Efficacy, safety, and exploratory biomarker analysis of rechallenge with immune checkpoint inhibitors combined with anlotinib in previously treated advanced non-small cell lung cancer

作者：Li Liu, H Yang, Xiong Yi, Chunhua Zhou, Wenjuan Jiang, X. Pu, Jianfu Heng · 发表于：BMC Pulmonary Medicine · 年份：2026 · DOI：10.1186/s12890-025-04093-y · 研究领域：Lung Cancer Research Studies、Cancer Immunotherapy and Biomarkers、Lung Cancer Treatments and Mutations

BACKGROUND: Immunotherapy is the standard treatment for driver-negative advanced non-small cell lung cancer (NSCLC), but resistance remains common. Combining anti-angiogenic agents with immune checkpoint inhibitors (ICIs) may reverse resistance. This study evaluated the efficacy, safety, and optimal biomarkers of rechallenge with ICIs combined with anlotinib in advanced NSCLC patients previously treated with ICIs. METHODS: A total of 110 advanced NSCLC patients who progressed after prior ICI therapy were rechallenged with ICIs in combination with anlotinib. Primary endpoints included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and duration of response (DOR). Proteomics was performed on a subset of patients pre- and post-treatment to identify differentially expressed proteins. Patients were categorized into Responder (PFS ≥ 6 months) and Non-responder (PFS < 3 months) groups for proteomic comparison and functional validation of candidate proteins. RESULTS: Partial response (PR), stable disease (SD), and progressive disease (PD) were achieved in 20.9%, 57.3%, and 20.9% patients. ORR was 20.9% and disease control rate (DCR) was 78.2%, with median DOR of 7 months. Median PFS was 6.0 months and median OS was 16.0 months after rechallenge. Proteomic analysis revealed 91 significantly altered proteins post-treatment. ORM2 and SERPINA1 were hub proteins in the interaction network. External validation suggested a trend toward prolonged surviv...