Response to Selpercatinib in a CCDC6-RET Lung Adenocarcinoma with an Acquired Novel RET p.L730_G731insL After Progression on Pralsetinib: A Case Report

RET fusion is one of the key driver oncogenes in lung cancer. Selective RET inhibitors have become the standard of care for these patients. However, acquired resistance remains inevitable Among the mechanisms of on-target resistance, solvent front mutations in the RET kinase domain are the most common. In contrast, kinase domain insertion mutations are rarely reported as a mechanism of resistance. This article reports a case of a patient with advanced lung adenocarcinoma. Initial genetic testing at diagnosis revealed a CCDC6-RET fusion. The patient achieved partial response after treatment with pralsetinib, but subsequently developed disease progression. After resistance developed, next-generation sequencing (NGS) was performed. The results showed that the original RET fusion persisted. Additionally, a newly acquired insertion mutation (p.L730_G731insL) was detected in the RET kinase domain. Based on this resistance mechanism, the patient discontinued pralsetinib. Treatment was switched to another selective RET inhibitor, selpercatinib. Follow-up imaging evaluation showed that the pulmonary lesions achieved a partial response (PR).This suggests that selpercatinib has therapeutic activity against the tumor carrying this RET insertion mutation. However, the patient received concurrent brain radiotherapy and radiofrequency ablation of liver lesions; therefore, the response in intracranial and hepatic sites cannot be solely attributed to selpercatinib. The observation is hypothesis-generating rather than proof of sensitivity. This case provides a reference for precision treatment strategies after resistance to RET inhibitors.