RET inhibitors in RET fusion-positive lung cancers: Past, present, and future Review
| Authors: | Chen, M. F.; Repetto, M.; Wilhelm, C.; Drilon, A. |
| Review Title: | RET inhibitors in RET fusion-positive lung cancers: Past, present, and future |
| 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. |
| Keywords: | mutation; drug efficacy; phenotype; carcinoma, non-small-cell lung; drug development; drug design; central nervous system; molecular structure; antineoplastic agents -- therapeutic use; treatment outcomes; antineoplastic agents -- pharmacodynamics; switzerland; thyroid neoplasms -- drug therapy; tyrosine kinase inhibitors -- therapeutic use; drugs, investigational -- therapeutic use; lung neoplasms -- drug therapy -- switzerland |
| Journal Title: | Drugs |
| Volume: | 84 |
| Issue: | 9 |
| ISSN: | 0012-6667 |
| Publisher: | Adis International Ltd |
| Date Published: | 2024-09-01 |
| Start Page: | 1035 |
| End Page: | 1053 |
| Language: | English |
| DOI: | 10.1007/s40265-024-02040-5 |
| PROVIDER: | EBSCOhost |
| PROVIDER: | cinahl plus with full text |
| PUBMED: | 38997570 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record and PDF. Corresponding MSK author is Alexander Drilon -- Source: CINAHL Plus with Full Text |
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