52P Liquid biopsy monitoring in BRAF V600E mutated NSCLC patients treated with dabrafenib plus trametinib: A prospective, explorative, multicentric study, LiBRA study (GOIRC-03-2020)

Dabrafenib plus trametinib (D+T) is the standard first-line (1L) treatment of advanced BRAF V600E mutated (mut) non-small cell lung cancer (NSCLC). To date, the role of liquid biopsy (LB) as a tool for predicting outcomes of 1L D+T in advanced BRAF V600E mut NSCLC has not been assessed. We conducted a prospective multicentric study in 25 Italian Centers aimed at exploring the role of LB in advanced BRAF V600E mut NSCLC patients treated with 1L D+T. Plasma samples were collected before treatment start (t0), after 4 weeks (t1), every 4 weeks during the first 16 weeks of treatment and every 8 weeks until progression (PD). Digital droplet PCR (ddPCR) was performed to monitor BRAF V600E in plasma samples. Next-Generation Sequencing (NGS) analysis was conducted on circulating tumor DNA positive t0 and PD plasma samples. We enrolled 41 BRAF V600E mut NSCLC patients treated with 1L D+T. Overall, 25 (61%) patients were male, median age was 71 years (range, 40–82), and 29 (71%) patients were smokers. D+T achieved an Overall Response Rate of 44% and a Disease Control Rate of 79% among 34 evaluable patients. After a median follow-up of 7.9 months (95% Confidence Interval CI, 6.8–11.7), median progression-free survival (mPFS) was 8.2 months (95% CI, 4.3–NR) and median Overall Survival (mOS) was 18.2 months (95% CI, 16.5–Not Reached NR). At ddPCR, t0 plasma sample was positive for BRAF V600E in 14/38 (37%) evaluable patients (shedders), with a median variant allele frequency of 4.2%, while the presence of co-mutations was observed in NGS analysis in 12 (86%) cases. Among 13 baseline shedders, clearance of BRAF V600E at t1 was observed in 10 (77%) patients. Baseline shedders had a shorter mOS than non-shedders (mOS 6.1 months vs NR, p=0.014). TP53 co-mutation at t0 was a poor predictive factor of D+T efficacy (mPFS TP53 mut vs TP53 wild type 2.3 months vs NR, p=0.014). A trend towards a better mPFS and mOS for patients who had a clearance of BRAF V600E at t1 was observed. Liquid biopsy might be a promising approach to predict the outcomes of 1L D+T in advanced BRAF-V600E mut NSCLC patients. NGS analyses on putative resistance mechanisms to 1L D+T are ongoing.