pamufetinib (TAS-115) / Otsuka - LARVOL DELTA

THERAPEUTIC POTENTIAL OF TAS-115 IN 3D BREAST CANCER MODELS. (PubMed, Biofabrication) - "Here, we investigated its therapeutic effects alone and in combination with doxorubicin (DOXO), using 3D heterotypic spheroid models, including free-standing, bioprinted static, and perfused systems. In perfused bioprinted models, TAS-115 markedly inhibited tumor cell migration, highlighting its potential to limit metastatic behavior. These findings identify TAS-115 as a promising therapeutic strategy for TNBC, either as a monotherapy or in combination with chemotherapy."

Journal • Preclinical • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • MET

TAS-115 (Pamufetinib) in Patients With Chronic Fibrosing Interstitial Lung Disease With a Progressive Phenotype: Results of Phase 2b Randomized Clinical Trial (ATS 2025) - "However, TAS-115 did not decelerate FVC decline in patients with CF-ILD with disease progression despite treatment with nintedanib or pirfenidone, compared to the control group. There was no benefit in switching from standard anti-fibrotic treatment to monotherapy with TAS-115."

Clinical • P2b data • Fibrosis • Idiopathic Pulmonary Fibrosis • Interstitial Lung Disease • Pulmonary Disease • Respiratory Diseases • CSF1R

AB122 Platform Study (clinicaltrials.gov) - P1 | N=715 | Recruiting | Sponsor: Taiho Pharmaceutical Co., Ltd. | N=367 ➔ 715 | Trial completion date: May 2024 ➔ May 2026 | Trial primary completion date: May 2024 ➔ May 2026

Enrollment change • Metastases • Trial completion date • Trial primary completion date • Alveolar Soft Tissue Sarcoma • Colon Cancer • Colorectal Adenocarcinoma • Colorectal Cancer • Esophageal Cancer • Gastric Cancer • Gastroesophageal Cancer • Gastrointestinal Cancer • Hepatology • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Sarcoma • Solid Tumor • KRAS • NRAS

Modulation of tumor immune microenvironment by TAS-115, a multi-receptor tyrosine kinase inhibitor, promotes antitumor immunity and contributes anti-PD-1 antibody therapy. (PubMed, Sci Rep) - "The combination treatment further increased the percentage of GzmbCD8 T cells and decreased the percentage of macrophages compared with either treatment alone. These results highlight the potential therapeutic effect of TAS-115 in combination with PD-1 blockade, mediated via activation of antitumor immunity by TAS-115."

IO biomarker • Journal • Colorectal Cancer • Gastrointestinal Cancer • Immune Modulation • Oncology • Solid Tumor • CSF1R • GZMB • IFNG • IL2

Exploratory phase 2 study of the novel oral multi-kinase inhibitor TAS-115 in patients with idiopathic pulmonary fibrosis. (PubMed, Respir Investig) - "TAS-115 treatment was effective, assessed using intra-patient change in slope of %FVC decline as a surrogate endpoint in patients with IPF pre-treated with pirfenidone or nintedanib and treatment-naïve patients. TAS-115 showed acceptable tolerability and a manageable safety profile."

Journal • P2 data • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases

AB122 Platform Study (clinicaltrials.gov) - P1 | N=292 | Recruiting | Sponsor: Taiho Pharmaceutical Co., Ltd. | N=180 ➔ 292

Enrollment change • Colorectal Cancer • Gastrointestinal Cancer • Hepatology • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • ALK • BRAF • KRAS • MET • NTRK • RET • ROS1

The K-BASKET trial: A prospective phase II biomarker-driven multiple basket trial in Korean solid cancer patients (ESMO 2019) - "Three treatment arms for the second step are the followings; 1) Patients with MET amplification or exon 14 skipping MET mutation will be assigned to the TAS-115 arm, a novel multikinase inhibitor. 2) Patients with activating PIK3CA or AKT mutations will be assigned to the TAS-117 arm, a novel selective AKT inhibitor...Legal entity responsible for the study: Yonsei University. Funding: National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea (HA16C0018)."

Biomarker • Clinical • IO Biomarker • P2 data • PD(L)-1 Biomarker

Design of phase 2 study of TAS-115, a novel oral multi-kinase inhibitor, in patients with idiopathic pulmonary fibrosis. (PubMed, Contemp Clin Trials Commun) - "This study consists of three cohorts: previously treated with pirfenidone (Cohort P, n = 20), with nintedanib (Cohort N, n = 20), and treatment naïve (Cohort U, n = 10). The safety and tolerability in this population will be assessed. JapicCTI-183898."

Clinical • Journal • P2 data • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases

A Phase II, Randomized, Open-Label, Multi-arm Study of TAS-115 for Castration-Resistant Prostate Cancer Patients With Bone Metastases. (PubMed, Clin Genitourin Cancer) - "TAS-115 appears to demonstrate anti-tumor activity and acceptable tolerability in CRPC patients with bone metastases."

Clinical • Journal • P2 data • Genito-urinary Cancer • Hematological Disorders • Oncology • Pain • Prostate Cancer • Renal Disease • Solid Tumor • CSF1R • MET

Efficacy and safety of TAS-115, a novel oral multi-kinase inhibitor, in osteosarcoma: an expansion cohort of a phase I study. (PubMed, Invest New Drugs) - "Conclusion the safety and tolerability of TAS-115 and long-term disease stability for patients with unresectable or recurrent osteosarcoma were confirmed in this study, suggesting that TAS-115 is a promising novel therapy for advanced osteosarcoma patients. Trial registration number: JapicCTI-132333 (registered on November 8, 2013)."

Clinical • Journal • P1 data • Oncology • Osteosarcoma • Sarcoma • Solid Tumor

Preclinical evaluation of the multi tyrosine kinase inhibitor TAS-115 in genetically engineered mouse models of prostate cancer (AACR 2018) - "In these studies, TAS-115 showed moderate growth inhibition. Overall our studies show that TAS-115 is capable of suppressing prostate tumor growth by acting primarily on the TME and provide evidence to support further investigation of TME modulation using small molecule multi-kinase inhibitors."

Prostate Cancer

[VIRTUAL] Final Results of the Primary Endpoint and Other Supportive Analysis: TAS-115 Phase 2 Study in Patients with Idiopathic Pulmonary Fibrosis (ATS-I 2020) - "In this phase 2 study, the efficacy of TAS-115 as a single agent was assessed in IPF patients with %FVC decline who had been treated with or were unfit for treatment with Nintedanib or Pirfenidone. TAS-115 as a single agent could be a novel therapeutic agent for IPF and confirmatory trials are currently being planned. JapicCTI-183898"

Clinical • P2 data • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Respiratory Diseases

[VIRTUAL] The multi tyrosine kinase inhibitor TAS-115 promotes innate and adaptive immune responses of androgen deprivation therapy in mouse prostate cancer (AACR-II 2020) - "We also use phenotyping, gene expression and immunohistochemical studies to show that reducing immunosuppressive immune cells led to increased CD8 T cell recruitment and activation. These findings provide evidence to support that TAS-115 sequenced with ADT has the potential to augment innate and adaptive antitumor immunity in prostate cancer."

Preclinical • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CD 163 • CSF1R • IL10 • ITGAM • MET • PTEN • TP53

MET/VEGFR/FMS signaling contributes prostate cancer-induced osteoclast differentiation and bone resorption (AACR 2018) - "These results indicated that administration of TAS-115 restored bone destruction induced by PC3, mainly by inhibiting the FMS-dependent and RANKL-induced differentiation of preosteoclasts into mature osteoclasts. The additional inhibition of the tyrosine kinase FMS by TAS-115 has profound effects on prostate cancer-driven osteoclastogenesis, and its proliferation extends the capability of this agent to act as a powerful antidote to the devastating effects of metastatic spread to bone."

Gastric Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • Urothelial Cancer

New challenges and inspired answers for anticancer drug discovery and development (Jpn J Clin Oncol) - PMID: 24014883; “Several promising programs are proceeding simultaneously in the clinical or preclinical development stage such as TAS-115, a dual inhibitor of c-Met and vascular endothelial growth factor receptor, TAS-2104, a selective Aurora A inhibitor, TAS-117, an allosteric Akt inhibitor, TAS-2985, an irreversible fibroblast growth factor receptor inhibitor and TAS-2913, a T790M mutant selective epidermal growth factor receptor inhibitor.”

Review • Oncology

MET/VEGFR dual inhibition and prominent safety profile of TAS-115 are favorable for the combination with chemotherapeutic drugs (AACR 2012) - Presentation Time: Monday, Apr 02, 2012, 8:00 AM -12:00 PM; TAS-115 markedly enhanced anti-tumor effect of paclitaxel, & brought tumor shrinkage of approximately 80% in the combination; TAS-115 has disturbed rapid tumor re-growth following paclitaxel treatment

Preclinical-animal • Preclinical-other • Oncology

Final Results of the Primary Endpoint and Other Supportive Analysis: TAS-115 Phase 2 Study in Patients with Idiopathic Pulmonary Fibrosis (ATS 2020) - "In this phase 2 study, the efficacy of TAS-115 as a single agent was assessed in IPF patients with %FVC decline who had been treated with or were unfit for treatment with Nintedanib or Pirfenidone.MethodThe primary analysis was to evaluate the intra-patient change of %FVC between before and after the administration of TAS-115. Those results suggest and support the robustness of the assessment using intra-patients comparison and the proof of concept of TAS-115 for IPF. TAS-115 as a single agent could be a novel therapeutic agent for IPF and confirmatory trials are currently being planned.JapicCTI-183898"

Clinical • P2 data • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Interstitial Lung Disease • Pulmonary Disease • Respiratory Diseases

TAS-115 inhibits PDGFRα/AXL/FLT-3 signaling and suppresses lung metastasis of osteosarcoma. (PubMed, FEBS Open Bio) - "We also show that these signaling pathways are activated in various human osteosarcoma cell lines and are involved in proliferation. Our results suggest that TAS-115 may have potential for development into a novel treatment for metastatic osteosarcoma."

Journal • FLT3

The Tyrosine Kinase Inhibitor TAS-115 Attenuates Bleomycin-Induced Lung Fibrosis in Mice. (PubMed, Am J Respir Cell Mol Biol) - "Nintedanib, the recently approved multiple kinase inhibitor, has shown promising antifibrotic effects in patients with idiopathic pulmonary fibrosis; however, its efficacy is still limited, and in some cases, treatment discontinuation is necessary owing to toxicities such as gastrointestinal disorders. In a mouse model of bleomycin-induced pulmonary fibrosis, TAS-115 significantly inhibited the development of pulmonary fibrosis and the collagen deposition in bleomycin-treated lungs. These data suggest that the strong inhibition of PDGFR and c-FMS by TAS-115 may be a promising strategy for overcoming the intractable pathogenesis of pulmonary fibrosis."

Journal • Preclinical

Phase I study of TAS-115, a novel oral multi-kinase inhibitor, in patients with advanced solid tumors. (PubMed, Invest New Drugs) - "TAS-115 was generally well tolerated, with manageable toxicities and recommended phase II dose was estimated as 650 mg SID, 5-on/2-off. Furthermore, promising antitumor activity was observed."

Clinical • Journal • P1 data

Late Breaking Abstract - Phase 2, multi-center, open label, single-arm study of TAS-115, a novel multi-kinase inhibitor in patients with idiopathic pulmonary fibrosis (ERS 2019) - "TAS-115 showed a remarkable clinical response in % FVC over the 13-week treatment period with manageable safety profile. TAS-115 could be a novel therapeutic agent after standard therapy for IPF."

Clinical • Late-breaking abstract • P2 data

Immunomodulation of the multi-tyrosine kinase inhibitor TAS-115 in a mouse model of prostate cancer (AACR 2019) - "In this study we examine the consequences of TAS-115 administration alone or in combination with androgen withdrawal via surgical castration or anti-androgen therapy with apalutamide, and focus on its influence on antitumor immunity. However, Treg infiltration was also increased after the administration of TAS-115. Overall our findings suggest that TAS-115 induced the reduction of immunosuppressive MDSCs and TAMs and may have induced an M2-M1 switch to provide a less immunosuppressive tumor microenvironment resulting in improved T cell mediated responses and provides evidence to support further investigation into using molecular targeting agents such TAS-115 as immune-modulators in combination with other immunotherapies to enhance or restore cytotoxic T cell activity."

IO Biomarker • Preclinical

A phase II, open-label, multi-arm study of TAS-115 for castration-resistant prostate cancer patients with bone metastases. (ASCO-GU 2019) - "In cohort A, TAS-115 ranging from 200 to 400 mg/day with abiraterone acetate was given to pts prior to docetaxel. Preliminary anti-tumor activity to bone lesion and improved pain were observed in CRPC pts with bone metastases, and safety of TAS-115 was acceptable. TAS-115 could be a novel therapeutic agent with a favorable safety profile for CRPC with bone metastases."

Clinical • P2 data

A phase II, open-label, multi-arm study of TAS-115 for castration-resistant prostate cancer patients with bone metastases. (ASCO-GU 2019) - "In cohort A, TAS-115 ranging from 200 to 400 mg/day with abiraterone acetate was given to pts prior to docetaxel. Preliminary anti-tumor activity to bone lesion and improved pain were observed in CRPC pts with bone metastases, and safety of TAS-115 was acceptable. TAS-115 could be a novel therapeutic agent with a favorable safety profile for CRPC with bone metastases."

Clinical • P2 data