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(Abstract)

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This abstract discusses the mechanisms of acquired resistance to ALK inhibitors in patients with ALK rearranged non-small cell lung cancer (NSCLC). The study, called ATORG004, is a prospective, multi-center study conducted throughout Asia. The study includes three cohorts of patients who have progressed on ALK inhibitors: those treated with second-generation ALK TKI alone, those treated sequentially with first and second-generation ALK TKI, and those treated with third-generation ALK TKI. Plasma samples from these patients are collected and analyzed for circulating tumor DNA using next-generation sequencing.<br /><br />The interim analysis includes 39 patients from Cohorts 1 and 2. The median age of the patients was 59 years, with the majority being female and never smokers. The ALK rearrangement was detected using various methods, including FISH, IHC, FISHIHC, and NGS. The most common fusion partner was EML4-ALK.<br /><br />CtDNA was detected in the plasma of 69% of patients, and known resistance mechanisms were observed in 37% of patients. These mechanisms included both ALK dependent and independent pathways. ALK resistance mutations were detected in 5 patients, and after receiving lorlatinib, 4 of these patients showed clearance of the resistance mutation. Other resistance alterations included MET amplification, ERBB2 amplification or mutation, NRAS mutation, TP53 alterations, DNA damage repair gene alterations, and cell cycle gene alterations.<br /><br />The study concludes that resistance mechanisms to ALK inhibitors are heterogeneous and involve both ALK dependent and independent pathways. DNA damage repair gene alterations and cell cycle gene alterations were commonly detected, which may represent previously unreported acquired resistance alterations. The comprehensive analysis of ctDNA using next-generation sequencing at disease progression can help detect novel resistance alterations in patients receiving ALK inhibitors.

Asset Subtitle

Aaron Tan

Meta Tag

Speaker Aaron Tan

Topic Metastatic NSCLC: Targeted Therapy - FUSIONS

Keywords

acquired resistance

ALK inhibitors

ALK rearranged NSCLC

ATORG004 study

circulating tumor DNA

next-generation sequencing

ctDNA

ALK resistance mutations

MET amplification

DNA damage repair gene alterations