The continuing improvements in the knowledge of the acquired EGFR-independent mechanisms of resistance to EGFR-TKIs, including oncogenic gene fusions, gene amplification, mutations affecting gene encoding for cell-cycle proteins, the activation of the epithelial-to-mesenchymal transition (EMT), as well as the NSCLC to SCLC histologic transformation, led to the investigation of the combination of additional targeted agents against identified secondary resistance to the previous EGFR-TKI, to bypass pathways or genetic aberrations [17]. The gene discussed is EGFR; the disease is small cell lung carcinoma.