Adverse events associated with immune checkpoint inhibitors in combination with chemotherapy in lung cancer: a real-world analysis

Background: Immune checkpoint inhibitors (ICIs) have transformed lung cancer treatment, but clinical trials often miss rare, life-threatening toxicities and safety patterns in complex combinations. Real-world pharmacovigilance is essential to identify toxicity profiles in unselected populations. This study aimed to characterize adverse event reporting patterns associated with ICI monotherapy and ICI-based combination regimens in lung cancer using real-world data.

Methods: We analyzed 34,223 adverse event reports from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database (Q1 2016–Q3 2025) for pembrolizumab, atezolizumab, and nivolumab and their combinations. Disproportionality analysis, time-to-onset, and stratified analysis were conducted.

Results: Programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors primarily caused endocrine and respiratory toxicities; ipilimumab caused dermatologic and hepatobiliary effects. Stress cardiomyopathy occurred across all agents, with pembrolizumab showed highest disproportionality signal. Males on atezolizumab had 73% lower odds of reported stress cardiomyopathy [odds ratio (OR) =0.27, P<0.01]. Combination-regimen analyses showed heterogeneous reporting profiles. For example, pembrolizumab-chemotherapy was associated with an earlier onset of duodenitis, atezolizumab-bevacizumab-platinum was uniquely associated with duodenal ulcer hemorrhage, and ventricular fibrillation was highlighted in by nivolumab-ipilimumab combination.

Conclusions: ICI toxicity is highly regimen-specific and combination therapy was associated with a shorter reported time-to-onset and increased odds of reporting cardiac and gastrointestinal events, informing tailored surveillance strategies.