At present, secondary resistance mechanisms associated with progression are better known: clonal selection of EGFR resistance mutation (T790M mutation in exon 20), amplification of transmembrane receptors for other growth factors (c-met, HER family, IGF1R, or AXL), downstream molecular alterations in EGFR signaling pathway (PI3K or PTEN), and epithelial-mesenchymal transition or transdifferentiation to small-cell cancer.