Severe renal and pancreatic toxicities associated with ipilimumab and nivolumab combination therapy in non-small cell lung cancer: a pharmacovigilance analysis of the FDA adverse event reporting system

Background: Ipilimumab plus nivolumab (Ipi+Nivo) has become a standard therapy for advanced non-small cell lung cancer (NSCLC), yet severe organ-specific toxicities remain inadequately characterized. This study aimed to characterize severe renal and pancreatic toxicities associated with Ipi+Nivo combination therapy versus nivolumab monotherapy in NSCLC patients. Methods: We analyzed the FDA Adverse Event Reporting System (FAERS) database from 2004 Q1 to 2025 Q2. Disproportionality analysis using reporting odds ratio (ROR) and information component (IC) identified safety signals. Time-to-onset and clinical severity were compared between treatment groups. Results: Among 2,292 reports, combination therapy demonstrated significant disproportionality signals for glomerular-predominant renal injury, including glomerulonephritis minimal lesion (ROR = 78.62, IC025 = 2.096), nephrotic syndrome (ROR = 37.25, IC025 = 1.914), and glomerulosclerosis (ROR = 61.79, IC025 = 2.015). Pancreatic toxicity showed strong signals (ROR = 61.79, IC025 = 2.015). Additional renal signals included nephritis (ROR = 24.99, IC025 = 1.832) and renal failure (ROR = 2.99, IC025 = 0.499). Among 447 combination therapy reports, 39 renal events and 23 pancreatic events were identified, compared to 114 and 48 events respectively in 1,814 monotherapy reports. Median time-to-onset was 73 days for renal events and 84 days for pancreatic events in the combination group. Co-reported renal and pancreatic events were infrequent at the report level (2 of 60 combination therapy reports with renal and/or pancreatic events), and serious clinical outcomes including death and hospitalization were prevalent in both groups without statistically significant between-group differences. Conclusions: Ipi+Nivo combination therapy is associated with prominent glomerular-predominant renal injury and pancreatic toxicity signals, potentially reflecting distinct immunological mechanisms whereby CTLA-4-dependent disruption of B-cell tolerance may predispose to glomerular injury while PD-1-mediated release of T-cell cytotoxicity may preferentially target pancreatic islets. These findings suggest the need for enhanced clinical vigilance and tailored monitoring strategies beyond conventional acute interstitial nephritis surveillance.