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RET Inhibitors in RET Fusion-Positive Lung Cancers: Past, Present, and Future

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Abstract

While activating RET fusions are identified in various cancers, lung cancer represents the most common RET fusion-positive tumor. The clinical drug development of RET inhibitors in RET fusion-positive lung cancers naturally began after RET fusions were first identified in patient tumor samples in 2011, and thereafter paralleled drug development in RET fusion-positive thyroid cancers. Multikinase inhibitors were initially tested with limited efficacy and substantial toxicity. RET inhibitors were then designed with improved selectivity, central nervous system penetrance, and activity against RET fusions and most RET mutations, including resistance mutations. Owing their success to these rationally designed features, the first-generation selective RET tyrosine kinase inhibitors (TKIs) had higher response rates, more durable disease control, and an improved safety profile compared to the multikinase inhibitors. This led to lung and thyroid cancer, and later tumor-agnostic regulatory approvals. While next-generation RET TKIs were designed to abrogate uncommon on-target (e.g., solvent front mutation) resistance to selpercatinib and pralsetinib, many of these drugs lacked the selectivity of the first-generation TKIs, raising the question of what the future holds for drug development in RET-dependent cancers.

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Author notes

  1. Monica F. Chen and Matteo Repetto contributed equally.

Authors and Affiliations

  1. Thoracic Oncology, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY, 10065, USA

    Monica F. Chen, Clare Wilhelm & Alexander Drilon

  2. Early Drug Development Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA

    Monica F. Chen, Matteo Repetto, Clare Wilhelm & Alexander Drilon

  3. Department of Medicine, Weill Cornell Medical College, New York, NY, USA

    Monica F. Chen & Alexander Drilon

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  1. Monica F. Chen
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Correspondence to Alexander Drilon.

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Funding

This research was partially supported by grants from the National Cancer Institute/National Institutes of Health (R01CA251591, R01CA273224-01, and P30CA008748), LUNGevity, and Happy Lungs.

Conflicts of Interest

Monica F. Chen reports funding from a T32-CA009207 and ASCO Young Investigator Award grant; stock: NVO, DGX, DOCS, FIGS. Matteo Repetto reports travel support from Sanofi. Clare Wilhelm reports no conflicts of interest. Alexander Drilon reports Honoraria/Advisory Boards: 14ner/Elevation Oncology, Amgen, Abbvie, ArcherDX, AstraZeneca, Beigene, BergenBio, Blueprint Medicines, Chugai Pharmaceutical, EcoR1, EMD Serono, Entos, Exelixis, Helsinn, Hengrui Therapeutics, Ignyta/Genentech/Roche, Janssen, Loxo/Bayer/Lilly, Merus, Monopteros, MonteRosa, Novartis, Nuvalent, Pfizer, Prelude, Repare RX, Takeda/Ariad/Millenium, Treeline Bio, TP Therapeutics, Tyra Biosciences, Verastem; Associated Research to Institution: Foundation Medicine, Teva, Taiho, GlaxSmithKlein; Equity: mBrace, Treeline; Copyright: Selpercatinib-Osimertinib (pending); Royalties: Wolters Kluwer, UpToDate, Food/Beverage: Boehringer Ingelheim, Merck, Puma: CME Honoraria: Answers in CME, Applied Pharmaceutical Science, Inc, AXIS, Clinical Care Options, EPG Health, Harborside Nexus, I3 Health, Imedex, Liberum, Medendi, Medscape, Med Learning, MJH Life Sciences, MORE Health, Ology, OncLive, Paradigm, Peerview Institute, PeerVoice, Physicians Education Resources, Remedica Ltd, Research to Practice, RV More, Targeted Oncology, TouchIME, WebMD.

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Author Contributions

Monica Chen, Matteo Repetto, and Alexander Drilon contributed to the study conception and design. The first draft of the manuscript was written by Monica Chen and Matteo Repetto. All authors critically revised the manuscript and read and approved the final manuscript.

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Chen, M.F., Repetto, M., Wilhelm, C. et al. RET Inhibitors in RET Fusion-Positive Lung Cancers: Past, Present, and Future. Drugs (2024). https://doi.org/10.1007/s40265-024-02040-5

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