Sequential targeted therapy in synchronous dual-primary lung adenocarcinomas with EGFR and RET alterations: a 5-year follow-up case report.

With the increasing detection of multiple primary pulmonary nodules, accurately distinguishing between multiple primary lung cancers and intrapulmonary metastasis is crucial for diagnosis and treatment. We herein report a case of a 71-year-old female with bilateral multiple primary lung adenocarcinomas, in which separate lesions harbored an EGFR 19del mutation and a RET fusion gene, demonstrating intratumoral genetic heterogeneity. The patient was successively treated with an EGFR-TKI, chemotherapy, and the RET inhibitor pralsetinib, the latter of which maintained a response for over three years. Following the development of resistance, combination therapy with pralsetinib and anlotinib successfully achieved a partial response again. This case underscores the importance of comprehensive molecular testing across multiple lesions to guide precision therapy and provides clinical insights into RET fusion-positive lung cancer treatment and post-resistance combination strategies.