---
title: "Real-world safety of enfortumab vedotin with or without pembrolizumab: FAERS comparative analysis"
id: "frontiers-in-immunology-4-the-real-world-safety-profile-of-enfortumab-vedotin-with-or-without"
canonical_url: "https://medichelpline.com/clinical-feed/frontiers-in-immunology-4-the-real-world-safety-profile-of-enfortumab-vedotin-with-or-without"
content_type: "clinical_feed_article"
specialty: "Infectious Disease"
source_name: "Frontiers in Immunology"
source_url: "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1831172"
published_at: "2026-07-24T00:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Real-world safety of enfortumab vedotin with or without pembrolizumab: FAERS comparative analysis
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/frontiers-in-immunology-4-the-real-world-safety-profile-of-enfortumab-vedotin-with-or-without
- **Specialty:** [Infectious Disease](https://medichelpline.com/clinical-feed/infectious-disease.md)
- **Primary Source:** Frontiers in Immunology
- **Source URL:** [Original Journal Publication](https://www.frontiersin.org/articles/10.3389/fimmu.2026.1831172)
- **Published At:** 2026-07-24T00:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- This FAERS-based case/non-case study compared adverse event (AE) reporting for **enfortumab vedotin (EV)** monotherapy versus EV combined with **pembrolizumab (EV+P)** using data from 2020 Q4–2025 Q3. 3,004 AE reports were identified for EV monotherapy and 2,265 for EV+P. - The combination (EV+P) showed significantly higher reporting for nine System Organ Classes (SOCs), with the largest odds observed for **endocrine disorders** (OR ~5.9), immune system disorders (OR ~2.0), and respiratory disorders (OR ~1.7). - At the Preferred Term (PT) level, EV+P was strongly associated with hepatitis, immune-mediated enterocolitis, adrenal insufficiency, and **pneumonitis** (ORs reported in the source). Some potential novel signals—hearing and dental/gingival disorders—were observed but lacked statistical robustness after multiple-testing correction. - High-Level Group Term (HLGT) analysis identified 15 robust signals, including adrenal gland and thyroid gland disorders, salivary gland conditions, gastrointestinal inflammatory conditions, myocardial disorders, and lower respiratory tract disorders. - Time-to-onset analysis using Kaplan–Meier suggested EV+P may lead to earlier onset for specific toxicities such as eye and skin disorders (FDR P values reported). A narrative literature review corroborated a higher incidence of any-grade pneumonitis with EV+P (10% vs. 3.5%) in clinical sources reviewed. - Demographics: most reports were in patients aged ≥65 years (peak in 70–75 years), male predominance (~3:1), and top reporting countries included Japan and the United States. Hospitalization and death were common serious outcomes. - Multiple sensitivity analyses (age/sex adjustment, Primary Suspect-restricted analysis, shrinkage ROR) supported the directionality and robustness of the main safety signals. - The authors conclude that EV+P presents a broader and more intense AE spectrum than EV alone, driven largely by **immune-related toxicities** and potential synergistic organ injury, underscoring the need for vigilant monitoring and early intervention in clinical practice.
## Clinical Analysis & Structured Key Points
Frontiers | The real-world safety profile of enfortumab vedotin with or without pembrolizumab: insights from a comparative analysis of FAERS ORIGINAL RESEARCH article Front. Immunol. , 24 July 2026 Sec. Cancer Immunity and Immunotherapy Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1831172 Published in Frontiers in Immunology Cancer Immunity and Immunotherapy 7 impact factor 11.3 citescore Part of a Research Topic Community Series in Reducing Adverse Effects of Cancer Immunotherapy: Volume IV Submission open 9863 views 8 articles Editor & Reviewers Edited by C M Cleber Machado-Souza Reviewed by D T Dianzhe Tian Q W Qian Wu B S Bushra Salman Outline Figures and Tables Figure 1 View in article Figure 2 View in article Figure 3 View in article Figure 4 View in article Figure 5 View in article Table 1 Evaluation of adverse event signals at the HLGT level. View in article Table 2 Top 30 disproportionality signals at the PT level. View in article ORIGINAL RESEARCH article Front. Immunol. , 24 July 2026 Sec. Cancer Immunity and Immunotherapy Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1831172 The real-world safety profile of enfortumab vedotin with or without pembrolizumab: insights from a comparative analysis of FAERS H C Heng Chen * J H Juanjuan Huang G H Gefei He * Department of Pharmacy, The First Hospital of Changsha (The Affiliated Changsha Hospital of Xiangya School of Medicine, Central South University), Changsha, Hunan, China Article metrics View details Abstract Introduction: The combination of enfortumab vedotin and pembrolizumab (EV+P) has revolutionized advanced urothelial carcinoma treatment, yet their combined real-world safety profile remains insufficiently characterized. This study aimed to quantitatively compare the adverse event (AE) landscapes of EV+P and EV monotherapy using the FAERS data. Methods: A case/non-case study design was conducted on FAERS data from 2020 Q4 to 2025 Q3. Disproportionality signals were evaluated at the System Organ Class (SOC), High-Level Group Term (HLGT), and Preferred Term (PT) levels. Time-to-onset was analyzed using the Kaplan–Meier method, and narrative review was performed to validate pneumonitis signals. Results: We identified 3, 004 and 2, 265 AE reports for EV and EV+P, respectively. EV+P demonstrated significantly higher risks across nine SOCs, most notably in endocrine (OR: 5.88), immune system (OR: 2.03), and respiratory (OR: 1.71) disorders. At the PT level, EV+P was strongly associated with hepatitis (OR: 14.79), immune-mediated enterocolitis (OR: 11.77), adrenal insufficiency (OR: 9.14), and pneumonitis (OR: 2.75). Potential novel signals like hearing disorders (OR: 10.64) and dental/gingival conditions (OR: 9.31) were noted but lacked statistical robustness post-correction. Literature validation confirmed a higher incidence of any-grade pneumonitis with EV+P (10% vs. 3.5%). Furthermore, EV+P suggested a potentially earlier onset for several toxicities, including eye (FDR P = 0.047) and skin disorders (FDR P = 0.011). Conclusion: EV + P demonstrates a broader and more intense AE spectrum than EV monotherapy, driven largely by immune-related toxicities and potential synergistic organ injury. These findings emphasize the need for vigilant clinical monitoring and early intervention when employing this combination therapy. Introduction Urothelial carcinoma (UC) is a major global health burden with high mortality in advanced stages ( 1 , 2 ). For decades, platinum-based chemotherapy was the standard of care ( 3 ). Recently, the therapeutic landscape for metastatic UC (mUC) has been transformed by immune checkpoint inhibitors (ICIs) and antibody-drug conjugates (ADCs). Among these, enfortumab vedotin (EV), an ADC directed against Nectin-4, has demonstrated notable efficacy as monotherapy in patients who progressed after platinum-based chemotherapy and an ICI ( 4 ). EV binds to Nectin-4-expressing tumor cells, is internalized, and releases monomethyl auristatin E (MMAE), resulting in microtubule disruption and cytotoxic cell death ( 5 ). Common toxicities associated with EV monotherapy include alopecia, peripheral sensory neuropathy, and pruritus ( 6 ). Selecting effective treatments for platinum-ineligible patients with locally advanced or metastatic UC (la/mUC) remains challenging. However, combining the targeted cytotoxicity of EV with the immune-potentiating effects of pembrolizumab (EV+P) has shown remarkable synergistic potential. Clinical trials, including EV-103 and the phase 3 EV-302 trial, demonstrated superior objective response rates, progression-free survival, and overall survival compared to traditional chemotherapy ( 7 , 8 ). Consequently, EV+P has been established as a new first-line standard for la/mUC. However, this enhanced efficacy is accompanied by a more complex toxicity profile. EV-related AEs, such as rash and neuropathy, occur alongside a wide spectrum of immune-related AEs (irAEs) linked to pembrolizumab, including pneumonitis, endocrinopathies, and hepatitis ( 9 ). Notably, the EV+P group exhibited higher rates of dose reductions and treatment discontinuations due to toxicities compared to chemotherapy ( 7 ). Although clinical trials are essential for drug approval, they are conducted in strictly controlled settings with highly selected populations. Therefore, real-world evidence is vital for assessing safety profiles across broader, more heterogeneous patient demographics. The FDA Adverse Event Reporting System (FAERS), a large post-marketing pharmacovigilance database containing millions of spontaneously reported AEs, offers a valuable resource for detecting rare, novel, or unexpectedly frequent AEs. While previous pharmacovigilance studies have independently evaluated the safety profiles of EV or ICIs like pembrolizumab ( 10 – 12 ), the real-world safety landscape of their concurrent use remains largely unexplored. With EV+P established as the new first-line standard for la/mUC, understanding how this combination alters the overall toxicity profile is clinically urgent. Therefore, this study aimed to address this gap by performing a FAERS-based disproportionality analysis specifically comparing the AE profiles of EV+P versus EV monotherapy. The findings may help refine clinicians’ understanding of treatment-related risks and support safer, evidence-based use of the EV + P combination in clinical practice. Methods Data source and acquisition The present retrospective investigation leveraged the FAERS, a premier global pharmacovigilance database containing over 28 million post-marketing safety records. We interrogated this extensive repository to aggregate AE data covering the period from the fourth quarter of 2020 through the third quarter of 2025. The study dataset was constructed by linking seven distinct ASCII files via “PRIMARYID” and “CASEID” identifiers: patient demographics (DEMO), pharmacological information (DRUG), adverse reactions (REAC), clinical outcomes (OUTC), report origins (RPSR), therapy duration (THER), and drug indications (INDI). Reaction terms were mapped to Preferred Term (PTs), and PTs were further aggregated to their corresponding High-Level Group Term (HLGT) and System Organ Classe (SOC) according to the standard Medical Dictionary for Regulatory Activities (MedDRA) (version 27) hierarchy. Institutional Review Board approval was waived as the research relied exclusively on de-identified, public-domain data. Data pre-processing and extraction Raw data files were downloaded from the official FDA portal ( https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html ) and imported into a MySQL 8.0, yielding an initial dataset of 8, 649, 232 reports. To maintain analytical rigor, a deduplication protocol aligned with FDA recommendations was executed ( 13 ). In instances of multiple entries sharing the same CASEID, priority was given to the record with the most recent FDA received date (FDA_DT) and the highest PRIMARYID. This cleansing process resulted in the elimination of 1, 274, 325 redundant records ( Figure 1 ). Target cases were identified through a dual-keyword search strategy encompassing the trade name and the generic name. For example, enfortumab vedotin reports were retrieved using the following query logic: DRUGNAME LIKE ‘%enfortumab%’ OR PROD_AI LIKE ‘%enfortumab%’ OR DRUGNAME LIKE ‘%Padcev%’ OR PROD_AI LIKE ‘%Padcev%’. EV+P exposure was operationally defined by the concurrent presence of both enfortumab vedotin and pembrolizumab recorded as suspect drugs within the same FAERS report. To evaluate the influence of drug role coding on the robustness of the results, we performed a sensitivity analysis restricted to Primary Suspect reports. In this analysis, reports were retained only when the target exposure-defining drug was coded as Primary Suspect. Figure 1 The flow chart of the study. Narrative review to validate risk signals To validate the identified risk signals, a comprehensive PubMed search was conducted to identify clinical trials published in the past five years evaluating EV monotherapy or EV combined with pembrolizumab. The search incorporated both MeSh terms and free-text keywords. Abstracts from recent ESMO and ASCO meetings were also reviewed for unpublished data. Eligible studies reported pneumonitis, immune-mediated lung disease, interstitial lung disease, or organizing pneumonia related to EV or EV + P. Data extracted included study name, cancer type, treatment arm, sample size, and pneumonitis incidence (any grade and grade ≥ 3). For overlapping cohorts, the study with the larger sample or latest publication was retained. The incidence was then derived as the ratio of patients with pneumonitis to the total number of patients in each respective treatment group. Statistical analysis Baseline characteristics of the study population were calculated. For categorical data, we reported counts alongside proportions, whereas continuous data were represented by median values and interquartile ranges (IQRs). To assess the safety profile of EV with or without pembrolizumab, we used a case/non-case study design. This evaluation was carried out across multiple hierarchy levels, specifically PT, HLGT, and SOC, with the aim of comparing the reporting frequency of specific drug-event pairs against a control group. Logistic regression was then used to compare the odds ratio (OR) of each AE in the EV plus pembrolizumab group with those in the EV monotherapy group. EV monotherapy served as the reference group. Therefore, an OR > 1 indicated that the corresponding AEs were more frequently reported in the combination therapy group than in the monotherapy group. To account for the increased risk of Type I errors arising from multiple comparisons across numerous MedDRA terms, P values were adjusted using the Benjamini-Hochberg False Discovery Rate (FDR) method. A significant disproportionality signal was defined when the lower limit of the 95% confidence interval (CI) for OR (OR 025 ) exceeded 1 and the FDR adjusted P value was < 0.05. To minimize the impact of potential confounders, we performed multivariable logistic regression to calculate adjusted ORs and their 95% CIs. Age and sex were included as covariates in the model to adjust for baseline demographic imbalances. To further assess whether sparse reporting could inflate disproportionality signals, we performed an additional shrinkage sensitivity analysis. Furthermore, the time to onset for an AE was calculated as the duration between the initiation of therapy (START_DT) and the AE occurrence date (EVENT_DT). Due to the inherent missing or inaccurate date fields in the FAERS database, a complete-case analysis was conducted for the time-to-onset evaluation. Cumulative incidence curves for AEs were generated using the Kaplan–Meier approach, where the x-axis denotes time since treatment initiation and the y-axis indicates the cumulative probability of AE occurrence. To assess the statistical significance of differences in AE incidence profiles between two groups, log-rank P values were adjusted using the FDR method and reported as FDR P values. A significance threshold of P < 0.05 was adopted. Two researchers independently managed data extraction via MySQL 8.0 and executed all statistical computations using Python 3.10 and SPSS 27.0. Results Demographic information 3, 004 cases of AE reports for EV monotherapy and 2, 265 cases for combination therapy were identified from the FAERS database (2020 Q4–2025 Q3) ( Figure 1 ). AE reports for combination therapy increased steadily over time, whereas reports for EV monotherapy peaked in 2023 and declined in 2024 ( Figure 2B ). In both groups, patients were primarily aged ≥65 years, with the highest proportion in the 70-75-year subgroup (22.53% and 23.53%, respectively; Figure 2A ). Males accounted for most reports, with a male-to-female ratio of approximately 3:1 ( Figure 2E ). For EV monotherapy, the highest number of AE reports originated from Japan, the United States, and France, whereas for the combination therapy, the top contributors were Japan, the United States, and Canada ( Figure 2C ). Regardless of the serious outcome, the most common was initial or prolonged hospitalization (EV monotherapy: 27.27%; combination therapy: 30.20%), followed by death (EV monotherapy: 24.23%; combination therapy: 21.56%) ( Figure 2D ). Figure 2 Demographic information of patients treated with enfortumab vedotin with or without pembrolizumab. (A) Age distribution of the reported cases; (B) Annual distribution of the number of cases; (C) Geographic distribution of the reports by country; (D) Distribution of the patient outcomes; (E) Sex distribution of the patients. Significant risk signals at the SOC level Figure 3 illustrated the SOC profile of AE signals associated with EV monotherapy compared with combination therapy. The results are presented in descending order based on the OR values. Among the 22 SOCs analyzed, 9 demonstrated statistically significant differences (FDR P < 0.05). The strongest signal was observed for endocrine disorders (OR: 5.88; 95%CI: 3.64-9.48), followed by immune system disorders (OR: 2.03; 95%CI: 1.22-3.38) and respiratory, thoracic, and mediastinal disorders (OR: 1.71; 95%CI: 1.44-2.04). Additional significant signals were identified in vascular disorders, hepatobiliary disorders, cardiac disorders, renal and urinary disorders, gastrointestinal disorders, and investigations. After adjusting for age and sex using multivariable logistic regression, the sensitivity analysis results were highly consistent with the primary unadjusted analysis ( Figure 3 ). The strongest adjusted signal remained endocrine disorders (OR: 5.47; 95% CI: 3.31-9.04). The additional ROR shrinkage analysis confirmed the directional consistency of all nine primary positive signals at the SOC level, with representative findings including endocrine disorders (sROR: 3.95; 95% CI: 2.59-6.02) ( Supplementary Figure 1 ). Figure 3 The odds ratio of AEs for combination therapy compared to monotherapy at the SOC level. EV monotherapy was used as the reference group. ORs greater than 1 indicate that the corresponding AEs were more frequently reported in the combination therapy group than in the monotherapy group. Crude ORs were estimated using univariable logistic regression, whereas adjusted ORs were derived from multivariable logistic regression adjusted for age and sex. Sensitivity analysis restricted to primary suspect reports To assess whether the inclusion of non-Primary Suspect drug reports influenced the main findings, we performed a sensitivity analysis restricted to reports in which the target exposure-defining drug was coded as Primary Suspect. After this restriction, 4, 187 reports were retained from the original 5, 269 reports, accounting for approximately 79.5% of the primary analytic population. As shown in Supplementary Figure 2 , the SOC-level results were directionally consistent with the primary analysis. The major organ-system differences observed in the full dataset remained stable after restricting the analysis to Primary Suspect reports, supporting the robustness of the comparative safety findings. Significant safety signals at the HLGT level Further evaluation of AE signals at the HLGT level was conducted, as detailed in Table 1 . After applying the Benjamini-Hochberg FDR correction, a total of 15 signals remained robustly significant (FDR P < 0.05). The most robust signals were identified within the gastrointestinal disorders, encompassing three categories, such as salivary gland conditions (OR: 3.59, 95%CI: 2.21-5.81) and gastrointestinal inflammatory conditions (OR: 2.76, 95%CI: 1.95-3.90). Notably, the signal for endocrine disorders emerged primarily from adrenal gland disorders (OR: 9.21, 95%CI: 3.90-21.73) and thyroid gland disorders (OR: 6.59, 95%CI: 3.21-13.53), with both ranking among the more pronounced risks. And the signal for immune system disorders was supported by immune disorders NEC (OR: 3.56, 95%CI: 1.65-7.68). For respiratory, thoracic and mediastinal disorders, significant risks were associated with respiratory tract signs and symptoms (OR: 2.68, 95%CI: 1.56-4.60) and lower respiratory tract disorders (excl obstruction and infection) (OR: 2.56, 95%CI: 1.99-3.30). In the vascular disorders and cardiac disorders SOCs, high-risk signals included vascular hypertensive disorders (OR: 3.07, 95%CI: 1.46-6.47) and myocardial disorders (OR: 5.55, 95%CI: 2.43-12.70). The strongest risk signal like hearing disorders (OR: 10.64, 95%CI: 1.33-85.16) and dental/gingival conditions (OR: 9.31, 95%CI: 1.14-75.72) were noted but lacked statistical robustness post-correction. Table 1 Adverse event N OR (95%CI) FDR P Hearing disorders 8 10.64 (1.33-85.16) 0.124 Dental and gingival conditions 7 9.31 (1.14-75.72) 0.161 Adrenal gland disorders 41 9.21 (3.90-21.73) < 0.001 Thyroid gland disorders 44 6.59 (3.21-13.53) < 0.001 Neuromuscular disorders 13 5.77 (1.64-20.29) 0.045 Myocardial disorders 29 5.55 (2.43-12.70) < 0.001 Cardiac and vascular investigations (excl enzyme tests) 94 4.29 (2.84-6.50) < 0.001 Seizures (incl subtypes) 15 4.00 (1.45-11.02) 0.05 Hypothalamus and pituitary gland disorders 12 3.99 (1.29-12.40) 0.088 Salivary gland conditions 61 3.59 (2.21-5.81) < 0.001 Immune disorders NEC 24 3.56 (1.65-7.68) 0.011 Leukaemias 10 3.33 (1.04-10.62) 0.17 Vascular hypertensive disorders 23 3.07 (1.46-6.47) 0.027 Gastrointestinal inflammatory conditions 99 2.76 (1.95-3.90) < 0.001 Respiratory tract signs and symptoms 40 2.68 (1.56-4.60) 0.003 Therapeutic and nontherapeutic effects (excl toxicity) 150 2.59 (1.96-3.42) < 0.001 Lower respiratory tract disorders (excl obstruction and infection) 182 2.56 (1.99-3.30) < 0.001 Vascular disorders NEC 20 2.42 (1.16-5.07) 0.096 Procedural related injuries and complications NEC 32 2.25 (1.27-3.98) 0.04 Enzyme investigations NEC 24 2.13 (1.12-4.08) 0.108 Renal and urinary tract investigations and urinalyses 31 2.07 (1.18-3.64) 0.075 Exocrine pancreas conditions 26 1.82 (1.01-3.30) 0.18 Hepatic and hepatobiliary disorders 166 1.64 (1.30-2.07) < 0.001 Muscle disorders 45 1.58 (1.02-2.45) 0.202 Decreased and nonspecific blood pressure disorders and shock 58 1.52 (1.04-2.23) 0.165 Gastrointestinal motility and defaecation conditions 227 1.44 (1.19-1.76) 0.137 Miscellaneous and site unspecified neoplasms malignant and unspecified 309 1.23 (1.04-1.44) 0.002 Evaluation of adverse event signals at the HLGT level. FDR P: P-value after Benjamini-Hochberg FDR correction for multiple testing. Top 30 risk signals at the PT level At the PT level, the top 30 significant risk signals (ranked by OR) were presented in Table 2 . Specifically, AEs related to vascular disorders involved the highest number of disproportionality signals, which were mainly associated with blood pressure fluctuations, and the strongest was blood pressure
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