Abstract 3756
Background
Targeted therapy (EGFR tyrosine kinase inhibitors, EGFR-TKIs) has been proven effective in NSCLC patients with activating EGFR mutations. Despite the initial response, most patients progress. Several acquired-resistance mutations have been described, including the EGFR T790M mutation. Here we use longitudinal plasma monitoring to identify different mechanisms of acquired resistance to EGFR-TKIs and demonstrate that tumor heterogeneity and clonal evolution may play a role in the outcome of subjects treated with osimertinib.
Methods
Tumor and plasma were collected from 13 subjects with metastatic lung adenocarcinoma treated with erlotinib followed by osimertinib, upon the development of resistance (T790M positive). Overall, 10 FFPE tumor and 115 longitudinally collected plasma specimens were analyzed with either the FDA-approved cobas® EGFR Mutation Test v2 or a 197-gene NGS assay (AVENIO ctDNA Surveillance Kit and AVENIO Tumor Tissue Surveillance Kit prototype, Research Use Only). Detected EGFR and non-EGFR mutations were correlated with disease control (evaluated by RECIST1.1).
Results
The concordance of EGFR mutations (L858R, T790M, Ex19Del) detected by cobas® and AVENIO assay in pre-osimertinib plasma samples was 92.31% (n = 12/13). The AVENIO assay detected additional mutations in ∼6 non-EGFR genes. Some of these mutations were already present in pre-erlotinib plasma samples. Not all mutations showed directional change in allelic fraction (AF) after treatment with osimertinib, i.e. some subjects had a complete loss of T790M mutation, whereas other mutations remained unchanged or their AF increased, suggesting clonal heterogeneity. In general, subjects with more than 5 non-EGFR mutations (median count = 5) had a significantly lower median overall survival (OS) benefit of 30.5 months (n = 13, logrank p-value=0.0048, HR = 12, 95% CI (1.5, 104)).
Conclusions
Longitudinal ctDNA monitoring of subjects treated with EGFR-TKIs with a multi-gene NGS panel enables identification of different resistance mechanisms and can potentially guide a selection of optimal treatment combination and sequencing strategies.
Clinical trial identification
Legal entity responsible for the study
Roche.
Funding
Roche.
Editorial Acknowledgement
Disclosure
J. Palma, N. Tikoo: Employment and stocks: Roche. P. Vitazka, A. Balasubramanyam, L. Xi, S. Yaung, E. Kwok, M. Heibeck, K. Probst, A. Rehfeldt, A. Lovejoy: Employment: Roche. D. Klass: Employment: Roche Sequencing Solutions; Royalties for ctDNA detection: IP; Former shareholder: CAPP Medical. B. Sorensen, P. Meldgaard: Research support and advisory board: Roche. All other authors have declared no conflicts of interest.
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