Repeat genomic testing of pleural fluid upon progression revealed persistent alterations in 12 genes, including the original EGFR sensitizing mutation, TP53, AKT2, RARA, and SETD2, alongside newly acquired mutations in CHEK1, CUL3, DNMT1, HMCN1, and TBX3, and RB1 copy number loss, in the absence of typical resistance mechanisms such as T790M or MET amplification or histologic transformation to small cell lung cancer. Here, DNMT1 is linked to small cell lung carcinoma.