Liquid Biopsy Monitoring in BRAF V600E–Mutated Patients With Non–Small Cell Lung Cancer Treated With Dabrafenib Plus Trametinib: The Prospective, Multicenter LiBRA Study (GOIRC-03-2020)

PURPOSE Dabrafenib plus trametinib is a standard first-line treatment for BRAF V600E–mutated non–small cell lung cancer (NSCLC). The LiBRA study aimed to explore the role of liquid biopsy in detecting and monitoring BRAF V600E mutation, assessing its potential to predict treatment response and emerging resistance. MATERIALS AND METHODS This prospective multicenter study enrolled patients with BRAF V600E–mutated NSCLC treated with first-line dabrafenib plus trametinib. Plasma samples were collected at baseline (t0), after 4 weeks (t1), and longitudinally until disease progression (PD). BRAF V600E was monitored by digital droplet PCR (ddPCR). Next-generation sequencing (NGS) was performed at t0 and PD to identify resistance mechanisms. RESULTS Forty patients were enrolled. Dabrafenib plus trametinib achieved an overall response rate of 42.5%, with a median progression-free survival (PFS) and overall survival (OS) of 8.3 and 21.1 months, respectively. At t0, BRAF V600E was detectable by ddPCR in 24 (62%) of 39 patients. Among 21 shedders evaluated at t1, 17 (81%) cleared the mutation. Higher baseline BRAF V600E allele frequency was associated with shorter PFS (hazard ratio HR, 1.09, P = .013) and OS (HR, 1.10, P = .010), whereas clearance at t1 correlated with longer PFS (8.3 v 1.4 months, P < .001) and OS (10.5 v 2.2 months, P < .001). Biological PD anticipated radiologic/clinical PD by a median of 4.9 weeks (IQR, 1.4-9.8). Baseline EGFR and MET CNVs were associated with shorter PFS and OS. Resistance mechanisms at PD included NRAS , KRAS , TP53 mutations and MET , EGFR , ERBB2 CNVs. CONCLUSION The LiBRA study supports liquid biopsy as a prognostic and monitoring tool in BRAF V600E–mutated NSCLC undergoing targeted therapy.