Regarding the development of first-, second-, and third-generations of EGFR-TKI, the controversy results of their treatment efficacy might be mainly due to ‘acquired resistance’ after EGFR-TKI treatment (either through secondary EGFR mutations or activation of EGFR-independent pathways) [99], genetic changes (including BRAF mutation [100,101], ALK-fusion [102], MET amplification/rearrangement/mutation [101], etc.), or the unexpected transformation into small cell lung cancer [103,104]. This evidence concerns the gene BRAF and small cell lung carcinoma.