Abstract
BACKGROUND: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality globally. Recent advancements in systemic therapy, particularly the combination of durvalumab and tremelimumab - dual immune checkpoint inhibitors - have redefined first-line treatment for advanced or unresectable HCC. However, limited real-world data are available on their safety profile outside clinical trials. OBJECTIVE: This study aimed to compare adverse drug reactions (ADRs) related to durvalumab and tremelimumab reported in the European EudraVigilance (EV) pharmacovigilance database with safety data from the Phase III HIMALAYA trial. The purpose of this study was not to perform a definitive quantitative or causal comparison between HIMALAYA and EudraVigilance - which would require reliable denominators and proper adjustment - but rather to integrate controlled trial data with spontaneous post-marketing reports to obtain a broader view of the safety profile and to highlight signals that may inform pharmacovigilance priorities and future observational studies. METHODS: A retrospective observational analysis was conducted on suspected ADRs related to durvalumab plus tremelimumab in advanced HCC patients. Data were collected from EV reports submitted in 2023 and compared with ADRs recorded in the HIMALAYA trial. Events were categorized by System Organ Class (SOC) and Preferred Terms (PTs) using MedDRA Version 26.1 terminology. RESULTS: A total of 236 EV reports encompassing 434 ADRs were analyzed. Most reports (97.5%) were classified as serious and originated from healthcare professionals. The most commonly reported SOCs in EV were gastrointestinal disorders (25.1%), skin disorders (11.8%), and hepatobiliary disorders (9.4%). The most frequent PTs included diarrhea (8.5%), interstitial lung disease (4.6%), and colitis (4.1%). In contrast, HIMALAYA data (n = 1722 ADRs) showed a similar prevalence of gastrointestinal disorders (25.6%) but higher frequencies of laboratory abnormalities and general systemic symptoms. Key discrepancies included higher reporting of immune-related and hepatic toxicities in EV and more systemic symptoms like fatigue and pyrexia in HIMALAYA. CONCLUSIONS: Real-world data from EV reveal a distinct ADR profile for durvalumab plus tremelimumab compared to clinical trial data, particularly highlighting a greater incidence of severe immune-related events in routine practice. However, it is important to note that incidence rates could not be estimated because the total number of patients exposed in EV is unknown, which limits the ability to quantify absolute risks. These findings underscore the importance of pharmacovigilance in capturing rare or delayed toxicities not fully observed in trials, and reinforce the need for continuous post-marketing monitoring to optimize patient safety in immunotherapy.