Abstract P233: TAS0953/HM06 is effective in preclinical models of diverse tumor types driven by RET alterations

Abstract

Fusions involving RET receptor tyrosine kinase are a common driver of tumors across different tissue types, such as lung, thyroid, colorectal, soft tissue and others. TAS0953/HM06 (hereby referred to as HM06) is a novel 2ndgeneration RET-specific inhibitor that is effective against RET solvent front (G810) and gatekeeper (V804) mutations. Here, we evaluated the efficacy of HM06 in lung and thyroid carcinomas, and soft-tissue sarcoma cell lines and PDXs derived from RET inhibitor-naive tumor samples or from tumors with acquired resistance to selpercatinib. HM06 was more effective than the RET multi-kinase inhibitors cabozantinib and vandetanib, and as effective as selpercatinib and pralsetinib in inhibiting growth of patient-derived and isogenic lung, thyroid and sarcoma cell lines (IC50=0.02-0.1 µM) harboring different RET fusions (KIF5B-RET, CCDC6-RET, TRIM33-RET, SPECCL1-RET) or activating mutations (RET C634W). Growth of non-tumor cells was up to 80-fold less sensitive to HM06 (IC50= 1.6 µM). Treatment of RET fusion-positive lung cancer cells with HM06 resulted in a dose-dependent inhibition of RET phosphorylation (Y905 and Y1062) and the downstream effectors AKT, ERK1/2, p70S6K and S6. Caspase 3/7 activity and markers of apoptosis (BIM, cleaved PARP) were induced by HM06 to a similar extent as pralsetinib and selpercatinib (dose range: 0.05-1 µM). HM06 induced changes in the core mediators of cell cycle regulation (upregulation of p27, downregulation of CCND1) and suppressed expression of MYC and ETV5. In vivo, HM06 blocked tumor growth and/or induced regression of up to 65% in seven patient-derived xenograft (PDX) models with RET fusions (five NSCLC PDXs, one sarcoma PDX and one NSCLC cell-line xenograft) to a similar extent as pralsetinib and selpercatinib. However, 6 weeks after cessation of treatment of the SPECCL1-RET-driven sarcoma PDX model, growth of tumors treated with HM06 was suppressed completely, whereas 3/5 pralsetinib-treated tumors and 1/5 selpercatinib-treated tumor regrew. Combination of HM06 and the MET inhibitor capmatinib effectively blocked growth of PDX tumors in a model that was derived from a patient sample that expressed RET fusion and METamplification, and was resistant to selpercatinib. These results suggest that HM06 may be an effective therapy for RET-driven tumors in a tissue-type agnostic manner and can effectively address common on-target and off-target resistance mechanisms such as RET G810X and V804X mutations. HM06 is currently in a phase 1 and 2 clinical trial for patients with advanced solid tumors with RET gene abnormalities (margaRET, NCT 04683250). Citation Format: Igor Odintsov, Renate I. Kurth, Kota Ishizawa, Lukas Delasos, Allan J.W. Lui, Inna Khodos, Connor J. Hagen, Qing Chang, Marissa S. Mattar, Morana Vojnic, Siddharth Kunte, Annalisa Bonifacio, Claudio Giuliano, Elisa De Stanchina, Emily Cheng, Emanuela Lovati, Marc Ladanyi, Romel Somwar. TAS0953/HM06 is effective in preclinical models of diverse tumor types driven by RET alterations [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P233.

The return of RET GateKeeper mutations? An In-silico exploratory analysis of potential resistance mechanisms to novel RET macrocyclic inhibitor TPX-0046

“…While Pralsetinib and Selpercatinib are able to overcome bulky GK mutations but are vulnerable to SF mutations, TPX-0046 might show the opposite activity spectrum being able to overcome SF mutations, but remaining vulnerable to GK mutations. Meanwhile GK and SF tolerant RET inhibitors have currently entered Phase-I clinical trials (TAS0953) [17].…”

Selective RET Inhibitors (SRIs) in Cancer: A Journey from Multi-Kinase Inhibitors to the Next Generation of SRIs

“…Vepafestinib inhibited the growth of multiple lung cancer patient-derived cell lines harboring RET fusions with different N-terminal partners ( CCDC6 , KIF5B , TRIM33 ) and an RET C634W mutation–positive MTC cell line and was active in a number of NSCLC xenograft models. Preclinical models suggested that vepafestinib penetrates the CNS more than selpercatinib and is superior in decreasing CNS disease and extending survival in mice [ 41 , 42 ]. Vepafestinib is currently undergoing a biomarker-driven phase I/II clinical trial (MARGARET) in the US and Japan for patients with solid tumors driven by RET alterations that have progressed on existing therapies (NCT04683250, accessed 3 November 2023).…”

RET signaling pathway and RET inhibitors in human cancer

“…While TPX-0046 cannot circumvent the V804 gatekeeper mutation, a Phase I/II clinical trial (NCT04161391) is ongoing in patients with advanced solid tumors harboring RET alterations. HM06, another investigational compound, selectively inhibits RET across multiple tumor types in vitro and in vivo , circumvents RET-V804X gatekeeper mutation and RET-G810X resistance mutations ( 284 , 285 ), and is currently in Phase I/II clinical trials in patients with RET-altered tumors (NCT04683250). Lastly, LOX-18228 is a novel compound that potently inhibits RET, RET fusions, and can even inhibit RET-V804X and RET-G810X mutations singly or in tandem ( 286 ), suggesting that LOX-18228 may be effective in targeting tumors with resistance to first-generation RET inhibitors.…”