Vepafestinib is a pharmacologically advanced RET-selective inhibitor with high CNS penetration and inhibitory activity against RET solvent front mutations

Sep 24, 2026

Uploaded by Stanley

RET receptor tyrosine kinase drives multiple cancers via oncogenic fusions and gain-of-function variants, and current small-molecule RET inhibitors are constrained by acquired target mutations and limited brain penetration. Preclinical characterization of vepafestinib (TAS0953/HM06), a next-generation RET inhibitor with a unique binding mode, demonstrates best-in-class RET selectivity and activity against on-target resistance mutations in RETL730, RETV804, and RETG810. Enhanced brain pharmacokinetics translate into improved tumor control in an intracranial RET-driven model, supporting clinical potential for RET-driven cancers.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages32

Reading Time1 h 21 min

AccessFree to download

RET signaling and limitations of current inhibitors

Preclinical characterization of vepafestinib

Selectivity and on-target resistance mutations

Brain pharmacokinetic advantages

Intracranial efficacy in RET-driven cancer models

Clinical implications for treating RET-driven cancers

nature cancer Article [https://doi.org/10.1038/s43018-023-00630-y](https://doi.org/10.1038/s43018-023-00630-y) Vepafestinibis apharmacologically advanced RET-selective inhibitor with high CNS penetration and inhibitory activity against RET solvent front mutations Received: 10 June 2022 Accepted: 8 August 2023 | Published online: 21 September 2023 | | --- | | Check for updates | Isao Miyazaki 1,13, Igor Odintsov2,3,7,13, Keiji Ishida1, Allan J. W. Lui 2,8, Masanori Kato 1, Tatsuya Suzuki1, Tom Zhang2, Kentaro Wakayama1, Renate I. Kurth2, Ryan Cheng2, Hidenori Fujita1, Lukas Delasos2,9, MoranaVojnic2,3,10, Inna Khodos4, Yukari Yamada1, Kota Ishizawa3,11, Marissa S. Mattar2, Kaoru Funabashi1, Qing Chang4, Shuichi Ohkubo1, Wakako Yano1, Ryuichiro Terada1, Claudio Giuliano 5, Yue Christine Lu2, Annalisa Bonifacio5, Siddharth Kunte2,12, Monika A. Davare 6, Emily H. Cheng 3, Elisa de Stanchina4, Emanuela Lovati5, Yoshikazu Iwasawa1, Marc Ladanyi2,3 & Romel Somwar 2,3 RET receptor tyrosine kinase is activated in various cancers (lung, thyroid, colon and pancreatic, among others) through oncogenic fusions or gain-of-function single-nucleotide variants. Small-molecule RET kinase inhibitors became standard-of-care therapy for advanced malignancies driven by RET. The therapeutic benefit ofRET inhibitors is limited, however, by acquired mutations in the drug target as well as brain metastasis, presumably due to inadequate brain penetration. Here, we perform preclinical characterization of vepafestinib (TAS0953/ HM06), a next-generation RET inhibitor with a unique binding mode. We demonstrate that vepafestinib has best-in-class selectivity against RET, while exerting activity against commonly reported on-target resistance mutations (variants in RETL730, RETV804 and RETG810), and shows superior pharmacokinetic properties in the brain when compared to currently approved RET drugs. We further show that these properties translate into improved tumor control in an intracranial model ofRET-driven cancer. Our results underscore the clinical potential of vepafestinib in treating RET-driven cancers. The rearranged during transfection (RET) protein belongs to the transmembrane receptor tyrosine kinase family and becomes anoncogenic driver when constitutively activated as a result of rearrangementsand point mutations1–4. Fusion of the RETkinase domain with several N-terminal partners such as kinesin family 5B (KIF5B) or coiled-coil domain-containing 6 (CCDC6) occurs in approximately 70% of patients with RET fusion-positive non-small cell lung cancer (NSCLC)5. RET fusions are now considered as driver oncogenes in A full list of affiliations appears at the end of the paper. e-mail: [isao-miyazaki@taiho.co.jp](isao-miyazaki@taiho.co.jp); [somwarr@mskcc.org](somwarr@mskcc.org) NSCLC, in which the prevalence is estimated tobe 1–2% ofunselected patients6–9. Earlier multi-kinase inhibitors (MKIs) such as cabozantiniband vandetanibhave been tested in clinical trials for the treatment of RETfusion-positive NSCLCor medullary thyroid cancers (MTCs) with RET mutations10–12. However, clinical efficacy of MKIshasnot reached expected outcomes, likely due to poor binding to RETand off-target interactions that may contribute to lower bioavailability in tumorsand increased toxicity13,14. The RET-selective inhibitors selpercatinib (LOXO-292) and pralsetinib (BLU-667), have shown durable clinical responses in patients with NSCLC and RET fusions, including some previously treated with MKIs or chemotherapy15–17, and their efficacy can be attributed to improved selectivity for RET compared to the MKIs used previously17,18. Selpercatinib and pralsetinib were approved in 2020 for patients with metastatic RET fusion-positive NSCLC, advanced or metastatic RET-altered MTCand papillary thyroid carcinoma. Despite early promising clinical benefits, recent reports describe RET solvent front (G810R, G810S, G810C), hinge (Y806C, Y806N) or ‘roof’ (L73

FAQs

What major factors limit the benefit of existing RET inhibitors?

Acquired mutations in the RET drug target and brain metastasis are major limitations, reflecting inadequate brain penetration and emerging resistance.

What does vepafestinib demonstrate in preclinical studies?

Vepafestinib shows best-in-class selectivity for RET, activity against common on-target resistance mutations (RET L730, V804, G810), and superior brain pharmacokinetic properties.

How do vepafestinib preclinical brain findings relate to tumor control?

Improved brain penetration and pharmacokinetics translate into better tumor control in an intracranial model of RET-driven cancer, supporting its clinical potential.

Sep 24, 2026

Uploaded by Stanley