Combined analysis of circulating tumor DNA and tumor tissue to overcome osimertinib resistance (OSIRIS); the second line osimertinib cohort

Introduction: Osimertinib resistance inevitably occurs in EGFR mutated NSCLC. We aimed to identify resistance mechanisms (RM) using paired plasma and tumor samples in patients that progressed on 2nd/3rd line osimertinib.

Methods: From 09 - 2019 to 02 - 2021, 51 patients were enrolled. Plasma sequencing used AVENIO Expanded Panel (research use only), tumor biopsies underwent DNA and RNA sequencing and histological evaluation. Sequencing was regarded successful when the driver mutation was confirmed with a variant allele frequency of ≥0.10%. Concordance between modalities was calculated for the driver mutation and RMs covered in both modalities. The Molecular Tumor Board formulated a treatment advice.

Results: The driver mutation was detected in 42/51 plasma samples (82%) and in 50/51 tumor samples (98%), concordance rate was 80%. In 41/51 (80%) patients ≥1 RM was identified. Thirty-two RMs covered in both modalities were found in plasma (61.5%), 39 in tumor (75%), nineteen in both. RM concordance rate was 36.5%.

Conclusion: Combined analysis of plasma and tumor samples post 2nd/3rd line osimertinib identifies additional RMs regardless of the comparative approach used. Plasma sequencing identified 61.5% of RMs, tumor analysis identified 75%. Combined, they provide a superior overview of osimertinib resistance, enabling more tailored treatment options.