2023 World Conference on Lung Cancer (Posters)-P2.10. Mechanisms of Acquired Resistance to ALK Inhibitors Using Plasma Sequencing - Preliminary Data from the ATORG004 Study

P2.10. Mechanisms of Acquired Resistance to ALK Inhibitors Using Plasma Sequencing - Preliminary Data from the ATORG004 Study - PDF(Slides)

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A study was conducted to investigate the mechanisms of acquired resistance to ALK inhibitors in patients with ALK rearranged lung cancer. The study included 39 patients who had progressed on ALK inhibitor therapy as their most recent treatment. Plasma samples were collected and analyzed for circulating tumor DNA using next-generation sequencing.<br /><br />The results showed that ctDNA was detected in the plasma of 69% of the patients. Among these patients, 89% had at least one non-synonymous alteration. Some of the known ALK-independent resistance alterations detected included MET amplification, ERBB2 amplification/SNV, EGFR mutation, and NRAS mutation.<br /><br />In addition to these known alterations, potential concurrent resistance mechanisms were also detected. These included ALK mutation and FGFR1 amplification, ALK mutation and ERBB2 amplification, and ALK mutation and ERBB2/RB1/TP53 alterations.<br /><br />The study also found that DDR and cell cycle gene alterations were commonly detected in the resistance mechanisms. These alterations, along with previously unreported resistance alterations, suggest the heterogeneity of ALK TKI resistance mechanisms.<br /><br />Furthermore, the study showed that repeat ctDNA NGS analysis after treatment with lorlatinib resulted in the clearance of ALK resistance mutations in 80% of patients. This suggests that comprehensive ctDNA NGS analysis at progression may help detect novel resistance alterations and guide treatment decisions.<br /><br />In conclusion, this study provides preliminary data on the mechanisms of acquired resistance to ALK inhibitors in patients with ALK rearranged lung cancer. The findings highlight the heterogeneity of resistance mechanisms and the potential for using ctDNA NGS analysis to detect and monitor resistance alterations.

Asset Subtitle

Aaron Tan

Meta Tag

Speaker Aaron Tan

Topic Metastatic NSCLC: Targeted Therapy - FUSIONS

Keywords

ALK inhibitors

acquired resistance

ALK rearranged lung cancer

ctDNA

MET amplification

EGFR mutation

NRAS mutation

ALK mutation

DDR gene alterations

lorlatinib