Integrated Genomics in Oncogene-driven NSCLC With Acquired Resistance

Currently, tyrosine kinase inhibitor (TKI) remains the standard of care for oncogene-driven non-small cell lung cancer (NSCLC). However, almost all oncogene-driven NSCLCs would develop acquired resistance against TKI in clinical practice. Therefore, understanding the molecular mechanisms underlying the acquired resistance is a critical issue in lung cancer. Based on the literature, acquired resistance mechanism against EGFR TKI includes EGFR secondary mutation (T790M, C797X, L792X, G796X, L718Q, and exon 20 insertions), MET amplification, HER2 amplification, acquired gene fusions, and other complex alterations. From the perspective of mutagenesis, the acquired resistance against TKI may be associated with APOBEC mutational processes, kataegis, chromothripsis, extrachromosomal DNA (ecDNA), and the interaction among them. However, still 30% to 50% of oncogene-driven NSCLCs had no identified mechanism attributed to the acquired resistance. Previous studies mostly used targeted-gene sequencing, which may overlook some structural variation and the transcriptomic dynamics. This study aims to investigate the genomic alterations, mutational processes, and the transcriptomic landscape underlying the acquired resistance using integrated genomics.

NCT Number	NCT07122882
Lead Sponsor	Chang Gung Memorial Hospital
Conditions	Oncogene-addicted Non Small Cell Lung Cancer, EGFR Mutation, ALK Fusion-positive Solid or CNS Tumors, ROS1 Fusion Positive, RET Fusion Positive, ERBB2 Mutation-Related Tumors, NTRK1 Fusion Positive, NTRK2 Fusion Positive +5 more
Enrollment	40 participants
Start Date	2025-09-01
Primary Completion	2027-05-11 (estimated)
Study Completion	2028-05-11 (estimated)
Updated on ClinicalTrials.gov	2026-03-17