Anlotinib plus oral etoposide: a potential salvage therapy based on insights from EGFR-TKI-resistant SCLC transformation PDX and clinical settings

Zixi Wang¹Xiaoyu Li²Lili Jiang³Weiya Wang³Kai Xiao⁴Ting Zhang⁵Li Li⁶Dan Li⁷Yongsheng Wang^1*

• ¹Division of Thoracic Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
• ²Clinical Trial Center, National Medical Products Administration Key Laboratory for Clinical Research and Evaluation of Innovative Drugs, West China Hospital, Sichuan University, Chengdu, China
• ³Department of Pathology, West China Hospital, Sichuan University, Chengdu, China
• ⁴Precision Medicine Research Center, Sichuan Provincial Key Laboratory of Precision Medicine, National Clinical Research Center for Geriatrics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
• ⁵Laboratory of Nonhuman Primate Disease Modeling Research, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
• ⁶Institute of Clinical Pathology, West China Hospital, Sichuan University, Chengdu, China
• ⁷Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, and Precision Medicine Research Center, Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, China

Small cell lung cancer (SCLC) transformation is one of the resistance mechanisms to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment in patients with lung adenocarcinoma (LUAD). Platinum-etoposide chemotherapy is the most common regimen for patients with SCLC transformation. Despite a high initial response rate, patients experience rapid disease progression, and there is a paucity of evidence for further-line therapy. In this study, we report two cases of patients with EGFR 19del-mutated and EGFR-TKI-resistant transformed SCLC who failed with platinum-etoposide chemotherapy. We explored a novel combination strategy of anlotinib and orally administered etoposide in these two patients, guided by the results of a patient-derived tumor xenograft (PDX) model. The combination regimen was clinically applied when platinum-etoposide chemotherapy failed, and both patients benefited from the treatment. To our knowledge, this is the first report of anlotinib plus oral etoposide as a potential salvage therapy for patients with EGFR-TKI-induced SCLC transformation resistant to platinum-based chemotherapy. Both the PDX model and clinical cases support the efficacy of this regimen, providing a promising therapeutic option for patients with SCLC transformation after platinum-etoposide chemotherapy resistance.