Determining the optimal approach to identify osimertinib resistance; the first line osimertinib cohort of the OSIRIS study.

BACKGROUND

Resistance mechanisms (RMs) inevitably develop during osimertinib treatment in EGFR mutation positive (EGFRm+) NSCLC, and may guide subsequent therapy. We hypothesized that a complete RM analysis requires next-generation sequencing (NGS) of tumor tissue and plasma in patients experiencing disease progression (PD) on first-line osimertinib.

METHODS

At time of PD during osimertinib treatment, patients underwent plasma and tissue NGS for RM analysis. Plasma was analyzed with AVENIO ctDNA expanded panel, tissue with DNA and RNA NGS following local standards. Successful sequencing was defined by EGFRm identification.

RESULTS

Between February 2020 and January 2024, 150 patients were enrolled. Plasma sequencing was successful in 84 %, tissue sequencing in 94 %, both in 81 % of patients. In total, 159 RMs covered by both modalities were identified, 76 % in tissue, 59 % in plasma. Concordance was 34 %. In 54 patients, EGFR, MET and/or ERBB2 were amplified. At least one amplification was found in both sources for 17 patients, in tissue only for 25. Median EGFRm variant allele frequency (VAF) in plasma differed between these groups (25.9 vs 3.0 %, P < 0.05).

CONCLUSIONS

In case of low EGFRm VAF in plasma, combining tumor and plasma sequencing uncovers additional RMs compared to any single modality. Utilizing both for complete RM assessment is therefore recommended.

CLINICALTRIALS: gov Identifier: NCT04737382.