Therapeutic Strategies After Immunotherapy Failure in Advanced Non-Small Cell Lung Cancer: Mechanisms of Resistance and Emerging Treatment Approaches

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.