Circulating Tumour DNA in Patients With EGFR-Mutated Non-Small-Cell Lung Cancer and Early Disease Progression After First-Line Osimertinib Treatment: The ELUCIDATOR Multicentre Prospective Observational Study

Background Osimertinib is the standard therapy for patients with chemotherapy-naive advanced non-small-cell lung cancer (NSCLC) harbouring sensitising epidermal growth factor receptor (EGFR) mutations. However, some patients treated with osimertinib experience progressive disease (PD). Therefore, this study aimed to explore mechanisms underlying osimertinib resistance, focusing on early PD (within 6 months). Methods This multicentre prospective observational study enrolled patients with advanced NSCLC receiving osimertinib as the first-line anti-cancer therapy. Mutations in cancer-associated genes were analysed using next-generation sequencing of circulating tumour DNA samples collected before osimertinib treatment and on detection of PD. Findings Between May 2019 and January 2021, 188 patients were enrolled, of whom 125 (66%) were women and 96 (51%) had EGFR exon 19 deletion mutations. In this interim analysis, 78 patients experienced PD and 36 experienced early PD. Compared with patients without early PD, those with early PD were more likely to test positive for EGFR-activating mutations at baseline (86.1% vs. 63.4%, p = 0.009) and had significantly more co-occurring gene mutations in addition to EGFR mutations (2.89 +/- 1.49 vs. 1.97 +/- 1.37, p = 0.002). In three patients with early PD, one patient each had a germline BRCA1, BRCA2 and BRINP3 mutation. Conclusion: EGFR mutations in ctDNA and multiple co-occurring gene mutations at baseline are associated with poor out-comes and early PD. Plasma-based serial comprehensive gene profiling could help predict and identify patients who are unlikely to benefit from osimertinib treatment.