vepafestinib (TAS0953/HM06) / Helsinn, Otsuka - LARVOL DELTA

Initial Results From Phase 1/2 Study of the RET-Selective Inhibitor Vepafestinib in Patients With RET-Aberrant Solid Tumors (IASLC-WCLC 2025) - P1/2 | "Vepafestinib (TAS0953/HM06), a RET-selective inhibitor, is being evaluated in patients with locally advanced or metastatic solid tumors harboring RET alterations in MARGARET (NCT04683250), an open-label, single-arm, phase 1/2, first-in-human study...Conclusions : Vepafestinib was well tolerated and displayed preliminary antitumor activity in patients with solid tumors harboring RET alterations, both in treatment-naïve and RET-selective inhibitor-pretreated cancers, indicating encouraging therapeutic potential. Enrollment in this trial continues."

Clinical • P1/2 data • Back Pain • Lung Cancer • Musculoskeletal Pain • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • Thyroid Gland Carcinoma

(MARGARET): Study of RET Inhibitor TAS0953/HM06 in Patients with Advanced Solid Tumors with RET Gene Abnormalities (clinicaltrials.gov) - P1/2 | N=202 | Recruiting | Sponsor: Taiho Pharmaceutical Co., Ltd. | Trial completion date: Sep 2025 ➔ Mar 2031 | Trial primary completion date: Mar 2025 ➔ Mar 2030

Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • RET

Vepafestinib: a RET-selective inhibitor with enhanced CNS penetrance targets therapy-resistant mutants. (PubMed, Nat Cancer) - No abstract available

Journal

Vepafestinib is a pharmacologically advanced RET-selective inhibitor with high CNS penetration and inhibitory activity against RET solvent front mutations. (PubMed, Nat Cancer) - "Here, we perform preclinical characterization of vepafestinib (TAS0953/HM06), a next-generation RET inhibitor with a unique binding mode...We further show that these properties translate into improved tumor control in an intracranial model of RET-driven cancer. Our results underscore the clinical potential of vepafestinib in treating RET-driven cancers."

Journal • Metastases • Oncology • Pancreatic Cancer • Solid Tumor • Thyroid Gland Carcinoma • RET

Preclinical evaluation of the blood-brain barrier permeability and intracranial efficacy of the nextgeneration RET inhibitor Vepafestinib. (AACR-NCI-EORTC 2023) - No abstract available

Preclinical • Oncology

Efficacy of vepafestinib in preclinical models of RET fusion-driven sarcoma models (AACR 2023) - P1/2 | "Background: Vepafestinib (TAS0953/HM06, Vepa) is a 2nd generation RET-selective inhibitor that effectively penetrates the brain, and inhibits the wildtype RET kinase domain (KD) and RET KD mutants (G810, V804, Y806, L730) (presented at AACR-NCI-EROTC 2021 meeting)...Vepa was more effective than vandetanib and similar to the FDA-approved RET inhibitors, selpercatinib (Selp) and pralsetinib (Pral), in all in vitro assays... Our preclinical results suggest that vepafestinib has the potential to more effectively manage CNS metastasis compared to selpercatinib, representing a promising new therapeutic option for patients with RET-driven sarcomas. Vepafestinib is currently in a phase 1/2 trial for adult patients with advanced solid tumors harboring RET alterations (margaRET, NCT04683250)."

Preclinical • Fibrosarcoma • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • CASP3 • CASP7 • CCND1 • MYC • RET • SELP • SPECC1L • STAT3

Comparison of TAS0953/HM06 and selpercatinib in RET fusion-driven preclinical disease models of intracranial metastases. (ASCO 2022) - P1/2 | "Tumor-bearing mice were treated with TAS0953/HM06 (50 mg/kg BID), selpercatinib (10 mg/kg BID) or vandetanib (multi-kinase RET inhibitor, 50 mg/kg QD), and assessed weekly for tumor growth via bioluminescence imaging. Our data in animal models suggest that TAS0953/HM06 penetrates the CNS more effectively than selpercatinib, and is superior at decreasing CNS disease and extending survival. TAS0953/HM06 represents a promising new therapeutic option for patients with RET fusions with acquired resistance mutations, including those with brain metastasis and those resistant to first-generation selective RET inhibitors. TAS0953/HM06 is currently undergoing a biomarker-driven phase 1/ 2 clinical trial for patients with solid tumors driven by RET alterations (NCT04683250)."

Preclinical • Brain Cancer • CNS Disorders • Immunology • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Sarcoma • Solid Tumor • RET • SPECC1 • TRIM33

(MARGARET): Study of RET Inhibitor TAS0953/HM06 in Patients With Advanced Solid Tumors With RET Gene Abnormalities (clinicaltrials.gov) - P1/2 | N=202 | Recruiting | Sponsor: Helsinn Healthcare SA | Trial completion date: Aug 2024 ➔ Sep 2025 | Trial primary completion date: Dec 2023 ➔ Mar 2025

Metastases • Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • RET

Vepafestinib is effective in preclinical models of sarcomas with RETfusion including a brain metastasis model (AACR-NCI-EORTC 2022) - "Vepafestinib (TAS0953/HM06) is a brainpenetrant 2nd generation RET-selective inhibitor that is also effective againstRET solvent front (G810) and gatekeeper (V804) mutations...In all in vitro assays vepafestinibwas more effective than vandetanib and as effective as the FDA-approvedRET inhibitors selpercatinib and pralsetinib... Our preclinical results suggest that vepafestinib is moreeffective than selpercatinib in the brain and represents a therapeutic strategyfor RET-driven sarcomas. Vepafestinib is currently in phase 1/2 clinical trialsfor adult patients with advanced solid tumors with RET alterations(margaRET, NCT 04683250)."

Preclinical • Fibrosarcoma • Oncology • Sarcoma • Solid Tumor • CASP3 • CASP7 • CCND1 • MYC • RET • SPECC1L • STAT3

Helsinn presents newly available data on vepafestinib at IASLC 2022 World Conference on Lung Cancer (GlobeNewswire) - "Helsinn Group...announces its participation in the upcoming IASLC 2022 World Conference on Lung Cancer (WCLC) hosted by the International Association for the Study of Lung Cancer, taking place from 6-9 August in Vienna, Austria. At the conference, new preclinical data for the investigational product vepafestinib (TAS0953/HM06), a selective RET inhibitor that has shown a distinct binding mode1 to RET and a high brain barrier permeability2, will be presented on August 9, 2022, 12:12 – 12:17 CEST....This Helsinn-sponsored study, which was conducted by Dr. Odintsov and colleagues in the Marc Ladanyi Lab at Memorial Sloan Kettering Cancer Center, explored the effect of vepafestinib (TAS0953/HM06), relative to other RET multi-kinase and selective inhibitors, on growth inhibition using in vitro and in vivo NSCLC extracranial and CNS disease models."

Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

New data on Helsinn’s oncology pipeline presented at American Society of Clinical Oncology (ASCO) Annual Meeting 2022 (GlobeNewswire) - "Helsinn Group...announces its participation in the upcoming 2022 American Society of Clinical Oncology (ASCO) Annual Meeting which will be held from 3-7 June....Two abstracts have been accepted for poster presentation. The first abstract shares results of a preclinical study exploring the brain penetrability of vepafestinib (TAS0953/HM06), Helsinn’s investigational oral treatment targeting rearranged during transfection (RET) abnormalities in solid tumors....The second abstract provides an overview of the ongoing PROOF 301 trial of infigratinib, a kinase inhibitor targeting cancers driven by fibroblast growth factor receptor 2 (FGFR2) fusions or other rearrangements."

Clinical protocol • Preclinical • Biliary Cancer • Biliary Tract Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor

Helsinn Group announces oral presentation of data at AACR-NCI-EORTC relating to a potent and highly selective investigational RET inhibitor (GlobeNewswire) - "One abstract has been accepted for oral presentation and shows findings on TAS0953/HM06, the selective RET inhibitor under investigation in non-small cell lung cancer (NSCLC) and other cancers. The abstract is entitled Discovery of TAS0953/HM06, a novel next generation RET-specific inhibitor capable of inhibiting RET solvent front mutations...Preliminary results demonstrate potency against the RET solvent front mutation resistance mechanism....the second abstract has been accepted as a video poster entitled TAS0953/HM06 is effective in preclinical models of diverse tumor types driven by RET alterations."

Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Helsinn Announces First Patient Dosed in Phase 1/2 Study of TAS0953/HM06 in Patients with Advanced Solid Tumors with RET Gene Abnormalities (GlobeNewswire) - "Helsinn...announces the first patient has been dosed in a Phase 1/2 Study of TAS0953/HM06 in Patients with Advanced Solid Tumors with RET Gene Abnormalities...The study will be initially conducted at sites in US and Japan."

Trial status • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thyroid Gland Medullary Carcinoma

(MARGARET): Study of RET Inhibitor TAS0953/HM06 in Patients With Advanced Solid Tumors With RET Gene Abnormalities (clinicaltrials.gov) - P1/2; N=202; Recruiting; Sponsor: Helsinn Healthcare SA

Clinical • New P1/2 trial • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • RET