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Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
Targeted Therapy For RET-Rearranged Non-Small Cell Lung Cancer: Clinical Development And Future Directions
Christoph Jakob Ackermann1, Gustavo Stock2, Rebecca Tay1
1Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK.
Abstract:
Approximately 1-2% of unselected patients with Non-small Cell Lung Cancer (NSCLC) harbor RET rearrangements resulting in enhanced cell survival and proliferation. The initial treatment strategy for RET rearranged NSCLC has been multi-target tyrosine kinase inhibition. With overall response rates (ORR) of 16-53% and a median progression-free survival (PFS) of 4.5-7.3 months these outcomes are clearly inferior to the efficacy outcomes of selective tyrosine kinase inhibitors (TKI) in other oncogene-addicted NSCLC. Additionally, multi-kinase inhibition in RET-driven NSCLC patients showed concerning rates of high-grade toxicity, mainly induced by anti-VEGFR-kinase activity. Novel selective RET inhibitors like BLU-667, LOXO-292 and RXDX-105 have been recently investigated in early phase clinical trials showing promising efficacy with a manageable toxicity profile.
Insights
New targeted therapies show promise for Non-small Cell Lung Cancer (NSCLC) with RET rearrangements. Selective RET inhibitors offer better efficacy and safety compared to older multi-target treatments.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- RET rearrangements occur in 1-2% of Non-small Cell Lung Cancer (NSCLC) patients, driving cancer cell survival and proliferation.
- Current treatment involves multi-target tyrosine kinase inhibitors (TKIs), which have shown limited efficacy and significant toxicity, particularly due to anti-VEGFR activity.
Purpose of the Study:
- To evaluate the efficacy and safety of novel selective RET inhibitors in patients with RET-rearranged NSCLC.
- To compare the outcomes of selective RET inhibitors with existing multi-target TKIs.
Main Methods:
- Review of early-phase clinical trials investigating novel selective RET inhibitors (e.g., BLU-667, LOXO-292, RXDX-105).
- Analysis of reported overall response rates (ORR) and median progression-free survival (PFS) for both selective and multi-target TKIs.
Main Results:
- Selective RET inhibitors demonstrated promising efficacy in early clinical trials.
- These novel agents exhibited a more manageable toxicity profile compared to multi-target TKIs.
- Outcomes from multi-target TKIs showed inferior response rates (16-53% ORR) and short PFS (4.5-7.3 months).
Conclusions:
- Novel selective RET inhibitors represent a significant advancement in treating RET-rearranged NSCLC.
- These targeted therapies offer improved efficacy and reduced toxicity, outperforming traditional multi-target inhibitors.
- Further clinical investigation is warranted to establish the role of selective RET inhibitors in NSCLC treatment paradigms.
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