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RET Inhibitors in RET Fusion-Positive Lung Cancers: Past, Present, and Future
Monica F Chen1,2,3, Matteo Repetto2, Clare Wilhelm1,2
1Thoracic Oncology, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY, 10065, USA.
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.
Insights
RET inhibitors have advanced cancer treatment, with selective tyrosine kinase inhibitors (TKIs) showing improved efficacy and safety over earlier drugs. Future research focuses on overcoming resistance mechanisms in RET-dependent cancers.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Activating RET fusions are key drivers in various cancers, notably lung cancer.
- Early treatments involved multikinase inhibitors with limited success and significant toxicity.
- RET fusion-positive lung and thyroid cancers have been central to RET inhibitor development.
Purpose of the Study:
- To review the clinical development of RET inhibitors for RET fusion-positive cancers.
- To compare the efficacy and safety of first-generation selective RET TKIs versus multikinase inhibitors.
- To discuss the evolution of RET inhibitors, including next-generation agents targeting resistance mutations.
Main Methods:
- Review of clinical trial data and scientific literature on RET inhibitors.
- Analysis of drug development timelines and therapeutic outcomes.
- Comparison of drug selectivity, efficacy, safety, and resistance profiles.
Main Results:
- First-generation selective RET tyrosine kinase inhibitors (TKIs) demonstrated superior response rates, durable disease control, and improved safety compared to multikinase inhibitors.
- Selective RET TKIs led to regulatory approvals for lung, thyroid, and other RET fusion-positive tumors.
- Next-generation RET TKIs were developed to address resistance mutations but often exhibit reduced selectivity.
Conclusions:
- Selective RET TKIs represent a significant advancement in treating RET-dependent cancers.
- The development of RET inhibitors has progressed from broad-acting agents to highly targeted therapies.
- Future drug development must balance efficacy against resistance with the need for target selectivity and safety.
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