Shuangru Chen,1 Liting Zhang,2 Jun Wang,1 Jiayao Lu,1 Ye Chen,2 Mingzhu Ling2 

1The Second School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China; 2Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China

Correspondence: Mingzhu Ling, Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Zhejiang Chinese Medical University, 318 Chaowang Road, Hangzhou, Zhejiang, 310005, People’s Republic of China, Email lynling002@163.com Ye Chen, Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Zhejiang Chinese Medical University, 318 Chaowang Road, Hangzhou, Zhejiang, 310005, People’s Republic of China, Email 20094012@zcmu.edu.cn

Abstract: 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.
Plain Language Summary: Lung cancer is one of the most common and deadliest malignant tumors worldwide. In recent years, the development of genetic testing technology and the widespread use of targeted therapy have greatly improved the prognosis for lung cancer patients with targetable mutations. EGFR is the most common target for lung cancer and it exhibits various mutation forms. For classical EGFR mutations, the efficacy of targeted therapy is well-established. However, for rare mutation forms such as EGFR-KDD, there is a lack of randomized controlled trials to confirm the effectiveness of targeted therapy. In this study, we report a case of an EGFR-KDD patient who showed promising response to targeted therapy, and we also conduct a literature review on EGFR-KDD to provide treatment information for patients with rare mutations.

Keywords: EGFR kinase domain duplication, targeted therapy, adenocarcinoma of lung, acquired resistance, tyrosine kinase inhibitors, afatinib