosarcoma • Sarcoma • Solid Tumor • CD8 • IFNG • MYC • TGFB1

Novel combination therapy for treating proteasome inhibitor-resistant multiple myeloma (AACR 2024) - "In vitro treatment of Vactosertib synergistically inhibited the growth of bortezomib (BTZ)-resistant MM cells in combination with either BTZ or ixazomib (IXZ) by suppressing TGF-β activation of Smad2/3 and expression of PSMB5, which encodes the proteasome 5 catalytic subunit targeted by PIs. Furthermore, therapy of BCMA+ CAR T cells in combination with Vactosertib exhibited a synergistic anti-tumor effect, compared to either CAR T cells or Vactosertib. Taken together, our data provide the rationale for clinical evaluation of Vactosertib in MM and demonstrate proof-of-concept that combination of Vactosertib and either PI or cell therapy may overcome drug resistance and enhance durable patient responses."

Combination therapy • IO biomarker • Hematological Malignancies • Multiple Myeloma • Oncology • FOXP3 • ITGAM • PSMB5 • SMAD2 • TGFB1

Antifibrotic Effect of the TGF-β Type I Receptor Inhibitor EW-7197 on Anastomotic Healing in a Rat Choledochojejunostomy Model. (PubMed, Biomedicines) - "These findings support the role of the TGF-β/Smad pathway in bilioenteric anastomotic fibrotic remodeling. However, further studies including molecular validation and functional assessments are required to clarify the translational relevance of these results."

Journal • Preclinical • Fibrosis • Immunology • Inflammation • TGFB1 • TGFBR1

TGF-β Inhibitor Potentiates Osimertinib-Induced Anti-Tumor Immunity in Egfr-Mutant Lung Cancer. (PubMed, Cancer Sci) - "We evaluated the antitumor effect of the combination therapy with osimertinib and either nintedanib (an indirect TGF-β inhibitor) or vactosertib (a specific TGF-β type I receptor kinase inhibitor). In conclusion, combination therapy with osimertinib and TGF-β inhibitors potentiates osimertinib-induced antitumor immunity. These findings highlight a novel therapeutic strategy for EGFR-mutated NSCLC and warrant further clinical investigation."

IO biomarker • Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Transplantation • CD8 • EGFR • GZMB • MRC1 • SMAD2 • TGFB1

Modeling hepatocellular carcinoma and its microenvironment on a chip. (PubMed, Cell Death Discov) - "Sorafenib, lenvatinib and atorvastatin also affected chemokine and cytokine release. Tocilizumab, galunisertib, and vactosertib decreased the level of IL6, a relevant prognostic marker for HCC, while IL6 was increased by halofuginone. In conclusion, HCC PDChip models enabled a detailed evaluation of drug-induced responses in the tumor and associated microenvironment, highlighting their importance in preclinical research for understanding diseases and developing new drugs."

Journal • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • IL6

Preoperative Immunotherapy (Pembrolizumab) for Patients With Colorectal Cancer and Resectable Hepatic Metastases (clinicaltrials.gov) - P2 | N=6 | Terminated | Sponsor: Chloe Atreya, MD, PhD | Trial completion date: Apr 2026 ➔ Sep 2025 | Active, not recruiting ➔ Terminated | Trial primary completion date: Apr 2026 ➔ Sep 2025; Sponsor decision

Trial completion date • Trial primary completion date • Trial termination • Colorectal Cancer • Oncology • Solid Tumor • MLH1 • MSH2 • MSH6 • PD-L1

Unmet Needs in Multiple Myeloma and Potential Solutions: A Systemic Literature Review (ASH 2024) - "Other unmet needs reported were patient and family experience/supportive care (11%), pathophysiology (4%), diagnosis/response assessment (4%), toxicity management/prevention (3%) and poor prognosis (4%).Unmet needs that were reported starting from 2010 [and their proposed solutions] include treatment of high-risk cytogenetic features (4%) [elotuzumab/isatuximab/melflufen/selinexor/anti-BCMA conjugates], treatment of plasma cell leukemia/extramedullary disease (3%) [utilizing MM drugs (daratumumab/boretezemib/melfufen/frontline ASCT etc.)], prevention/management of toxicities (mucositis, neuropathy, nephropathy and GVHD) (1%) [CR4056/amifostine/cannabidiol], treatment/prevention of thromboembolism (1%) [risk assessment model for thromboembolism/studies on anticoagulation], treatment of frail/elderly (1%) [SEA BCMA/melflufen], immune response in MM (<1%) [immunological studies], and measures to assess response to treatment (<1%) [heavy light chain ratio/DW..."

Review • Geriatric Disorders • Graft versus Host Disease • Hematological Malignancies • Immunology • Infectious Disease • Leukemia • Mucositis • Multiple Myeloma • Oncology • Orthopedics • Plasma Cell Leukemia • Renal Disease • Respiratory Diseases

The TGFβ Type I Receptor Kinase Inhibitor Vactosertib Improves T-Cell Fitness in Relapsed/Refractory Multiple Myeloma: A Phase 1b Trial (ASH 2024) - P1 | "Vactosertib combined with pomalidomide was well-tolerated at all dose levels, displayed a manageable adverse event profile and induced durable responses. Current studies are focused on defining the antimyeloma effects of vactosertib in combination with immune checkpoint inhibitors, autologous and allogeneic chimeric antigen receptor (CAR) T-cells and bispecific T-cell engagers. Accumulating evidence suggests that functional blockade of the TGF pathway offers promise to optimize CAR-T-cell therapy for hematologic and solid tumors, albeit with efficacy anticipated restricted to specific populations."

IO biomarker • P1 data • Hematological Malignancies • Multiple Myeloma • Oncology • Solid Tumor • CD8 • TGFB1

Vactosertib, a Novel TGFb Type I Receptor Kinase Inhibitor, Improves T-Cell Fitness:a Single-Arm, Phase 1b Trial in Relapsed/Refractory Multiple Myeloma (ASH 2023) - "To probe the tumor intrinsic anti-myeloma activity of vactosertib, we first determined the relative effect of vactosertib compared to the IMiDs pomalidomide and lenalidomide (Fig. Vactosertib combined with pomalidomide was well-tolerated at all doses, had a manageable adverse event profile and induced durable responses with 80% progression-free survival (PFS-6) at 6 months, Vactosertib reduced TGFβ in patient bone marrow and suppressed PD-1 expression on CD8+ T-cells and lead to reduction of PD-L1/PD-L2 expression on CD138+ cells and enhanced autologous T-cell cytotoxicity. Taken together, our results support the safety and efficacy of vactosertib to treat RRMM and revealed that vactosertib modulates the T-cell immunophenotype and reinvigorates T-cell fitness."

IO biomarker • P1 data • Hematological Malignancies • Multiple Myeloma • Oncology • BTLA • CD8 • CTLA4 • HAVCR2 • LAG3 • PD-1 • PD-L1 • PD-L2 • SDC1

The company announced interim results from a global Phase 1 clinical trial of its immunotherapy candidate, "vactosertib," targeting osteosarcoma patients at SITC 2025, held in Maryland, USA, from the 7th to the 9th. [Google translation] (HIT News) - "One patient achieved complete remission (CR) and three achieved partial remission (PR). The objective response rate (ORR) was 36.4%. Safety and tolerability were good, and no dose-limiting toxicities (DLTs) were observed."

P1 data • Osteosarcoma