Objective: Pembrolizumab has transformed the treatment of multiple solid tumors, but immune-related adverse events (irAEs) remain clinically relevant. Whether toxicity patterns differ according to biological sex and tumor histology is incompletely characterized in real-world pharmacovigilance data.

Materials and Methods: Individual Case Safety Reports associated with pembrolizumab monotherapy were extracted from EudraVigilance in March 2026. The analysis was restricted to reports with a reporting date between 1 January 2025 and 31 December 2025. irAEs were grouped into nine Medical Dictionary for Regulatory Activities System Organ Classes (MedDRA SOCs). Associations with sex and common tumor histologies (at least 100 reports per histology) were assessed using chi-square tests and Cramér’s V. Rare histologies (10–99 reports) were explored using Fisher’s exact tests. A Bonferroni-adjusted significance threshold of p < 0.0056 was used for the nine SOC comparisons.

Results: The overall cohort included 8,488 reports. Sex was specified in 7,991 cases: 4,159 females (52.1%) and 3,832 males (47.9%). The histology analysis included 6,482 cases across 14 common tumor types. Seven of nine SOCs were associated with tumor histology after multiplicity correction. Endocrine toxicity showed the strongest association (χ² = 202.6; Cramér’s V = 0.177), ranging from 27.7% in breast cancer to 10.1% in head and neck cancer. Respiratory toxicity was highest in bladder cancer (20.7%) and lowest in cervical cancer (2.4%; χ² = 144.4; V = 0.149). Immune system disorders were most frequent in non-small cell lung cancer (19.3%; χ² = 52.8; V = 0.090), cardiac disorders in melanoma (19.4%; χ² = 72.6; V = 0.106), and gastrointestinal disorders in cervical cancer (25.1%; χ² = 32.3; V = 0.071). Overall toxicity burden did not differ by sex (p = 0.110); however, females had more endocrine (18.4% vs. 12.4%) and hematologic/lymphatic disorders (13.4% vs. 9.5%), whereas males had more respiratory (12.4% vs. 7.0%) and cardiac disorders (13.9% vs. 11.5%). All four sex-associated differences met the adjusted threshold. Exploratory rare-histology analyses identified high rates of multisystem irAEs in brain tumors (84.6%; OR 6.58, 95% CI 1.46–29.71; p = 0.009) and sarcoma (71.4%; OR 2.99, 95% CI 1.16–7.72; p = 0.026), although these findings did not meet the Bonferroni-adjusted threshold.

Conclusions: Pembrolizumab-associated irAE reporting patterns differed by sex and tumor histology. These findings are hypothesis-generating and may inform risk-adapted vigilance, but they require validation in denominator-based clinical cohorts with adjustment for confounding and treatment exposure.