enbezotinib (TPX-0046)

Selpercatinib and pralsetinib are the most frequently studied RET inhibitors. Notably, research on next-generation RET inhibitors as monotherapy approaches (e.g., LOXO-260, enbezotinib, SY-5007 and TY-1091) is currently underway...While selective RET inhibitors have demonstrated therapeutic potential, concerns regarding drug resistance and toxicity persist. Therefore, future strategies should prioritize the development of next-generation inhibitors and the optimization of combination regimens to improve outcomes for RET-altered thyroid cancer patients.

Traditional multi-kinase inhibitors (MKIs, such as cabozantinib and vandetanib) exhibit significant side effects due to non-selective inhibition of targets like VEGFR, and also suffer from resistance associated with RET mutations (e.g., V804L/M, G810C/S/R), both of which limit their clinical application...To overcome drug resistance, the design strategies of novel inhibitors focus on multi-target inhibition (such as PLM-101 targeting RET/YES1/FLT3, TPX-0046 targeting RET/SRC), structural optimization (such as helical ring derivatives enhancing binding stability), and natural compound screening (such as ZINC series molecules)...For instance, selpercatinib combined with crizotinib can inhibit MET amplification-driven resistance, while arsenic trioxide combined with pralsetinib restores sensitivity by inhibiting the HH-Gli pathway. Current clinical trials show that novel RET inhibitors such as SY-5007 have a significant objective response rate in advanced RET fusion-positive non-small cell lung cancer and are safer than traditional drugs. In the future, it is necessary to further develop broad-spectrum mutation coverage and highly selective inhibitors, and explore individualized combination treatment regimens to improve prognosis. This article systematically reviews the progress, resistance mechanisms and coping strategies of RET-targeted therapy, providing a theoretical basis and direction for the development of precision anti-cancer drugs.

P1/2, N=41, Terminated, Turning Point Therapeutics, Inc. | Trial completion date: Nov 2023 --> May 2023 | Active, not recruiting --> Terminated; Adverse change in the risk/benefit.

Thus, the novel highly potent and RET-specific inhibitors selpercatinib and pralsetinib have been accelerated for approval by the Food and Drug Administration (FDA), and clinical trials of TPX-0046 and zetletinib are underway. It is well tolerated and a potential therapeutic for RET-altered cancers. Thus, we will focus on current state-of-the-art therapeutics with these novel RET inhibitors and show their efficacy and safety in therapy.

P1/2, N=462, Active, not recruiting, Turning Point Therapeutics, Inc. | Recruiting --> Active, not recruiting

P1/2, N=462, Recruiting, Turning Point Therapeutics, Inc. | Trial completion date: Mar 2025 --> Nov 2026 | Trial primary completion date: May 2024 --> Dec 2025

Selective RET inhibitors (selpercatinib/pralsetinib) are active in patients with these cancers; unfortunately, resistance often occurs. TPX-0046 is a unique next-generation RET inhibitor that possesses potent in vitro and in vivo activity against a diverse range of RET alterations, including SFM-mediated resistance. A phase 1/2 trial for RET inhibitor-resistant and naïve RET-driven cancers is on-going (NCT04161391). Research Funding: Turning Point Therapeutics