Sex-specific reporting patterns and onset timing of immune-related adverse events associated with nivolumab and pembrolizumab: a dual-database pharmacovigilance analysis

Background: Nivolumab and pembrolizumab are associated with various immune-related adverse events (irAEs). However, sex-specific differences in irAE reporting patterns remain incompletely characterized, especially regarding timing of onset. Therefore, we conducted a dual-database pharmacovigilance study to evaluate the sex-specific reporting patterns and time-to-onset (TTO) of irAEs associated with nivolumab and pembrolizumab. Methods: The U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) and Japanese Adverse Drug Event Report (JADER) databases from 2014 to 2025 were used for the analyses. Eligible reports included those in which sex of a patient was known and nivolumab or pembrolizumab was recorded as a suspected drug. Sex-stratified disproportionality signals were assessed using multivariable logistic regression to estimate the adjusted reporting odds ratios, and sex differences in onset timing were evaluated using multivariable Weibull accelerated failure time models to estimate the adjusted time ratios. Results: In total, 146,796 eligible reports from FAERS and 56,767 from JADER were included. At the System Organ Class level, endocrine disorders showed consistent female-predominant reporting signals in both databases, whereas respiratory, thoracic, and mediastinal disorders showed consistent male-predominant patterns in both databases. At the individual irAE level, hypothyroidism and hyperthyroidism were the most prominent female-predominant signals, whereas interstitial lung disease was the most prominent male-predominant signal. TTO analysis results showed that endocrine disorders, especially hypothyroidism, occurred earlier in females than in males in both databases. Conclusions: This study identified sex-associated patterns in endocrine and pulmonary irAEs related to nivolumab and pembrolizumab. However, our findings should be interpreted as signal-generating rather than causal, as they suggest that sex may be a clinically relevant factor in refining toxicity surveillance and individualized safety management during PD-1 inhibitor therapy.