Circulating Tumor DNA Genomics Reveal Potential Mechanisms of Resistance to BRAF-Targeted Therapies in Patients withBRAF-Mutant Metastatic Non–Small Cell Lung Cancer

Abstract

Purpose: The limited knowledge on the molecular profile of patients with BRAF-mutant non-small cell lung cancer (NSCLC) who progress under BRAF-targeted therapies (BRAF-TT) has hampered the development of subsequent therapeutic strategies for these patients. Here, we evaluated the clinical utility of circulating tumor DNA (ctDNA)-targeted sequencing to identify canonical BRAF mutations and genomic alterations potentially related to resistance to BRAF-TT, in a large cohort of patients with BRAFmutant NSCLC.Experimental Design: This was a prospective study of 78 patients with advanced BRAF-mutant NSCLC, enrolled in 27 centers across France. Blood samples (n ¼ 208) were collected from BRAF-TT-naïve patients (n ¼ 47), patients nonprogressive under treatment (n ¼ 115), or patients at disease progression (PD) to BRAF-TT (24/46 on BRAF monotherapy and 22/46 on BRAF/ MEK combination therapy). ctDNA sequencing was performed using InVisionFirst-Lung. In silico structural modeling was used to predict the potential functional effect of the alterations found in ctDNA.Results: BRAF V600E ctDNA was detected in 74% of BRAF-TTnaïve patients, where alterations in genes related with the MAPK and PI3K pathways, signal transducers, and protein kinases were identified in 29% of the samples. ctDNA positivity at the first radiographic evaluation under treatment, as well as BRAF-mutant ctDNA positivity at PD were associated with poor survival. Potential drivers of resistance to either BRAF-TT monotherapy or BRAF/MEK combination were identified in 46% of patients and these included activating mutations in effectors of the MAPK and PI3K pathways, as well as alterations in U2AF1, IDH1, and CTNNB1.Conclusions: ctDNA sequencing is clinically relevant for the detection of BRAF-activating mutations and the identification of alterations potentially related to resistance to BRAF-TT in BRAFmutant NSCLC.

Phase 2 Study of Dabrafenib Plus Trametinib in Patients With BRAF V600E-Mutant Metastatic NSCLC: Updated 5-Year Survival Rates and Genomic Analysis

“…1,30 Hence, the overall results of this study are clinically relevant revealing durable efficacy of dabrafenib plus trametinib in this subset of NSCLC, also reinforcing the importance of other targeted therapies for first-line treatment of patients with NSCLC harboring oncogenic driver mutations. [34][35][36][37][38][39][40][41][42][43] Indeed, the overall clinical benefit found in this study is in the range of first and second generation of EGFR inhibitors or first-generation ALK inhibitors. [36][37][38][39][40] The clinical use of genomic analyses has been outlined in multiple studies 41,42 and consequently in the NCCN and ESMO guidelines.…”

Liquid Biopsy for Advanced NSCLC: A Consensus Statement From the International Association for the Study of Lung Cancer

“…Today, this "plasma first" approach should be considered as a standard of care in this setting. Since the first IASLC liquid biopsy statement, 11 additional literature supports extension of ctDNA analysis to all guideline-recommended and treatable oncogenic drivers, including ALK rearrangements, [70][71][72] ROS1 rearrangements, 71,73 BRAF mutations, 74 and, more recently, MET exon-14 skipping mutations, 75,76 RET rearrangements, 77 and HER2 mutations. 78 It is likely that the KRAS exon 2 p.G12C mutation will soon join this group.…”

BRAF as a positive predictive biomarker: Focus on lung cancer and melanoma patients

“…In this setting, liquid biopsy may represent a valid alternative to tissue specimens for the assessment of the molecular status of the different biomarkers (Rijavec et al, 2019;Siravegna et al, 2019). As for EGFR, the utility of ctDNA has also been demonstrated for BRAF mutational assessment (Bracht et al, 2019;Wu et al, 2019;Ortiz-Cuaran et al, 2020).…”