Circulating tumour DNA (ctDNA) analysis depicts mechanisms of resistance and tumour response to BRAF inhibitors in BRAF-mutant non-small cell lung cancer (NSCLC)

Abstract

Abstract Background Oncogenic BRAF-V600 mutations are observed in 1-2% of NSCLC. Targeted therapies (TT) including vemurafenib (V), dabrafenib (D) or dabrafenib plus trametinib (D+T) are associated with favorable outcomes in these patients (pts). The mechanisms of resistance to BRAF-TT in NSCLC are largely unknown. Methods We performed genomic profiling of serial ctDNA in 79 metastatic BRAF-mutant NSCLC pts (96% V600E, 4% non-V600). BRAFstatus was ascertained based on local testing. Plasma samples were collected, from 2014-2018 in 27 hospitals, from pts treated with V (n\xa0=\xa034), D (n\xa0=\xa02) or D+T (n\xa0=\xa023). We collected 41 plasma samples at baseline to BRAF-TT, 40 at progressive disease (PD) and ∼200 during treatment follow-up, concurrent to routine radiological evaluation. Inivata InVisionSeq™ assay was used to detect the presence of genomic alterations in 36-cancer related genes. Results At baseline, 72.5% of BRAF mutations were detected in plasma. BRAF-V600E detection in plasma was associated with the presence of liver metastasis (22%), versus BRAF-V600E negative pts (7%). Co-occurring alterations at baseline were observed in 18/26 (70%) pts: FGFR2 (1pt), PIK3CA (2pts), ERBB2 (1pt), CTNNB1 (2pts) and IDH1 (2pts). FGFR2, PIK3CAor CTNNB1 alterations were associated with PD as the best response to subsequent BRAF-TT. Complete clearance of baseline BRAF-V600E in ctDNA was observed at the 1stCT-scan evaluation in 42% (3/7) and 82% (9/11) pts who responded to V or D+T, respectively. At PD, a consistent rebound in BRAF-V600E plasma levels was observed in 60% (24/40) pts. PD to V was associated with alterations in the MAPK pathway: KRAS(1pt), GNA11 (1pt), NRASand GNAS (1pt) and MAP2K1and NFE2L2 (1pt). Activating PI3KCA mutations were observed in 4 pts who progressed in\xa0 Conclusions ctDNA monitoring might be an informative tool for assessing disease response and and understand mechanisms of resistance in BRAF-mutant NSCLC pts treated with BRAF-TT. MAPK reactivation remains an important resistance mechanism. Legal entity responsible for the study Sandra Ortiz-Cuaran, David Planchard, Jean-Yves Blay, Pierre Saintigny. Funding Fondation ARC (PJA 2017-1206573). Disclosure L. Mezquita: Advisory / Consultancy: Roche Diagnostics; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy, Lectures and educational activities: Tecnofarma; Advisory / Consultancy, Lectures and educational activities: Roche; Advisory / Consultancy, Lectures and educational activities: AstraZeneca; Travel / Accommodation / Expenses: Chugai. J. Mazieres: Advisory / Consultancy: Roche; Research grant / Funding (self): Roche; Advisory / Consultancy: Novartis. K. Howarth: Shareholder / Stockholder / Stock options: Inivata Ltd; Full / Part-time employment: Inivata Ltd. C. Morris: Shareholder / Stockholder / Stock options: Inivata Ltd; Full / Part-time employment: Inivata Ltd. E. Green: Shareholder / Stockholder / Stock options: Inivata Ltd; Full / Part-time employment: Inivata Ltd. M. Perol: Advisory / Consultancy: Roche ; Advisory / Consultancy: Novartis. B. Besse: Research grant / Funding (institution): AbbVie, Amgen, AstraZeneca, Biogen, Blueprint Medicines, BMS, Celgene, Eli Lilly, GSK, Ignyta, Ipsen, Merck KGaA, MSD, Nektar, Onxeo, Pfizer, Pharma Mar, Sanofi, Spectrum Pharmaceuticals, Takeda, Tiziana Pharma. J. Blay: Research grant / Funding (institution), Travel grants: Roche; Research grant / Funding (institution), Travel grants: Novartis. P. Saintigny: Advisory / Consultancy: HTG Molecular; Research grant / Funding (institution): BMS, AstraZeneca, Roche, HTG Molecular. D. Planchard: Advisory / Consultancy: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Merck, MedImmune, Novartis, Pfizer, prIME Oncology, Peer CME, Roche; Honoraria (self): AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche; Research grant / Funding (institution): AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, Medimmun, Sanofi-Aventis, Taiho ; Travel / Accommodation / Expenses: AstraZeneca, Roche, Novartis, prIME Oncology, Pfizer. All other authors have declared no conflicts of interest.