Tumor re-biopsies performed in EGFR mutated NSCLC patients at the time of progression to erlotinib, gefitinib, afatinib, or osimertinib have documented several mechanisms of acquired resistance [40,41,42,43], including transformation to SCLC, the emergence of secondary resistance mutations able to interfere with drug binding, the activation of alternative signaling pathways, and mesenchymal changes in the tumor phenotype (Table 2). Here, EGFR is linked to non-small cell lung carcinoma.