We report a case of non-small-cell lung cancer (NSCLC) to small-cell lung cancer (SCLC) transformation after epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment. The patient was a man who diagnosed with EGFR-mutant advanced NSCLC. After he was introduced afatinib, his tumor had been reduced by the treatment. However, plasma pro-gastrin-releasing peptide (ProGRP) became higher with disease progression, and SCLC was detected at the second biopsy. It is suggested that elevation of plasma ProGRP level before EGFR-TKI therapy is useful for predicting EGFR-mutant NSCLC to SCLC transformation.