2021 Targeted Therapies of Lung Cancer (TTLC) Meeting - Posters-P08. Precision Targeted Therapy for RET-driven NSCLC and Emerging Evidence of Acquired Resistance to RET-Specific Tyrosine Kinase Inhibitors

P08. Precision Targeted Therapy for RET-driven NSCLC and Emerging Evidence of Acquired Resistance to RET-Specific Tyrosine Kinase Inhibitors - PDF

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This abstract discusses precision targeted therapy for RET-driven non-small cell lung cancer (NSCLC) and the emerging evidence of acquired resistance to RET-specific tyrosine kinase inhibitors (TKIs). The use of TKIs in NSCLC has revolutionized treatment, with multiple TKIs targeting other molecular drivers of tumor growth already approved in the first-line setting. RET-fusion driven NSCLCs are the most recent addition to the list of targetable drivers, with the recent FDA approval of two novel RET kinase inhibitors, pralsetinib and selpercatinib. However, like other TKIs, resistance to RET-specific TKIs can develop in patients. The case of a patient who developed TKI resistance via MET amplification following treatment with cabozantinib and selpercatinib for RET-fusion NSCLC is presented to highlight the role of serial mutational analysis in managing evolving TKI resistance and to review what is known about overcoming MET-dependent resistance.<br /><br />The case involves a patient with KIF5B-RET fusion advanced NSCLC who underwent treatment with various TKIs. Molecular profiling revealed the fusion at initial diagnosis, and the patient showed a partial response to initial treatment. However, disease progression occurred, and the patient was subsequently treated with selpercatinib. The patient experienced progression again, and molecular analysis did not reveal any alterations known to cause TKI resistance. Eventually, a new MET amplification was detected, suggesting a potential mechanism of resistance. The literature indicates that MET amplifications at baseline may contribute to a shortened duration of benefit from selpercatinib.<br /><br />In conclusion, precision medicine approaches have greatly improved the treatment of NSCLC. While multikinase TKIs have largely failed RET-fusion driven cancers, the approval of RET-specific TKIs has provided better treatment responses for this subset of patients. However, there is still a need for a better understanding of resistance mechanisms to RET-specific TKIs, the use of serial mutational analysis, and the exploration of dual RET and MET inhibition. Further research and evidence are necessary to address these needs.

Asset Subtitle

Johnathan Ebben

Meta Tag

Speaker Johnathan Ebben

Topic Targeted Therapies - All Others

Keywords

precision targeted therapy

RET-driven non-small cell lung cancer

acquired resistance

RET-specific tyrosine kinase inhibitors

NSCLC treatment

molecular drivers

RET-fusion driven NSCLCs

novel RET kinase inhibitors

TKI resistance

MET amplification