^
    11d
    Review and analysis of clinical trials of selective RET inhibitors for the treatment of thyroid cancer. (PubMed, Front Oncol)
    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.
    Journal
    |
    RET (Ret Proto-Oncogene)
    |
    Retevmo (selpercatinib) • Gavreto (pralsetinib) • SY-5007 • TY-1091 • enbezotinib (TPX-0046) • LOXO-260
    3ms
    Overcoming resistance in RET-altered cancers through rational inhibitor design and combination therapies. (PubMed, Bioorg Chem)
    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.
    Review • Journal
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    FLT3 (Fms-related tyrosine kinase 3) • MET (MET proto-oncogene, receptor tyrosine kinase) • RET (Ret Proto-Oncogene) • FGFR (Fibroblast Growth Factor Receptor) • STAT1 (Signal Transducer And Activator Of Transcription 1)
    |
    MET amplification • RET fusion • RET mutation • RET V804* • RET positive
    |
    Xalkori (crizotinib) • Cabometyx (cabozantinib tablet) • Retevmo (selpercatinib) • Gavreto (pralsetinib) • Caprelsa (vandetanib) • arsenic trioxide • SY-5007 • enbezotinib (TPX-0046) • PLD-101
    over1year
    A Study to Evaluate the Mass Balance of [14C] SY-5007 in Healthy Adult Male Subjects in China (clinicaltrials.gov)
    P1, N=8, Not yet recruiting, Shouyao Holdings (Beijing) Co. LTD
    New P1 trial
    |
    SY-5007
    over1year
    A Study to Evaluate the Effect of Itraconazole and Rifampicin on the Pharmacokinetics of SY-5007 in Healthy Subjects (clinicaltrials.gov)
    P1, N=28, Not yet recruiting, Shouyao Holdings (Beijing) Co. LTD
    New P1 trial
    |
    SY-5007 • itraconazole • rifampicin
    over1year
    A Study to Evaluate the Food Effects on Pharmacokinetics of SY-5007 Tablets in Healthy Subjects (clinicaltrials.gov)
    P1, N=28, Not yet recruiting, Shouyao Holdings (Beijing) Co. LTD
    New P1 trial
    |
    SY-5007
    2years
    Phase III Study of SY-5007, a RET Inhibitor, in Patients With Locally Advanced or Metastatic RET Fusion-positive NSCLC (clinicaltrials.gov)
    P3, N=120, Recruiting, Shouyao Holdings (Beijing) Co. LTD
    New P3 trial • Metastases
    |
    RET (Ret Proto-Oncogene)
    |
    RET fusion • RET positive
    |
    SY-5007
    over2years
    A first-in-human phase I, dose-escalation and dose-expansion study of SY-5007, a highly potent and selective RET inhibitor, in Chinese patients with advanced RET positive solid tumors. (ASCO 2023)
    Recently, selective RET TKIs, selpercatinib and pralsetinib, were approved for RET positive solid tumors by FDA. SY-5007 was well tolerated in patients. Preliminary antitumor activity was also observed in patients with advanced RET-fusion positive NSCLS and RET mutant MTC. The pivotal Phase II clinical study of SY-5007 in NSCLC patients is ongoing.
    Clinical • P1 data • Metastases
    |
    RET (Ret Proto-Oncogene)
    |
    RET fusion • RET mutation • RET positive
    |
    Retevmo (selpercatinib) • Gavreto (pralsetinib) • SY-5007
    over2years
    Phase I/II Study of SY-5007, a RET Inhibitor, in Patients With RET-altered Advanced Solid Tumor (clinicaltrials.gov)
    P1/2, N=184, Recruiting, Shouyao Holdings (Beijing) Co. LTD | Trial primary completion date: Mar 2023 --> Jan 2025
    Trial primary completion date • Metastases
    |
    PD-L1 (Programmed death ligand 1) • RET (Ret Proto-Oncogene)
    |
    RET fusion • RET mutation • RET positive
    |
    SY-5007
    almost3years
    Phase I/II Study of SY-5007, a RET Inhibitor, in Patients With RET-altered Advanced Solid Tumor (clinicaltrials.gov)
    P1/2, N=200, Recruiting, Shouyao Holdings (Beijing) Co. LTD | Phase classification: P1 --> P1/2 | N=80 --> 200 | Trial completion date: Jun 2023 --> Feb 2025
    Phase classification • Enrollment change • Trial completion date • Metastases
    |
    PD-L1 (Programmed death ligand 1) • RET (Ret Proto-Oncogene)
    |
    RET fusion • RET mutation • RET positive
    |
    SY-5007
    over3years
    A Phase I Study to Evaluate the Safety, Pharmacokinetics and Efficacy of SY-5007 in Patients With Advanced Solid Tumors (clinicaltrials.gov)
    P1, N=80, Recruiting, Shouyao Holdings (Beijing) Co. LTD | Trial primary completion date: Mar 2022 --> Mar 2023
    Trial primary completion date
    |
    RET (Ret Proto-Oncogene)
    |
    RET fusion • RET mutation
    |
    SY-5007
    over3years
    A Phase I Study to Evaluate the Safety, Pharmacokinetics and Efficacy of SY-5007 in Patients With Advanced Solid Tumors (clinicaltrials.gov)
    P1, N=80, Recruiting, Shouyao Holdings (Beijing) Co. LTD
    New P1 trial
    |
    RET (Ret Proto-Oncogene)
    |
    RET fusion • RET mutation
    |
    SY-5007