Dynamic serum tumor-marker and immune-inflammatory biomarker changes for risk stratification of immune checkpoint inhibitor-associated myasthenia gravis in non-small cell lung cancer.
Immune checkpoint inhibitors (ICIs) have reshaped the treatment landscape of non-small cell lung cancer (NSCLC), but immune-related neuromuscular toxicities remain difficult to anticipate. ICI-associated myasthenia gravis is uncommon, frequently occurs early after treatment initiation, and may overlap with myositis or myocarditis. Clinically accessible blood-based indicators that help identify patients entering this high-risk period remain insufficiently defined.
This study evaluated whether early dynamic changes in serum tumor markers and immune-inflammatory biomarkers could serve as noninvasive indicators of subsequent ICI-associated myasthenia gravis in patients with NSCLC.
Consecutive patients with NSCLC who received their first ICI-based therapy between 1 January 2018 and 31 January 2025 were retrospectively screened at a single center. Baseline, Day-21, and Day-42 laboratory windows were prespecified before endpoint modeling. Serum tumor markers included carcinoembryonic antigen, cytokeratin 19 fragment antigen 21-1, neuron-specific enolase, squamous cell carcinoma antigen, and carbohydrate antigen 125. Immune-inflammatory biomarkers included neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, systemic immune-inflammation index, systemic inflammation response index, C-reactive protein, lactate dehydrogenase, and albumin. The primary endpoint was definite or probable ICI-associated myasthenia gravis occurring within 180 days after first ICI exposure. Landmark models were developed using Firth bias-reduced logistic regression and internally validated by bootstrap resampling. The Day-21 dynamic score used clinically pragmatic thresholds defined before endpoint modeling.
The final baseline cohort included 826 patients, of whom 27 developed definite or probable ICI-associated myasthenia gravis within 180 days. The Day-21 landmark cohort included 782 patients and 21 events occurring after Day 21. Compared with non-event patients, patients who later developed ICI-associated myasthenia gravis showed greater Day-21 increases in cytokeratin 19 fragment antigen 21-1, carcinoembryonic antigen, neutrophil-to-lymphocyte ratio, C-reactive protein, and lactate dehydrogenase, together with a larger decline in albumin. A four-component Day-21 dynamic score combining tumor-marker instability, neutrophil-to-lymphocyte ratio activation, C-reactive protein/lactate dehydrogenase flare, and albumin decline stratified event rates after Day 21 from 1.2% in the low-risk group to 6.7% in the high-risk group. The integrated Day-21 model achieved an apparent area under the receiver operating characteristic curve of 0.759 and an optimism-corrected area under the receiver operating characteristic curve of 0.731, indicating moderate internal discrimination.
Early dynamic changes in routine serum tumor markers and immune-inflammatory biomarkers were associated with increased risk of ICI-associated myasthenia gravis in patients with NSCLC. The Day-21 integrated biomarker score may help identify patients requiring closer neuromuscular and cardiac toxicity surveillance during the first few weeks of ICI therapy, but external validation is required before clinical implementation.
This study evaluated whether early dynamic changes in serum tumor markers and immune-inflammatory biomarkers could serve as noninvasive indicators of subsequent ICI-associated myasthenia gravis in patients with NSCLC.
Consecutive patients with NSCLC who received their first ICI-based therapy between 1 January 2018 and 31 January 2025 were retrospectively screened at a single center. Baseline, Day-21, and Day-42 laboratory windows were prespecified before endpoint modeling. Serum tumor markers included carcinoembryonic antigen, cytokeratin 19 fragment antigen 21-1, neuron-specific enolase, squamous cell carcinoma antigen, and carbohydrate antigen 125. Immune-inflammatory biomarkers included neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, systemic immune-inflammation index, systemic inflammation response index, C-reactive protein, lactate dehydrogenase, and albumin. The primary endpoint was definite or probable ICI-associated myasthenia gravis occurring within 180 days after first ICI exposure. Landmark models were developed using Firth bias-reduced logistic regression and internally validated by bootstrap resampling. The Day-21 dynamic score used clinically pragmatic thresholds defined before endpoint modeling.
The final baseline cohort included 826 patients, of whom 27 developed definite or probable ICI-associated myasthenia gravis within 180 days. The Day-21 landmark cohort included 782 patients and 21 events occurring after Day 21. Compared with non-event patients, patients who later developed ICI-associated myasthenia gravis showed greater Day-21 increases in cytokeratin 19 fragment antigen 21-1, carcinoembryonic antigen, neutrophil-to-lymphocyte ratio, C-reactive protein, and lactate dehydrogenase, together with a larger decline in albumin. A four-component Day-21 dynamic score combining tumor-marker instability, neutrophil-to-lymphocyte ratio activation, C-reactive protein/lactate dehydrogenase flare, and albumin decline stratified event rates after Day 21 from 1.2% in the low-risk group to 6.7% in the high-risk group. The integrated Day-21 model achieved an apparent area under the receiver operating characteristic curve of 0.759 and an optimism-corrected area under the receiver operating characteristic curve of 0.731, indicating moderate internal discrimination.
Early dynamic changes in routine serum tumor markers and immune-inflammatory biomarkers were associated with increased risk of ICI-associated myasthenia gravis in patients with NSCLC. The Day-21 integrated biomarker score may help identify patients requiring closer neuromuscular and cardiac toxicity surveillance during the first few weeks of ICI therapy, but external validation is required before clinical implementation.
Authors
Cui Cui, Lin Lin, Luo Luo, Zhang Zhang, Zhang Zhang, Xu Xu, Lai Lai, Xiong Xiong, Chen Chen, Huang Huang, Xu Xu
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