Challenging BRAF/EGFR co-inhibition in NSCLC using sequential liquid biopsies

Abstract Objectives There is some controversy surrounding the BRAF V600E mutation in patients with lung adenocarcinomas. Although the BRAF V600E mutation is sensitive to BRAF inhibitors, the efficiency of these inhibitors on patients harboring an EGFR L858R/del19 / EGFR T790M / BRAF V600E pattern remains unknown. Materials and methods Here, we presented the case of a patient with initial response followed by progression on osimertinib. Resistance mutations ( EGFR T790M , EGFR C797S , BRAF V600E , MET amp and HER2 amp) were assessed in the tissue or plasma DNA using NGS and digital droplet PCR at progression and during osimertinib treatment. Results Resistance to osimertinib coincided with the emergence of an additional tumor cell subpopulation carrying the known BRAF V600E resistance mutation. The patient exhibited two tumor subclones ( EGFR del19/T790M and BRAF V600E ) that displayed distinct responses to successive tyrosine kinase inhibitors. Conclusion We report the first successful example of using sequential treatment with dabrafetinib/trametinib and osimertinib. Our finding provided that unique tumor biopsies deliver incomplete genetic information, and highlighted the complementary role of circulating tumor DNA to tissue biopsies and CT-scans to efficiently monitor response to osimertinib.