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  • Review Article
  • Published:

Rechallenge with immune-checkpoint inhibitors in patients with advanced-stage lung cancer

Abstract

Lung cancer remains the leading cause of cancer-related mortality globally, with many patients diagnosed with advanced-stage disease. Treatment in this setting relies on systemic therapies, including chemotherapy, targeted therapy and immunotherapy. Immune-checkpoint inhibitors (ICIs), which promote or restore antitumour immunity by inhibiting immunosuppressive signalling pathways, are currently the most widely used immunotherapies in these patients. However, immune-related adverse events (irAEs) or disease progression often necessitate discontinuation of these agents, leaving many patients with limited subsequent treatment options. In this scenario, ICI rechallenge has emerged as a potential strategy. Despite this potential, evidence for ICI rechallenge after either disease progression or irAEs in patients with non-small-cell lung cancer is limited and evidence for those with small cell lung cancer seems to be non-existent. In this Review, we provide a comprehensive overview of the available data on ICI rechallenge in the context of both disease progression and irAEs, including a summary of current guidance on clinical management and detailed discussions of safety and efficacy. We also highlight important unanswered questions in an attempt to guide future research in this area.

Key points

  • Rechallenge with an immune-checkpoint inhibitor (ICI) in patients with non-small-cell lung cancer (NSCLC) can be considered to be either retreatment or resensitization based on whether other treatments were administered between initial ICI administration and rechallenge.

  • The success of ICI rechallenge is often dependent on the initial reasons for disease progression: drug resistance (primary or secondary resistance) and discontinuation-related progression (probable resistance-related discontinuation progression and complete discontinuation progression).

  • ICI rechallenge is encouraged after discontinuation progression but should be pursued with caution after resistance progression.

  • Several guidelines (American Society of Clinical Oncology, Chinese Society of Clinical Oncology, National Comprehensive Cancer Network, Society for Immunotherapy of Cancer) provide recommendations on ICI rechallenge after discontinuation owing to immune-related adverse events, although recommendations differ between guidelines.

  • Performance status, PD-L1 expression, treatment interval and initial duration of treatment are all predictive of effective ICI rechallenge.

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Fig. 1: Immune checkpoints and immune-checkpoint inhibitors.
Fig. 2: Definitions of ICI treatment strategies after progression following different ICI modalities.
Fig. 3: Classification of disease progression following treatment with ICIs.
Fig. 4: irAEs that can lead to ICI discontinuation in patients with advanced-stage NSCLC.
Fig. 5: Optimized management decisions regarding ICI rechallenge after irAEs based on current guidelines.

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Acknowledgements

The authors’ work is supported by grants from Noncommunicable Chronic Diseases — National Science and Technology Major Project (Grant Number 2023ZD0501700), the National Natural Science Foundation of China (Grant No. 82373349), Guangzhou Science and Technology Program (Grant Number 2025A03J4506), MOE Changjiang Distinguished Professor Supporting Project (Grant Number KY0120240205), and Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer (Grant Number 2017B030314120).

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Correspondence to Qing Zhou.

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C.-R.X. has acted as a consultant and/or advisor of Allist Pharmaceuticals, AstraZeneca, Avistone, BeiGene, Bristol–Myers Squibb, Burning Rock Biotech, CStone Pharmaceuticals, Dizal Pharma, Geneplus, MSD, Pfizer, Roche, SciClone, Takeda and Zhengda Tianqing Pharmaceutical Group. Q.Z. has received honoraria from AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly, MSD, Pfizer, Roche and Sanofi for consultancy and/or advisory work. The other authors declare no competing interests.

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Tang, LB., Peng, YL., Chen, J. et al. Rechallenge with immune-checkpoint inhibitors in patients with advanced-stage lung cancer. Nat Rev Clin Oncol 22, 546–565 (2025). https://doi.org/10.1038/s41571-025-01029-7

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