PIK3CA and neoplasm: SNVs or insertions/deletions (indels) in EGFR, BRAF, KRAS, TP53, PIK3CA, MEK, IGF-1R, SRC, or HER, amplifications in KIT or MET and RET fusions were previously described as potential off-target resistance alterations.7 Moreover, the transformation into small cell lung cancer (SCLC) or epithelial-to-mesenchymal transition which leads to the loss of polarity and intercellular connections of epithelial cells and enhances migration and invasion of tumor cells represent additional off-target resistance mechanisms.13