1050P Association of Ctdna Quantification with Prognosis and Early Prediction of Response to First-Line Osimertinib in NSCLC Patients

Osimertinib is the new standard of care in epidermal growth factor receptor (EGFR)-mutated non-pretreated advanced non-small-cell lung cancer (NSCLC). The MELROSE study, a multicentric, open label, phase II trial (NCT03865511) was designed to identify resistance mechanisms at the time of disease progression in treatment-naive EGFR-mutated NSCLC patients receiving osimertinib. While these analyses are in progress, we explored secondary endpoints including ctDNA analysis. The MELROSE trial enrolled 150 patients with treatment-naive EGFR-mutated (L858R or exon 19 deletion) NSCLC. All patients received osimertinib. Tumor assessment was performed every 3 months, with brain and thoracoabdominal CT-scan (RECIST 1.1). Blood was collected in Streck tubes at baseline (d0) and after 7 days of treatment (d7). Cell free DNA was extracted from plasma (3 mL) using the Maxwell RSC LV kit (Promega). EGFR mutations were quantified by digital PCR using a Naica system (Stilla Technologies), and the IDEGFR SENSI detection kit (IDSolutions). Data from 138 patients were analyzed (8 consents withdrawn and 4 patients with missing data). 81 patients (58.7%) presented an exon 19 deletion, and 57 (41.3%) an L858R mutation. Primary analysis (data cutoff on April 4, 2022) showed a median PFS of 19.6 months (1-year PFS: 69.8%). At baseline, 94 patients (68.1%) were found to contain ctDNA (detectable EGFR mutation) in plasma. The presence of ctDNA was associated with liver metastases (p<0.001). High baseline ctDNA concentrations were associated with worse PFS (p=0.001), and were an independent prognostic factor in multivariate analysis (p=0.014). PFS was correlated with the presence of ctDNA after 1 week on osimertinib (d7) (p=0.009; HR 1.971; 95% CI 1.187-3.272). Patients presenting a significant increase in ctDNA concentration between d0 and d7 had a greatly reduced PFS (3.3 months) as compared to patients with a significant decrease in ctDNA concentration at d7 (PFS=18.2 months) (p=0.002; HR 11.648; 95% CI 2.536-53.505). PFS was independently associated with baseline ctDNA in NSCLC patients receiving first-line osimertinib. At day 7, an increase in ctDNA was associated with primary resistance.