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Background <p>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.</p> Methods <p>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 &lt; 3 months) groups for proteomic comparison and functional validation of candidate proteins.</p> Results <p>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 survival with high ORM2 and SERPINA1 expression.</p> Conclusion <p>Rechallenge with ICIs plus anlotinib demonstrated encouraging efficacy and safety in pretreated advanced NSCLC. Additionally, ORM2 and SERPINA1 were associated with response and survival outcomes in patients treated with the combined ICI + anlotinib regimen and may represent candidate biomarkers of clinical benefit, warranting prospective validation.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月26日

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  • Li Liu,
  • Haiyan Yang,
  • Yi Xiong,
  • Chunhua Zhou,
  • Wenjuan Jiang,
  • Xingxiang Pu,
  • Jianfu Heng

摘要

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 survival with high ORM2 and SERPINA1 expression.

Conclusion

Rechallenge with ICIs plus anlotinib demonstrated encouraging efficacy and safety in pretreated advanced NSCLC. Additionally, ORM2 and SERPINA1 were associated with response and survival outcomes in patients treated with the combined ICI + anlotinib regimen and may represent candidate biomarkers of clinical benefit, warranting prospective validation.