Response to EGFR/NTRK/MET Co-Inhibition Guided by Paired NGS in Advanced NSCLC With Acquired EGFR L858R/T790M/C797S Mutations
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Laboratory of Clinical Cell Therapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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Laboratory of Clinical Cell Therapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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EGFR tyrosine kinase inhibitors (TKIs) have significantly improved clinical outcomes for patients with non–small cell lung cancer (NSCLC) harboring EGFR-activating mutations. However, resistance to TKI therapy often develops due to secondary EGFR mutations or the activation of bypass signalling pathways. Next-generation sequencing (NGS) can efficiently identify actionable genetic alterations throughout treatment. MET amplification is a well-established off-target resistance mechanism. Additionally, rarer mechanisms, such as NTRK1 gene fusions, have been reported. This report highlights a case of a 58-year-old male diagnosed with bone-metastatic NSCLC harboring the EGFR L858R mutation. After receiving dacomitinib and almonertinib sequentially, plasma-based NGS revealed the emergence of EGFR T790M-trans-C797S mutations, prompting a switch to a combination therapy of almonertinib and gefitinib. Upon disease progression, repeat NGS identified EGFR T790M-cis&trans-C797S mutations and a novel POT1::NTRK3 fusion in the blood. The fusion retained a complete NTRK kinase domain without frameshift variants, making it a target for treatment. Larotrectinib was incorporated into the dual EGFR-TKI regimen, forming a triplet therapy. Although this resulted in grade 3 dermatitis, the condition resolved after discontinuing gefitinib. At multiorgan progression, matched tissue- and plasma-based NGS identified MET amplification. Subsequently, the patient was started on a triple-inhibition regimen targeting EGFR, NTRK, and MET, which achieved a partial response with favorable tolerability. This is the first reported case of a novel, targetable POT1::NTRK3 fusion as a potential off-target mechanism mediating EGFR-TKI resistance, occurring alongside MET amplification in a patient with NSCLC harboring acquired EGFR L858R/T790M/C797S mutations. Concomitant inhibition of EGFR, NTRK, and MET was safe and resulted in a significant response, underscoring the importance of precision medicine guided by matched NGS.
Submitted June 21, 2024; final revision received July 25, 2024; accepted for publication August 26, 2024. Published online December 27, 2024.
X. Yang, X. Li, and J. Yan contributed equally.
Disclosures: The authors have disclosed that they have not received any financial considerations from any person or organization to support the preparation, analysis, results, or discussion of this article.
Funding: This work was supported by funding from the National Natural Science Foundation of China (82373021; J. Xue); 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University (ZYYC23010 to J. Xue; ZYJC21003 to Y. Lu); and Science and Technology Department of Sichuan Province (00402053A29Z1).
Supplementary material: Supplementary material associated with this article is available online at https://doi.org/10.6004/jnccn.2024.7070. The supplementary material has been supplied by the author(s) and appears in its originally submitted form. It has not been edited or vetted by JNCCN. All contents and opinions are solely those of the author. Any comments or questions related to the supplementary materials should be directed to the corresponding author.
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