Epidermal growth factor receptor kinase domain duplication (EGFR-KDD) is a rare form of EGFR mutation. Unlike the classical mutations such as exon 19 deletion and exon 21 p.L858R point mutation, EGFR-KDD is a special type of large genomic rearrangement (LGR) that results in the duplication of the tyrosine kinase domain at the protein level, leading to the formation of an intramolecular dimer and activation of the EGFR signaling pathway. Case reports and in vitro experiments have shown that EGFR-KDD patients can benefit from EGFR TKI treatment. Similar to classical EGFR mutations, EGFR-KDD inevitably develops resistance during EGFR TKI treatment, leading to disease progression. Due to the rarity of EGFR-KDD, the acquired resistance mechanisms are not yet fully understood, but known mechanisms include EGFR amplification and T790M mutation. In this study, we report a 71-year-old female EGFR-KDD patient who showed a positive response to afatinib treatment initially, but developed resistance upon tumor progression. Subsequent next-generation sequencing (NGS) on the re-biopsy revealed TP53 exon c.688_764 deletion and MET exon 15-20 duplication, suggesting that MET bypass activation might be the acquired resistance mechanisms. Additionally, we conducted a literature review on EGFR-KDD and examined case reports of EGFR-KDD patients treated with EGFR TKIs to summarize the treatment outcomes and resistance mechanisms. We hope to provide more treatment information for patients with rare gene mutations in lung cancer.