Abstract Rationale Immune checkpoint inhibitors (ICIs) combined with chemotherapy have transformed the management of advanced lung cancer, improving survival across diverse histologic and molecular subtypes. However, pivotal clinical trials have primarily focused on oncologic efficacy and may underestimate the spectrum of pulmonary toxicities associated with these regimens. Both ICIs and cytotoxic agents can independently cause lung injury through immune-mediated inflammation or direct alveolar damage. Emerging real-world data suggest that combining these modalities may increase the risk of serious pulmonary complications, including acute respiratory distress syndrome (ARDS), pneumonitis, pulmonary fibrosis, and infectious pneumonias. Comprehensive comparative evidence between chemo-immunotherapy and chemotherapy alone across all lung cancer types remains limited. Methods We conducted a multicenter retrospective cohort analysis using the TriNetX Research Network, a federated database of de-identified electronic health records. Adults with lung cancer who received either chemo-immunotherapy or chemotherapy alone were included. Pulmonary outcomes—ARDS, pneumonitis, pulmonary fibrosis, viral pneumonia, and bacterial pneumonia—were identified using ICD-10 codes. Confounders adjusted for included heart failure, COPD, asthma, interstitial lung disease, metastatic cancer, type 2 diabetes, obesity, chronic kidney disease, oxygen dependence, prior thoracic radiation, and nicotine dependence. Propensity-score matching (1:1, caliper 0.2 SD) was applied to balance baseline demographics and comorbidities between cohorts for comparative outcome analysis. Results After 1:1 matching (n = 47,651 per group), the incidence of ARDS was 0.8% among patients receiving chemo-immunotherapy versus 1.0% in those treated with chemotherapy alone (OR 0.79, 95% CI 0.69-0.90; p = 0.001). Pneumonitis occurred in 0.6% versus 0.1% (OR 6.76, 95% CI 4.93-9.29; p 0.001). Pulmonary fibrosis developed in 4.1% versus 3.2% (OR 1.29, 95% CI 1.20-1.38; p 0.001). Viral pneumonia was more frequent with chemo-immunotherapy (2.4% vs 1.3%, OR 1.82, 95% CI 1.65-2.01; p 0.001), as was bacterial pneumonia (6.0% vs 5.5%, OR 1.11, 95% CI 1.05-1.17; p 0.001). Conclusion In this large real-world analysis, chemo-immunotherapy for lung cancer was associated with a distinct pulmonary toxicity profile compared with chemotherapy alone. While the risk of ARDS was slightly lower, patients treated with ICIs experienced significantly higher rates of pneumonitis, pulmonary fibrosis, and both viral and bacterial pneumonias. These findings underscore the importance of close pulmonary monitoring, early recognition of immune- or therapy-related lung injury, and multidisciplinary collaboration to optimize the safety of chemo-immunotherapy in lung cancer care. This abstract is funded by: NONE
Aldarabah et al. (Fri,) studied this question.