Temporal Heterogeneity of ROS1 Fusion and Braf Fusion Conferred Resistance to First-and Third-generation EGFR Tkis: a Case Report.

Background: The development of EGFR-tyrosine kinase inhibitors (EGFR-TKIs) have revolutionized the treatment paradigms for non-small cell lung cancer (NSCLC) patients. However, acquired resistance inevitably develops with a median progression-free survival (PFS) less than a year. The advancements in sequencing technologies have significantly promoted the identification of potential resistant mechanisms to targeted therapies.Case presentation: A 39-year-old Chinese male was diagnosed stage IVB NSCLC with EGFR exon 19 deletion (EGFR 19del) and received icotinib but got primary EGFR-TKI resistance caused by ROS1 fusion one month later. Then he received icotinib plus crizotinib and achieved partial response with a profession free survival of 4.8 months. Then he switched to osimertinib plus crizotinib due to the emergence of EGFR T790M mutation. TRIM24-BRAF fusion was detected after osimertinib failure, which might be potential resistant mechanism to osimertinib.Conclusions: This is the first case to confirm crizotinib plus icotinib in patients harboring both EGFR 19del and ROS1 fusion. This case displays the temporal heterogeneity of different resistant mechanisms emerging during disease course, highlighting the importance of dynamic genetic monitoring for better clinical managements.