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

Abstract

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