3020 - Circulating tumor DNA (ctDNA) analysis depicts mechanisms of resistance and tumor response to BRAF inhibitors in BRAF-mutant non-small cell lung cancer (NSCLC)

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 = 34), D (n = 2) or D+T (n = 23). 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 1^stCT-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 < 6 months on V. Similar to pts who progressed on V, alterations in KRAS, NRAS, PIK3CAand CTNNB1were associated with D+T resistance. The impact of these alterations was assessed by in silico structure modeling.

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.

Clinical trial identification

Editorial acknowledgement

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.