We report the case of an 80-year-old male with relapsed EGFR exon 19 deletion lung adenocarcinoma treated with EGFR-tyrosine kinase inhibitor (TKI), but with poor response and rapid increase of serum neuron specific enolase (NSE). Repeat biopsy identified pathological transformation to small cell lung cancers (SCLC) retaining the same EGFR mutation. This case highlights routine serological testing of NSE may benefit for the lung adenocarcinoma patients resistant to TKIs.