560P Triple-targeted therapy of dabrafenib, trametinib and osimertinib for the treatment of acquired BRAF V600E mutation after progression on EGFR-TKIs in advanced EGFR-mutant NSCLC

This study represents, to our knowledge, the first cohort study investigation into the efficacy and safety of a triple-targeted therapy comprising EGFR/BRAF/MEK inhibitors dabrafenib, trametinib and osimertinib for NSCLC patients with acquired BRAF V600E mutation after EGFR-TKI treatment. Patient-derived organoid (PDO) experiments were conducted to further elucidate the drug response. A retrospective review of medical records was performed in multi-centers to analyze EGFR-mutant advanced NSCLC patients who developed acquired BRAF V600E mutation following EGFR-TKI treatment. All patients subsequently received dabrafenib, trametinib and osimertinib treatment. Clinical characteristics were documented, and progression-free survival (PFS) and adverse events (AEs) were assessed. In vivo drug response of PDOs were observed concurrently. Next-generation sequencing (NGS) was performed upon progression to triple-targeted therapy. Twelve patients with NGS-detected acquired BRAF V600E mutations were included in the study. Following triple-targeted therapy, the corresponding objective response rate (ORR) and disease control rate (DCR) was 58.3%, and 83.3%, respectively. The median PFS was 13.5 (95% CI: 9.8-17.2) months. No patients discontinued the treatment due to severe AEs. PDOs derived from one patient’s tumor sample were established, revealing that the triple-targeted therapy demonstrated a significantly lower IC50 value compared to other regimens. The tumor growth inhibitory rate was 99.36% for dabrafenib, trametinib plus osimertinib, 99.25% for osimertinib plus vemurafenib, 98.92% for osimertinib, encorafenib plus cetuximab, and 62.83% for pemetrexed plus carboplatin, respectively. NGS analysis identified major resistance mechanism following triple-targeted therapy, including EGFR-dependent pathway, EGFR and BRAF V600E-dependent pathway, and off-target mechanism. EGFR/BRAF/MEK triple-targeted therapy is an effective and safety approach for treating acquired BRAF V600E mutation in EGFR-mutant NSCLC patients resistant to EGFR-TKIs.