Therapeutic Strategies After Immunotherapy Failure in Advanced Non-Small Cell Lung Cancer: Mechanisms of Resistance and Emerging Treatment Approaches
- 1Second Department of Surgery, University of Occupational and Environmental Health, Japan, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan
Abstract
Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape of advanced non-small cell lung cancer (NSCLC), but disease progression during or after immunotherapy remains a major therapeutic challenge. ICI failure is biologically and clinically heterogeneous and may manifest as primary resistance, acquired resistance, oligoprogressive disease, hyperprogressive disease, or disease recurrence following treatment discontinuation. These distinct patterns may require different therapeutic approaches. In this review, we summarize the current evidence for treatment strategies after immunotherapy failure in advanced NSCLC. Cytotoxic chemotherapy remains a key subsequent-line treatment, though evidence supporting enhanced chemotherapy sensitivity after prior ICI exposure is largely derived from retrospective or non-randomized studies. Docetaxel plus ramucirumab is an established treatment option, but its specific efficacy after ICI failure has not been confirmed in randomized trials. Local therapies, including stereotactic body radiotherapy and salvage surgery, may provide meaningful local control in carefully selected patients with oligoprogressive or otherwise localized disease, though prospective evidence remains limited. ICI rechallenge generally has limited activity after progression during active ICI treatment, whereas re-exposure may be considered in selected patients after planned treatment completion or discontinuation because of immune-related adverse events. Biomarker development, including tissue biomarkers, circulating tumor DNA, circulating tumor cells, and emerging tumor–immune profiling approaches, may facilitate more individualized treatment selection. Overall, management after immunotherapy failure should be guided by the pattern and tempo of disease progression, prior treatment history, and the feasibility of systemic and local treatment. Further prospective studies are needed to establish effective treatment strategies and validated biomarkers for patient selection.
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BibTeX
@article{kanayama2026therapeutic,
title = {{Therapeutic Strategies After Immunotherapy Failure in Advanced Non-Small Cell Lung Cancer: Mechanisms of Resistance and Emerging Treatment Approaches}},
author = {Masatoshi Kanayama and Masaru Takenaka and Hidetaka Uramoto},
journal = {Cancers},
year = {2026},
month = nov,
doi = {10.3390/cancers18213523},
url = {https://www.mdpi.com/2072-6694/18/21/3523},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Therapeutic Strategies After Immunotherapy Failure in Advanced Non-Small Cell Lung Cancer: Mechanisms of Resistance and Emerging Treatment Approaches
AU - Masatoshi Kanayama
AU - Masaru Takenaka
AU - Hidetaka Uramoto
PY - 2026
DA - 2026/11/02
JO - Cancers
DO - 10.3390/cancers18213523
UR - https://www.mdpi.com/2072-6694/18/21/3523
AB - Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape of advanced non-small cell lung cancer (NSCLC), but disease progression during or after immunotherapy remains a major therapeutic challenge. ICI failure is biologically and clinically heterogeneous and may manifest as primary resistance, acquired resistance, oligoprogressive disease, hyperprogressive disease, or disease recurrence following treatment discontinuation. These distinct patterns may require different therapeutic approaches. In this review, we summarize the current evidence for treatment strategies after immunotherapy failure in advanced NSCLC. Cytotoxic chemotherapy remains a key subsequent-line treatment, though evidence supporting enhanced chemotherapy sensitivity after prior ICI exposure is largely derived from retrospective or non-randomized studies. Docetaxel plus ramucirumab is an established treatment option, but its specific efficacy after ICI failure has not been confirmed in randomized trials. Local therapies, including stereotactic body radiotherapy and salvage surgery, may provide meaningful local control in carefully selected patients with oligoprogressive or otherwise localized disease, though prospective evidence remains limited. ICI rechallenge generally has limited activity after progression during active ICI treatment, whereas re-exposure may be considered in selected patients after planned treatment completion or discontinuation because of immune-related adverse events. Biomarker development, including tissue biomarkers, circulating tumor DNA, circulating tumor cells, and emerging tumor–immune profiling approaches, may facilitate more individualized treatment selection. Overall, management after immunotherapy failure should be guided by the pattern and tempo of disease progression, prior treatment history, and the feasibility of systemic and local treatment. Further prospective studies are needed to establish effective treatment strategies and validated biomarkers for patient selection.
SN - 2072-6694
ER -