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

Background

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.

Methods

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.

Results

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.

Conclusions

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.

Clinical trial identification

Editorial acknowledgement

Thanks for supports of Novartis

Legal entity responsible for the study

J. Yang.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.