Hepatobiliary Adverse Events Associated with Pembrolizumab: A Pharmacovigilance Study from the FDA Adverse Event Reporting System (FAERS) Database

Abstract

Background: Immuno-oncology has transformed cancer treatment, with immune checkpoint inhibitors (ICIs) like pembrolizumab playing a key role. While highly effective, these therapies can also cause immune-related adverse events. This study examines the incidence and characteristics of hepatobiliary adverse events (AEs) linked to pembrolizumab, using data from the FDA Adverse Event Reporting System (FAERS). Objective: To investigate the rates of hepatobiliary AEs linked to pembrolizumab, providing insights into the risks of liver and biliary system damage in patients prescribed pembrolizumab. Methods: This study utilized the FAERS database via OpenVigil 2.1. Adverse events (AEs) related to pembrolizumab were identified and compared to those associated with other drugs. Reporting odds ratios (RORs) were calculated to assess the likelihood of hepatobiliary AEs in pembrolizumab-treated patients. Results: In total, 594 hepatic AEs and 181 biliary AEs were identified. Significant hepatic AEs included elevated ALT (ROR 3.00, 95% CI: 2.685–3.351), hepatotoxicity (ROR 6.436, 95% CI: 5.72–7.242), and hepatic cytolysis (ROR 15.721, 95% CI: 13.854–17.84). Immune-mediated hepatitis exhibited the highest ROR of 346.716 (95% CI: 303.568–395.997). For biliary AEs, cholangitis (ROR 19.597, 95% CI: 16.852–22.791) and sclerosing cholangitis (ROR 24.735, 95% CI: 19.888–30.763) were the most prominent. Conclusions: Pembrolizumab is associated with a significant risk of hepatobiliary adverse events, particularly immune-mediated hepatitis and cholangitis. The elevated RORs for these conditions highlight the importance of close monitoring and managing liver and biliary functions in patients undergoing pembrolizumab checkpoint blockade. These findings emphasize the need for personalized treatment strategies to mitigate risks and optimize outcomes in cancer immunotherapy, especially for those with preexisting hepatobiliary conditions.

1. Introduction

The advent of immuno-oncology modalities has markedly transformed the paradigm of cancer treatment. A prominent category within this domain, the immune checkpoint inhibitors (ICI), including pembrolizumab, has significantly advanced the management of melanoma, non-small cell lung cancer, renal cell carcinoma, and cervical cancer. These agents have demonstrated substantial improvements in both overall survival and progression-free survival across various malignancies, notably those exhibiting high programmed death ligand 1 (PD-L1) expression [1,2,3,4]. Pembrolizumab is an antibody-based therapeutic which binds to the programmed cell death protein 1 (PD-1) on CD8+ T lymphocytes, thereby preventing the suppression of T-cell activity. This boosts the immune response within the tumor microenvironment, resulting in cytotoxic effects on tumor cells [5]. It has been observed that a downstream effect of this pembrolizumab-induced immune activation is hepatobiliary damage, with many patients experiencing associated symptoms. However, these events are not well understood, nor are the rates of their occurrence [6,7]. The utilization of the United States Food and Drug Administration Adverse Event Reporting System (FAERS) to understand the hepatobiliary adverse events (AEs) associated with pembrolizumab can offer invaluable insights for physicians. Being aware of these events can play a crucial role in enhancing the overall treatment efficacy and a decrease in morbidity for patients undergoing immunotherapy.

2. Methods

FAERS is a comprehensive database for recorded adverse drug reactions associated with various pharmaceutical products. These reports are submitted by pharmaceutical companies, healthcare professionals, and consumers within the United States. Additionally, FAERS includes post-marketing clinical trial data from studies conducted both domestically and internationally. As the data are publicly available, no ethics committee approval was required for this study. Disproportionality analyses were used to compare the reported incidence of a specific AE associated with a particular drug against the background rate of AEs linked to all other drugs. Using OpenVigil 2.1 (OpenVigil, Kiel, Germany), individual queries were performed to extract AEs for the anti-PD-1 drug pembrolizumab. Reports submitted up to the first quarter of 2024 (31 December 2023) were analyzed. These data were used to calculate reporting odds ratios (ROR), a statistical measure used in drug safety monitoring to determine if a specific adverse event is reported more often for a particular drug than others. If the ROR is greater than 1.00, it suggests a potential association that warrants further investigation, but it does not prove causation. OpenVigil calculates RORs from FAERS by constructing a 2 × 2 contingency table that includes: the number of reports of the AE with the drug, the number of reports without the AE with the drug, the number of reports of the AE for all other drugs, and the number of reports without the AE for all other drugs in the FAERS database, including other ICIs. Statistical significance was determined if the lower bound of the 95% confidence interval was greater than 1.00 and the ROR exceeded 2.00. Only AEs with at least ten reports were considered. The results were filtered to include reports where the drug was the primary suspect. OpenVigil 2.1 applies data-cleaning procedures such as removing duplicate records, correcting formatting errors, and consolidating different terms for the same drug into a single standardized term.

3. Results

The analysis of adverse events related to the use of pembrolizumab in the hepatobiliary system reveals a range of varying conditions (

Table 1. Hepatic and biliary adverse events associated with the use of pembrolizumab.

Adverse Event	ROR (95% CI)	Number of Events
Hepatic Adverse Events
Abnormal Liver Function	9.347 (95% CI: 8.609, 10.148)	594
Immune-Mediated Hepatitis	346.716 (95% CI: 303.568, 395.997)	485
ALT Increased	3 (95% CI: 2.685, 3.351)	319
AST Increased	3.256 (95% CI: 2.901, 3.654)	294
Hepatotoxicity	6.436 (95% CI: 5.72, 7.242)	284
Hepatic Cytolysis	15.721 (95% CI: 13.854, 17.84)	255
Drug-Induced Liver Injury	3.316 (95% CI: 2.858, 3.847)	177
Hepatic Failure	2.368 (95% CI: 2.001, 2.803)	137
Transaminitis	2.822 (95% CI: 2.346, 3.394)	114
Hepatocellular Injury	2.663 (95% CI: 2.065, 3.434)	60
Mixed Liver Injury	9.919 (95% CI: 7.264, 13.546)	41
Acute Hepatitis	2.414 (95% CI: 1.664, 3.502)	28
Cholestatic Hepatitis	2.819 (95% CI: 1.929, 4.119)	27
Fulminant Hepatitis	3.681 (95% CI: 2.341, 5.788)	19
Liver Abscess	3.535 (95% CI: 2.248, 5.558)	19
Cholestatic Liver Injury	4.933 (95% CI: 3.095, 7.862)	18
Hepatitis Viral	7.342 (95% CI: 4.139, 13.024)	12
Total		2883
Biliary Adverse Events
Cholangitis	19.597 (95% CI: 16.852, 22.791)	181
Cholecystitis	7.002 (95% CI: 5.944, 8.25)	147
Hyperbilirubinemia	2.366 (95% CI: 1.969, 2.843)	115
Cholestasis	3.335 (95% CI: 2.735, 4.067)	99
Sclerosing Cholangitis	24.735 (95% CI: 19.888, 30.763)	88
GGT Increased	2.094 (95% CI: 1.668, 2.629)	75
Acute Cholecystitis	5.39 (95% CI: 4.117, 7.056)	54
Immune-Mediated Cholangitis	199.335 (95% CI: 136.623, 290.833)	46
Gallbladder Enlargement	13.82 (95% CI: 8.719, 21.906)	19
Biliary Obstruction	7.452 (95% CI: 4.296, 12.927)	13
Acute Cholangitis	9.891 (95% CI: 5.421, 18.046)	11
Biliary Tract Disorder	4.235 (95% CI: 2.335, 7.682)	11
ALP Increased	6.966 (95% CI: 3.719, 13.047)	10
Bile Duct Stenosis	5.465 (95% CI: 2.922, 10.218)	10
Total		879

).

3.1. Hepatic Adverse Events

Abnormalities in liver function were notably prevalent, presenting with an ROR of 9.347 (95% CI: 8.609, 10.148) across 594 instances. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were associated with RORs of 3.00 (95% CI: 2.685, 3.351) and 3.256 (95% CI: 2.901, 3.654), corresponding to 319 and 294 events, respectively, while transaminitis occurred in 114 cases with an ROR of 2.822 (95% CI: 2.346, 3.394). Hepatotoxicity was reported in 284 cases, exhibiting an ROR of 6.436 (95% CI: 5.72, 7.242), and hepatic cytolysis manifested with an ROR of 15.721 (95% CI: 13.854, 17.84) from 255 events. Drug-induced liver injury and hepatic failure were observed in 177 and 137 instances, respectively, with RORs of 3.316 (95% CI: 2.858, 3.847) and 2.368 (95% CI: 2.001, 2.803). Less frequently reported were hepatocellular injury (ROR 2.663, 95% CI: 2.065, 3.434) and mixed liver injury (ROR 9.919, 95% CI: 7.264, 13.546) in 60 and 41 cases, respectively. Acute hepatitis (ROR 2.414, 95% CI: 1.664, 3.502), cholestatic hepatitis (ROR 2.819, 95% CI: 1.929, 4.119), and fulminant hepatitis (ROR 3.681, 95% CI: 2.341, 5.788) were observed with 28, 27, and 19 events, respectively. Liver abscess (ROR 3.535, 95% CI: 2.248, 5.558), cholestatic liver injury (ROR 4.933, 95% CI: 3.095, 7.862), and viral hepatitis (ROR 7.342, 95% CI: 4.139, 13.024) occurred in 19, 18, and 12 cases, respectively. Notably, immune-mediated hepatitis showed a substantial ROR of 346.716 (95% CI: 303.568, 395.997) with 485 cases, aligning with established literature linking ICIs to immune-related adverse events [8,9].

3.2. Biliary Adverse Events

Biliary adverse events were observed with varying frequencies and strengths of association. Cholangitis and cholecystitis were the most commonly reported, with respective rates of occurrence of 181 and 147 cases. Cholangitis exhibited the highest ROR at 19.597 (95% CI: 16.852, 22.791), followed by sclerosing cholangitis at 24.735 (95% CI: 19.888, 30.763). Cholecystitis showed an ROR of 7.002 (95% CI: 5.944, 8.25). Hyperbilirubinemia, reported 115 times, had an ROR of 2.366 (95% CI: 1.969, 2.843). Other notable biliary adverse events included cholestasis (ROR 3.335, 95% CI: 2.735, 4.067) and immune-mediated cholangitis (ROR 199.335, 95% CI: 136.623, 290.833), observed in 99 and 88 cases, respectively. Again, immune-mediated adverse events are common [8,9]. Increased GGT was noted in 75 events with an ROR of 2.094 (95% CI: 1.668, 2.629), while acute cholecystitis had an ROR of 5.39 (95% CI: 4.117, 7.056) across 54 events. Less frequent events included gallbladder enlargement (ROR 13.82, 95% CI: 8.719, 21.906) and biliary obstruction (ROR 7.452, 95% CI: 4.296, 12.927), noted in 19 and 13 cases, respectively. Acute cholangitis (ROR 9.891, 95% CI: 5.421, 18.046), biliary tract disorder (ROR 4.235, 95% CI: 2.335, 7.682), ALP increased (ROR 6.966, 95% CI: 3.719, 13.047), and bile duct stenosis (ROR 5.465, 95% CI: 2.922, 10.218) each occurred in approximately 10–11 cases.

4. Discussion

The findings underscore the significant prevalence of hepatobiliary AEs associated with pembrolizumab. Among these, immune-mediated hepatitis demonstrated an exceptionally high ROR, highlighting its clinical significance as a severe immune-related AE. Similarly, immune-mediated cholangitis demonstrated a pronounced risk of biliary complications. Other biliary AEs, such as cholangitis, sclerosing cholangitis, and cholecystitis, further emphasize the vulnerability of the biliary system to immune-mediated damage. These findings reflect the need for heightened vigilance, timely recognition, and proactive management strategies to mitigate the progression of these potentially life-threatening conditions, ensuring improved safety and outcomes for patients receiving pembrolizumab.

The findings emphasize the critical intersection between immuno-oncology advancements and the evolving understanding of irAEs. Pembrolizumab has demonstrated efficacy in treating various cancers, but its association with hepatobiliary complications highlights a growing area of concern in immunotherapy safety [10]. While pivotal clinical trials including KEYNOTE-001 and KEYNOTE-522 reported irAEs, colitis and pneumonitis were much more significant than any disorder of the hepatobiliary system [11,12]. Moreover, numerous case reports from this year highlight a myriad of hepatobiliary AEs following pembrolizumab treatment [13,14,15,16]. This underscores the potential underrepresentation of hepatobiliary AEs in controlled trial environments, which often feature selective patient populations and limited follow-up periods. Real-world data, however, reveal a more comprehensive risk profile, including significant RORs for rare but severe events. These findings reinforce the importance of post-marketing surveillance in capturing the full spectrum of ICI-related toxicities and highlight the need for targeted monitoring protocols in immuno-oncology. By bridging gaps between clinical trials and real-world observations, clinicians can better anticipate, detect, and manage hepatobiliary irAEs, ultimately improving patient safety and therapeutic outcomes.

Awareness of hepatobiliary AEs associated with pembrolizumab can enhance patient management by informing tailored monitoring and early intervention strategies for patients receiving ICIs. Recognizing the elevated risk for these events enables clinicians to implement proactive measures, such as routine LFTs and imaging, to detect early signs of hepatocellular or biliary damage. Elevated ALT, AST, GGT, and ALP levels, for instance, provide easily accessible biomarkers for associated injury, while imaging modalities can identify structural changes like biliary obstruction or gallbladder enlargement. These tools are critical for early diagnosis, allowing timely interventions to mitigate progression toward severe outcomes like fulminant hepatitis. It is also worth noting that hepatobiliary adverse events are common across ICIs, though little research exists across the drug class [8,17,18].

Balancing pembrolizumab’s therapeutic benefits against its potential toxicities is essential in optimizing its use. While pembrolizumab offers significant survival advantages in treating various malignancies, its risk of hepatobiliary irAEs necessitates a cautious approach, particularly for patients with preexisting liver or biliary conditions. Individualized treatment plans that incorporate baseline assessments, regular monitoring, and rapid response to emerging AEs can minimize complications while preserving the efficacy of therapy. This balance underscores the importance of integrating robust adverse event management protocols into immunotherapy regimens to ensure patient safety without compromising the clinical benefits.

The study has several limitations stemming from the inherent characteristics of FAERS data. First is the potential for underreporting, as not all AEs are documented in voluntary reporting systems. This issue may lead to an incomplete representation of the true incidence of hepatobiliary AEs. Additionally, reporting biases, such as selective submission of severe or unusual cases, could skew the data and affect the generalizability of the findings. Furthermore, FAERS data cannot establish causation, as they are based on associations rather than controlled experimental conditions. The study’s reliance on ROR thresholds presents another limitation. While RORs are useful for identifying potential drug–AE associations, they do not confirm causality or account for confounding factors. Lastly, distinguishing pembrolizumab-specific AEs from those commonly associated with other ICIs poses a challenge, as the mechanisms underlying irAEs are shared across ICIs. This limitation underscores the need for comparative studies and mechanistic investigations to delineate pembrolizumab’s unique safety profile.

Future research should focus on prospective clinical studies to validate the findings from this analysis and identify the mechanisms underlying pembrolizumab-associated hepatobiliary AEs. Such studies could provide robust, causative insights into how ICIs trigger hepatic and biliary damage, helping to identify specific risk factors and biomarkers for early detection. Improving adverse event reporting and integrating real-world data sources, such as electronic health records and clinical registries, are essential for enhancing drug safety monitoring. These advancements could address underreporting and biases while providing more comprehensive datasets to analyze the safety profiles of pembrolizumab and other ICIs. Additionally, research should prioritize strategies to mitigate hepatobiliary AEs without compromising the therapeutic efficacy of pembrolizumab. These efforts would contribute to more effective, patient-centered immunotherapy protocols.

In conclusion, identifying and understanding AEs is critical to improving the safety and efficacy of pembrolizumab in clinical practice. The significant risks highlight the need for ongoing vigilance, early detection, and tailored management strategies. By addressing these challenges, physicians can better balance the therapeutic benefits of pembrolizumab with its potential toxicities. A collaborative approach between oncologists and pharmacovigilance researchers is essential for advancing patient outcomes in immunotherapy. Integrating real-world data with clinical insights will enhance the identification and management of AEs, fostering a safer and more effective application of pembrolizumab therapy.