Abstract
Background:
Overall risks of hepatotoxicity with immune checkpoint inhibitors (ICIs) have yet to be compared in primary liver cancers to other solid tumors.
Methods:
We reviewed data from the PubMed, Embase, and Scopus databases, and assessed the risk of hepatotoxicity associated with ICIs.
Results:
A total of 117 trials were eligible for the meta‐analysis, including 7 trials with primary liver cancers. The most common hepatotoxicity was ALT elevation (incidence of all grade 5.29%, 95% CI 4.52-6.20) and AST elevation (incidence of all grade 5.88%, 95% CI 4.96-6.97). The incidence of all grade ALT and AST elevation was 6.01% and 6.84% for anti-PD‐1 (95% CI 5.04-7.18/5.69-8.25) and 3.60% and 3.72% for anti-PD-L1 (95% CI 2.72-4.76/2.82-4.94; p< 0.001/p<0.001). The incidence of ≥ grade 3 ALT and AST elevation was 1.54% and 1.48% for anti-PD‐1 (95% CI 1.19-1.58/1.07-2.04) and 1.03% and 1.08% for anti-PD-L1 (95% CI 0.71-1.51/0.80-1.45; p= 0.002/p<0.001). The incidence of all grade ALT and AST elevation was 13.3% and 14.2% in primary liver cancers (95% CI 11.1-16.0 and 9.93-20.36) vs. 4.92% and 5.38% in other solid tumors (95% CI 4.21-5.76 and 4.52-5.76 in other solid tumors; p <0.001/p<0.001).
Conclusion:
Our study indicates that anti-PD-1 is associated with a higher risk of all‐ and high‐grade hepatotoxicity compared to anti-PD-L1, and primary liver cancers are associated with a higher risk of all‐ and high‐grade hepatotoxicity compared to other solid tumors.
Introduction
Liver cancers are the fourth leading cause of cancer-related mortality worldwide (, ) with over 800,000 new primary liver cancer cases diagnosed around the world each year (). Hepatocellular carcinoma (HCC) is one of the most aggressive liver cancers and accounts for 75-85% of these cases (). Biliary tract carcinoma (BTC) originates in the intra- and extrahepatic biliary ductal system and is the second most common primary liver cancer after HCC. Surgical resection or liver transplantation are potential curative options for patients with early stage disease, however, the majority of patients present with advanced stage disease and are not candidates for curative therapies.
Immunotherapy has shown promising, effective and durable antitumor responses through immune mediated mechanisms by blocking internal immunosuppressive mechanism (e.g. CTLA-4 and PD-1/PD-L1 axis) and reactivating T cell-mediated host immune surveillance. Among these, immune checkpoint inhibitors (ICIs) have shown remarkable efficacy in the therapy of multiple cancers including HCC that has led to the regulatory approval of ICI in the first and second-line setting. Unfortunately, the antitumor effects of ICIs in BTC is much more limited and is still an ongoing active research field.
Although ICIs have achieved success as cancer therapies, their use comes with risks evidenced by toxic effects (treatment-related adverse events, TRAEs), including immune-related adverse events (IRAEs) caused by stimulation of the immune system (–). Those IRAEs are considered a consequence of T lymphocyte hyperactivation triggered by ICI introduction to attack auto-antigens located in the normal tissue. IRAEs lead to autoimmune-like manifestations in individual organs where the activated immune surveillance machinery attacks self-antigens on normal tissues. Hepatotoxicity derived from ICIs exhibits either a hepatocellular or cholestatic injury pattern with abnormal laboratory findings (, ). Clinically, hepatotoxicity can present with a range findings, from mild elevation of liver enzymes to hepatobiliary disorders like autoimmune hepatitis, cholangitis, jaundice and liver failure (, ). Currently, there are several meta-analyses that have evaluated hepatotoxicity from ICIs and found a general incidence of 2-30% (, , –).
Although there is overlapped antigenicity between normal liver tissue and tumors derived from the liver, it is unknown if ICI exposure can increase the incidence or severity of hepatotoxicity in patients with primary liver cancers in comparison to other cancer types. Therefore, we conducted a meta-analysis with the aim to compare liver-specific toxicities among patients with primary liver cancers versus other solid cancers.
Methods
Search Strategy and Study Selection
This study strictly followed the preferred reporting items for systematic reviews and meta‐analyses (PRISMA) guideline. A systematic search of the literature was conducted in PubMed, Web of Science and Embase to identify published clinical trials of ICIs that reported hepatotoxicity. The search was done using keywords anti-PD‐1, PD-1 inhibitor, anti-PD‐L1, PD-L1 inhibitor, nivolumab, pembrolizumab, avelumab, durvalumab and atezolizumab from June 1, 2008 through final research for updates on August 3, 2020. Phase I studies were excluded due to concerns about different dose ranges used. Studies eligible for this analysis must have met all of the following criteria: (1) prospective phase 2 or phase 3 human trials/cohorts in cancer therapy, (2) participants were treated with a single ICI agent to avoid cumulative hepatotoxicity from other agents, (3) reported tabulated data on any treatment-related hepatotoxicity, (4) sample size over 20, and (5) published in English. Meeting abstracts were excluded except for the phase 3 Checkmate 459 study that was included. When encountered with multiple publications from the same study population was identified, the one with the most recent, relevant and/or comprehensive hepatotoxicity data was included. The literature search, study selection, and data extraction were performed independently by 3 of the co-authors (F. J., W-Z. L and M.N.). The discrepancies were reviewed by another two investigators on the team (Y-Q. X and X.C) and resolved by consensus.
Data Collection
A standard checklist was used for all studies including name of first author, year of publication, phase of the study, registration identity at clinicaltrial.gov, targeted cancer, ICI(s) involved, number of patients enrolled, number with liver metastases of enrolled patients, and number of patients recorded with hepatotoxicity in each trial. The hepatotoxicity in this analysis are all‐grades and high‐grade (≥grade 3) liver adverse events (AEs), which can be further classified into the elevation of alanine aminotransferase (ALT), aspartate aminotransferase(AST), blood bilirubin, blood alkaline phosphatase (ALP), γ‐glutamyl transpeptidase (GGT), immune related-hepatitis (ir-hepatitis), and hepatobiliary disorders (if separated from abovementioned items, including autoimmune hepatitis, acute hepatitis, liver failure, hepatic hemorrhage, transaminitis, elevated liver enzyme, cholecystitis, cholangitis, cholelithiasis, cholestasis, hepatocellular injury, drug-induced liver injury, jaundice, and hyperbilirubinemia).
Statistical Analysis
Using the extracted data, we recorded the number of patients treated and the number of patients with hepatotoxicity reported. Meta-analysis of single incidence rates to calculate a pooled rate was performed using inverse variance method (). Random effect models were fit using log transformation and were implemented to calculate a pooled incidence of each toxic effect and corresponding 95% confidence intervals (CIs). Continuity correction of 0.5 in studies with zero cell frequencies was applied in order to calculate individual study results with confidence limits and to conduct meta-analysis. Statistical heterogeneity was evaluated by the Cochran Q statistic and quantified with I2 statistics. A P value of less than 0.05 for Chi-square was regarded as the indicator of the presence of heterogeneity. I2 values of higher than 50% represented a high level of heterogeneity. To estimate the between-study variation in the meta-analysis, we also calculated the incidence rate of hepatotoxicity by study-level moderators, including the cancer type and drug type. Incidence differences between the different groups were compared with the Two-Proportions Z-Test.
All statistical analyses were performed by using R software (version 4.0.2, R Foundation for Statistical Computing) and the “meta” package.
Results
Eligible Studies and Characteristics
The search strategy revealed 987 potentially suitable records on ICIs from PubMed, Web of Science and Embase databases. The reasons for study exclusion are shown in Figure 1. Accordingly, a total of 117 clinical trials were considered eligible for the analysis (–132). The trials involved the treatment of liver cancer (7 cohorts, n = 1362, 6 HCC and 1 BTC), lung cancer (27 cohorts, n = 7208), other gastrointestinal cancer (14 cohorts, n = 1798), genitourinary cancer (26 cohorts, n = 4963), melanoma (14 cohorts, n = 4169), head and neck cancer (10 cohorts, n = 1844), and other cancer types (15 cohorts, n = 994, including one cohort of thymic carcinoma, 2 cohorts of sarcoma, 2 cohorts of neuroendocrine tumor, 2 cohorts of mesothelioma, 3 cohorts of Merkle cell carcinoma and 5 cohorts of mixed solid tumors) (Supplemental Table S1). We categorized the regimens by ICI class using PD-1 inhibitor (88 cohorts; n = 16554 patients), and PD-L1 inhibitor (30 cohorts; n = 7113 patients). Specific PD-1 inhibitors included nivolumab (44 cohorts; n = 8368 patients) and pembrolizumab (44 cohorts; n = 7537 patients). Specific PD-L1 inhibitors included atezolizumab (14 cohorts, n = 4069), avelumab (5 cohorts, n = 743), and durvalumab (11 cohorts, n = 2301).
Figure 1
Some trials had not reported information of hepatotoxicity related to ICIs. Supplemental Figure S1 shows the proportion and pattern of missing data from all trials included in this study. The most available reported hepatoxicity parameters are elevated ALT, AST, and hepatobiliary disorders, named transaminitis, acute liver injury, hepatocellular injury, and acute liver failure. The most common missed parameter was GGT that accounted over 60% missing data (Supplemental Figure S1). This may be due to the rare incidence of GGT change with ICI exposure that was absent from reports.
Incidence of All-Grade Hepatotoxicity Across All Tumor Types
All-grade hepatotoxicity parameters were reported as following (Figure 2A and Table 1): elevated ALT was reported in 92 studies (incidence 5.29%; 95% CI 4.52 - 6.20); elevated AST in 92 studies (incidence 5.88%; 95% CI 4.96 – 6.97); elevated bilirubin in 69 studies (incidence of 1.21%; 95% CI 0.82 – 1.79); elevated ALP in 49 studies (incidence 3.19%; 95% CI 2.30 – 4.41); elevated GGT in 36 studies (incidence of 1.85%; 95% CI 1.33 – 2.59); hepatobiliary disorder in 99 studies (incidence of 2.28%; 95% CI 1.78 – 2.91); and ir-hepatitis in 88 studies (incidence of 1.24%; 95% CI 0.91 – 1.68). Across all studies, the anti-PD‐1 subgroup showed statistically higher incidence of all-grade elevated ALT, AST, bilirubin and ALP, and ir-hepatitis in comparison with the anti-PD-L1 subgroup (p<0.05, Supplemental Figure S2A and Table 2), but not the incidence of elevated GGT and hepatobiliary disorders.
Figure 2
Table 1
| Hepatotoxicity | All Grade (95% CI) | ≥Grade 3 (95% CI) |
|---|---|---|
| ALT increased | 5.29 (4.52−6.20) | 1.38 (1.11−1.72) |
| AST increased | 5.88 (4.96−6.97) | 1.32 (1.00−1.74) |
| Bilirubin increased | 1.21 (0.82−1.79) | 0.62 (0.43−0.88) |
| ALP increased | 3.19 (2.30−4.41) | 0.86 (0.59−1.25) |
| GGT increased | 1.85 (1.33−2.59) | 0.98 (0.69−1.38) |
| Hepatobiliary disorders | 2.28 (1.78−2.91) | 1.59 (1.28−1.97) |
| Ir-hepatitis | 1.24 (0.91−1.68) | 0.97 (0.75−1.26) |
Incidence of all grade and ≥grade 3 hepatotoxicity with ICIs (anti-PD-1/PD-L1).
ICIs, immune checkpoint inhibitors; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP: alkaline phosphatase; GGT, γ‐glutamyl transpeptidase; Ir-hepatitis: immune related hepatitis.
Table 2
| Hepatotoxicity | Grade | Anti-PD-1 (95% CI) | Anti-PD-L1 (95% CI) | P value |
|---|---|---|---|---|
| ALT increased | All | 6.01 (5.04−7.18) | 3.60 (2.72−4.76) | <0.001 |
| ≥Grade 3 | 1.54 (1.19−1.58) | 1.03 (0.71−1.51) | 0.002 | |
| AST increased | All | 6.84 (5.69−8.25) | 3.72 (2.82−4.94) | <0.001 |
| ≥Grade 3 | 1.48 (1.07−2.04) | 1.08 (0.80−1.45) | <0.001 | |
| Bilirubin increased | All | 1.36 (0.87−2.13) | 1.04 (0.70−1.54) | <0.001 |
| ≥Grade 3 | 0.63 (0.41−0.97) | 0.63 (0.40−1.00) | 0.294 | |
| ALP increased | All | 3.89 (2.71−5.58) | 1.64 (0.87−3.06) | <0.001 |
| ≥Grade 3 | 0.92 (0.59−1.43) | 0.74 (0.42−1.28) | 0.112 | |
| GGT increased | All | 1.66 (1.05−2.60) | 2.16 (1.30−3.59) | 0.405 |
| ≥Grade 3 | 1.18 (0.87−1.61) | 1.08 (0.69−1.68) | 0.649 | |
| Hepatobiliary disorders | All | 2.28 (1.70−3.07) | 2.22 (1.38−2.57) | 0.252 |
| ≥Grade 3 | 1.60 (1.22−2.10) | 1.55 (1.09−2.22) | 0.460 | |
| Ir-hepatitis | All | 1.17 (0.79−1.72) | 1.37 (0.80−2.33) | 0.043 |
| ≥Grade 3 | 0.96 (0.71−1.29) | 0.99 (0.60−1.65) | 0.047 |
Incidence of hepatotoxicity secondary from anti-PD-1 vs. anti-PD-L1.
ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; GGT, γ‐glutamyl transpeptidase; Ir-hepatitis, immune related hepatitis. Incidence differences between groups were tested with the Two-Proportions Z test.
Incidence of High-Grade Hepatotoxicity Across All Tumor Types
The incidence of ≥ grade 3 hepatotoxicity was reported as follows (Figure 2B and Table 1): elevated ALT in 94 studies with an incidence of 1.38% (95% CI 1.11 – 1.72); elevated AST in 96 studies with an incidence of 1.32% (95% CI 1.00 – 1.74); elevated bilirubin in 75 studies with an incidence of 0.62% (95% CI 0.43 – 0.88); elevated ALP in 49 studies with an incidence of 0.86% (95% CI 0.59 – 1.25); elevated GGT in 36 studies with an incidence of 0.98% (95% CI 0.69 – 1.38); hepatobiliary disorders in 100 studies with an incidence of 1.59% (95% CI 1.28 – 1.97); and ir-hepatitis in 89 studies with an incidence of 0.97% (95% CI 0.75 – 1.26). Across all studies, the anti-PD‐1 subgroup showed statistically higher incidence of ≥ grade 3 elevation of ALT/AST and ir-hepatitis in comparison with the anti-PD-L1 subgroup (p<0.05, Supplemental Figure S2B and Table 2).
Individual All-Grade Hepatoxicity in Primary Liver Cancers Compared to Other Cancer Types
Overall incidence of all grade elevated ALT from anti-PD-1 or anti-PD-L1 in patients with primary liver cancer was 14.22% (95% CI 9.93 – 20.36); elevated AST 13.30% (95% CI 11.10 – 16.00); elevated bilirubin 7.95% (95% CI 2.96 – 21.33); elevated ALP 2.30% (95% CI 1.10 – 4.83); elevated GGT 1.62% (95% CI 0.75 – 3.50), non-specific liver toxicity was 11.7% (95% CI 9.74 – 14.00); and ir-hepatitis 2.02 (95% CI 1.05 – 3.88) (Figure 3A and Supplemental Figure S3). Interestingly, the incidence of all-grade elevated ALT, AST and bilirubin, and hepatobiliary disorders was statistically higher in primary liver cancer versus other cancer types (p<0.001, Table 3), but not the elevation of ALP/GGT and ir-hepatitis.
Figure 3
Table 3
| Hepatotoxicity | Grade | Primary liver cancer (95% CI) | Other solid tumors (95% CI) | P value* |
|---|---|---|---|---|
| ALT increased | All | 13.3 (11.1−16.0) | 4.92 (4.21-5.76) | <0.001 |
| ≥Grade 3 | 4.57 (3.38−6.17) | 1.26 (1.02-1.56) | <0.001 | |
| AST increased | All | 14.2 (9.93−20.36) | 5.38 (4.52-5.76) | <0.001 |
| ≥Grade 3 | 6.74 (4.09−11.11) | 1.19 (0.95-1.48) | <0.001 | |
| Bilirubin increased | All | 7.95 (2.96−21.33) | 1.14 (0.81-1.57) | <0.001 |
| ≥Grade 3 | 5.95 (4.07−8.71) | 0.62 (0.48-0.79) | <0.001 | |
| ALP increased | All | 2.30 (1.10−4.83) | 3.21 (2.30-4.47) | 0.401 |
| ≥Grade 3 | 0.56 (0.08−3.95) | 0.87 (0.59-1.27) | 0.165 | |
| GGT increased | All | 1.62 (0.75−3.50) | 1.86 (1.31-2.65) | 0.801 |
| ≥Grade 3 | 1.11 (0.44−2.78) | 0.94 (0.64-1.37) | 0.384 | |
| Hepatobiliary disorders | All | 11.7 (9.74−14.0) | 2.13 (1.65-2.75) | <0.001 |
| ≥Grade 3 | 6.25 (4.83−8.07) | 1.57 (1.28-1.93) | <0.001 | |
| Ir-hepatitis | All | 2.02 (1.05−3.88) | 1.20 (0.87-1.66) | 0.866 |
| ≥Grade 3 | 1.27 (0.55−2.93) | 0.96 (0.73-1.25) | 0.768 |
Incidence of hepatotoxicity in primary liver cancers and other solid tumors treated with anti-PD-1/PD-L1.
ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; GGT, γ‐glutamyl transpeptidase; Ir-hepatitis, immune related hepatitis. *Incidence differences between groups were tested with the Two-Proportions Z test.
Individual High-Grade Hepatoxicity in Primary Liver Cancers Compared to Other Cancer Types
The incidence of ≥ grade 3 hepatotoxicity from anti-PD-1 or anti-PD-L1 in patients with primary liver cancers was as follows: elevated ALT 6.74% (95% CI 4.09 – 11.11); elevated AST 4.57% (95% CI 3.38 – 6.17); elevated bilirubin 5.95% (95% CI 4.07 – 8.71); elevated ALP 0.56% (95% CI 0.08 – 3.95); elevated GGT 1.11% (95% CI 0.44 – 2.78), hepatobiliary disorder 11.7% (95% CI 9.74 – 14.00); and ir-hepatitis 1.27 (95% CI 0.55 – 2.93) (Figure 3B and Supplemental Figure S4). Furthermore, the incidence of ≥ grade 3 elevated ALT, AST, bilirubin, and hepatobiliary disorders were significantly higher in primary liver cancers versus other cancer types (p<0.001, Table 3).
Discussion
In the present meta-analysis of all published phase 2 and 3 clinical trials of anti-PD-1 and anti-PD-L1 in patients with solid tumors, we reported the overall incidence of individual hepatotoxicity parameters secondary to treatment. There was an increased risk of all-grade and ≥ grade 3 ALT/AST elevation and ir-hepatitis when patients were treated with anti-PD-1 compared to anti-PD-L1. The overall incidence of all-grade and ≥ grade 3 elevated ALT, AST, bilirubin, and hepatobiliary disorders was increased in patients with primary liver cancer compared with other cancer types, treated with anti-PD-1/PD-L1, though incidence of reported ir-hepatitis was not significantly increased.
Hepatotoxicity triggered by ICI has been recognized as an important cause of morbidity and mortality and considered to be contributed by immune related mechanisms of action of ICIs. The elevation of ALT and AST is the earliest sign of liver injury. Hepatotoxicity can emerge days after ICI administration or be delayed by several months with a median onset ranging from 3 to 9 weeks (133). It commonly presents with isolated elevations of liver transaminases that can often subside after treatment discontinuation (133). Some severe cases are associated with other manifestations of liver dysfunction, e.g. coagulopathy, or even life-threatening liver failure. Previous meta-analyses have showed the incidence of all-grade liver toxicity induced by single agent of ICIs ranges from 2-37% (, , 134–136) and this incidence increases when ICIs are administrated in combination with anti-CTLA-4 monoclonal antibodies or traditional chemotherapy (, 136). In this study, we found that ALT and AST elevation were the most common presentation of all-grade treatment related hepatotoxicity with an incidence rate of 5.29% and 5.88%, respectively. There was a 1.24% incidence of reported all grade ir-hepatitis with high grade 0.97%. Other less common laboratory findings of liver toxicities included ALP elevation, hepatobiliary disorders, elevated bilirubin and GGT. The differences of reported incidence of hepatotoxicity from ICIs between this current study and previous results may be due to the substantial variations of terms used to report hepatotoxicity.
In addition, the anti-PD-1 treated patient population had higher incidence of all grade and ≥ grade 3 elevated ALT/AST and ir-hepatitis compared to anti-PD-L1. The causative mechanism is unclear. It has been proposed that the PD-L2 ligand may stimulate additional checkpoint signaling when anti-PD-L1 only targets PD-L1 versus anti-PD- blocks both PD-L1 and PD-L2 (135). Moreover, the anti-PD-1 executes an unselected T-Cell hyperactivation given generalized PD-1 expression on T cell membrane, that leads to potentially higher and more severe IRAEs than anti-PD-L1 (137). Furthermore, PD-1 expression is upregulated upon T cell activation and prevents the self-reactive and pathognomonic T cell activation (138). Therefore, the blockade of PD-1 by anti-PD-1 on dendric cells and other antigen-presenting cells could be relevant to worsen side effects than anti-PD-L1 (139). There are no head-to-head randomized clinical trials available to compare hepatotoxicity between anti-PD-1 and anti-PD-L1 inhibitors. Nevertheless, baseline liver dysfunction and primary or metastatic liver tumor burden in the trials may also contribute to these differences between trials using anti-PD-1 or anti-PD-L1.
Interestingly, in our study, there was a significantly higher incidence of elevated ALT/AST/bilirubin and hepatobiliary disorders in patients with primary liver cancers in comparison with other solid tumors. Although the majority of participants in the trials may or may not have abnormal liver function test results in the beginning with the background of liver disease, e.g. chronic viral hepatitis and cirrhosis, it is important to note that these underlying liver diseases may exacerbate/magnify the presentation of damaged liver functions after the administration of ICIs. Anti-PD-1/PD-L1 blocks the PD-1/PD-L1 pathway and activates T cells to target tumor antigens and kill tumors, but T cell activation may also be reactive against an antigen shared between normal tissue and tumors, that leads to normal organ injury (140). However, there is no consensus for the definition of drug induced ir-hepatitis related to ICI treatment in cancer. In our study, there was a significant percentage of missing information regarding ir-hepatitis. However, surrogate markers like elevated ALT/AST may be indication of ir-hepatitis and the incidence may be underestimated. This likely contributes to no difference seen between primary liver cancers and other solid tumors in incidence of ir-hepatitis.
The results of this analysis should be interpreted cautiously as there were several limitations to the study. First, there is publication bias given that the data was collected from published studies and only prevalent AEs were reported. For example, the incidence of > 5- 10% AEs were reported in the studies, dependent on the sample size of the trials. Since hepatotoxicity is not a common AE from ICIs, the information may not always be available for review. As a result, missing information can generate an overestimation of the incidence of hepatoxicity from ICIs. Second, potential co-founders were not reported in all publications. For instance, case numbers of liver metastasis for other solid tumors were missing. Metastatic liver lesions can result in hypoperfusion of normal liver tissues causing liver injury, which can be exacerbated by treatment caused by immune cell infiltration. Therefore, the incidence of liver toxicity directly contributed by ICIs in patients with solid tumors other than primary liver cancers could be inflated. Nevertheless, the hepatotoxicity derived from non-immune related factors is not able to be distinguished. Thirdly, the type and terms of reported hepatotoxicity were highly variable between trials, although every trial followed similar grading systems. Some studies reported hepatotoxicity as a whole labeled as one TRAEs or AE of interest, whereas others presented various laboratory liver function changes or clinical diagnoses like transaminitis and acute liver failure, or pathologic diagnoses like hepatocellular injury and liver injury. Moreover, there was significant variation or heterogeneity in the definition of hepatotoxicity across trials. Fourthly, the data was analyzed from published aggregated data and not from individual patients which is a common pitfall of meta-analysis data collection. It would be challenging to establish additional potential risk factors associated with the development of liver toxicity. Lastly, variations in the trial design, including eligibility criteria and phase of trial, can lead to selection bias. However, such a bias should not be significant because evaluation for hepatotoxicity was done with objective laboratory tests, rather than subjective AEs.
Conclusion
This analysis found that primary liver cancers are associated with a higher risk of all‐ and high‐grade hepatotoxicity compared to other solid cancer types. Additionally, we found that anti-PD‐1 therapy results in a higher risk of hepatotoxicity compared to anti-PD-L1.
Funding
Y-QX is sponsored by National Natural Science Foundation of China (Program Grants 81572665). CX is supported by NIH/NCI/CCR Physician-Scientist Early Investigator Program (ZIA BC 011888).
Statements
Data availability statement
The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author.
Author contributions
Conceptualization Y-QX, CX. Methodology JF, W-ZL, Y-QX, CX. Software JF, W-ZL. Validation Y-QX, CX. Formal analysis JF, W-ZL, CX. Investigation JF, WZ-L, NM, Y-QX, CX. Resources JF, WL, NM, CX. Data curation JF, W-ZL, NM, CX. Writing—original draft preparation JF, NM, CX. Writing—review and editing JF, W-ZL, NM, GB, CL, Y-QX, CX. Visualization Y-QX, CX. Supervision Y-QX, CX. Project administration NM, CX. Funding acquisition Y-QX, CX. All authors contributed to the article and approved the submitted version.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Supplementary material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2021.650292/full#supplementary-material
References
1
MathersCDLoncarD. Projections of global mortality and burden of disease from 2002 to 2030. PloS Med (2006) 3:e442. doi: 10.1371/journal.pmed.0030442
2
ArnoldMAbnetCCNealeREVignatJGiovannucciELMcGlynnKAet al. Global Burden of 5 Major Types Of Gastrointestinal Cancer. Gastroenterology (2020) 159:335–49. doi: 10.1053/j.gastro.2020.02.068
3
BrayFFerlayJSoerjomataramISiegelRLTorreLAJemalA. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin (2018) 68:394–424. doi: 10.3322/caac.21492
4
Barroso-SousaRBarryWTGarrido-CastroACHodiFSMinLKropIEet al. Incidence of Endocrine Dysfunction Following the Use of Different Immune Checkpoint Inhibitor Regimens: A Systematic Review and Meta-analysis. JAMA Oncol (2018) 4:173–82. doi: 10.1001/jamaoncol.2017.3064
5
MaKLuYJiangSet al. The Relative Risk and Incidence of Immune Checkpoint Inhibitors Related Pneumonitis in Patients With Advanced Cancer: A Meta-Analysis. Front Pharmacol (2018) 9:1430. doi: 10.3389/fphar.2018.01430
6
WangDYSalemJ-ECohenJVChandraSMenzerCYeFet al. Fatal Toxic Effects Associated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis. JAMA Oncol (2018) 4:1721–8. doi: 10.1001/jamaoncol.2018.3923
7
WangP-FChenYSongS-YWangT-JJiW-JLiS-Wet al. Immune-Related Adverse Events Associated with Anti-PD-1/PD-L1 Treatment for Malignancies: A Meta-Analysis. Front Pharmacol (2017) 8:730. doi: 10.3389/fphar.2017.00730
8
JenningsJJMandaliyaRNakshabandiALewisJH. Hepatotoxicity induced by immune checkpoint inhibitors: a comprehensive review including current and alternative management strategies. Expert Opin Drug Metab Toxicol (2019) 15:231–44. doi: 10.1080/17425255.2019.1574744
9
ParlatiLVallet-PichardABatistaRHernvannASogniPPolSet al. Incidence of grade 3-4 liver injury under immune checkpoints inhibitors: A retrospective study. J Hepatol (2018) 69:1396–7. doi: 10.1016/j.jhep.2018.08.014
10
AlessandrinoFTirumaniSHKrajewskiKMShinagareABJagannathanJPRamaiyaNHet al. Imaging of hepatic toxicity of systemic therapy in a tertiary cancer centre: chemotherapy, haematopoietic stem cell transplantation, molecular targeted therapies, and immune checkpoint inhibitors. Clin Radiol (2017) 72:521–33. doi: 10.1016/j.crad.2017.04.003
11
ChascsaDMRakelaJ. Knowns and Unknowns: the Safety and Efficacy of Cancer Immunotherapy in Chronic Liver Disease. Curr Hepatol Rep (2018) 17:153–5. doi: 10.1007/s11901-018-0408-8
12
WangWLiePGuoMHeJ. Risk of hepatotoxicity in cancer patients treated with immune checkpoint inhibitors: A systematic review and meta-analysis of published data. Int J Cancer (2017) 141:1018–28. doi: 10.1002/ijc.30678
13
PeeraphatditTWangJOdenwaldMAHuSHartJCharltonMR. Hepatotoxicity From Immune Checkpoint Inhibitors: A Systematic Review and Management Recommendation. Hepatology (2020) 72:315–29. doi: 10.1002/hep.31227
14
MillerEDAbu-SbeihHStyskelBNogueras GonzalezGMBlechaczBNaingAet al. Clinical Characteristics and Adverse Impact of Hepatotoxicity due to Immune Checkpoint Inhibitors. Off J Am Coll Gastroenterol | ACG (2020) 115:251–61. doi: 10.14309/ajg.0000000000000398
15
BorensteinMHedgesLVHigginsJPRothsteinHR. A basic introduction to fixed-effect and random-effects models for meta-analysis. Res Synth Methods (2010) 1:97–111. doi: 10.1002/jrsm.12
16
AdamsSLoiSToppmeyerDCesconDWDe LaurentiisMNandaRet al. Pembrolizumab monotherapy for previously untreated, PD-L1-positive, metastatic triple-negative breast cancer: cohort B of the phase II KEYNOTE-086 study. Ann Oncol (2019) 30:405–11. doi: 10.1093/annonc/mdy518
17
AdamsSSchmidPRugoHSWinerEPLoiratDAwadaAet al. Pembrolizumab monotherapy for previously treated metastatic triple-negative breast cancer: cohort A of the phase II KEYNOTE-086 study. Ann Oncol (2019) 30:397–404. doi: 10.1093/annonc/mdy517
18
AntoniaSJBalmanoukianABrahmerJOuSIHellmannMDKimSWet al. Clinical Activity, Tolerability, and Long-Term Follow-Up of Durvalumab in Patients With Advanced NSCLC. J Thorac Oncol (2019) 14:1794–806. doi: 10.1016/j.jtho.2019.06.010
19
AntoniaSJLópez-MartinJABendellJOttPATaylorMEderJPet al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol (2016) 17:883–95. doi: 10.1016/S1470-2045(16)30098-5
20
AntoniaSJVillegasADanielDVicenteDMurakamiSHuiRet al. Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med (2017) 377:1919–29. doi: 10.1056/NEJMoa1709937
21
AzadNSGrayRJOvermanMJSchoenfeldJDMitchellEPZwiebelJAet al. Nivolumab Is Effective in Mismatch Repair-Deficient Noncolorectal Cancers: Results From Arm Z1D-A Subprotocol of the NCI-MATCH (EAY131) Study. J Clin Oncol (2020) 38:214–22. doi: 10.1200/JCO.19.00818
22
BalarAVGalskyMDRosenbergJEPowlesTPetrylakDPBellmuntJet al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet (2017) 389:67–76. doi: 10.1016/S0140-6736(16)32455-2
23
BalarAVCastellanoDO’DonnellPHGrivasPVukyJPowlesTet al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol (2017) 18:1483–92. doi: 10.1016/S1470-2045(17)30616-2
24
BangYJKangYKCatenacciDVMuroKFuchsCSGevaRet al. Pembrolizumab alone or in combination with chemotherapy as first-line therapy for patients with advanced gastric or gastroesophageal junction adenocarcinoma: results from the phase II nonrandomized KEYNOTE-059 study. Gastric Cancer (2019) 22:828–37. doi: 10.1007/s10120-018-00909-5
25
BangYJVan CutsemEFuchsCSOhtsuATaberneroJIlsonDHet al. Phase III KEYNOTE-585 study of chemotherapy (Chemo) + pembrolizumab (Pembro) vs chemo + placebo as neoadjuvant/adjuvant treatment for patients (Pts) with gastric or gastroesophageal junction (G/GEJ) cancer. Ann Oncol (2018) 29:viii268. doi: 10.1093/annonc/mdy282.167
26
BarlesiFVansteenkisteJSpigelDIshiiHGarassinoMde MarinisFet al. Avelumab versus docetaxel in patients with platinum-treated advanced non-small-cell lung cancer (JAVELIN Lung 200): an open-label, randomised, phase 3 study. Lancet Oncol (2018) 19:1468–79. doi: 10.1016/S1470-2045(18)30673-9
27
BaumlJSeiwertTYPfisterDGWordenFLiuSVGilbertJet al. Pembrolizumab for platinum- and cetuximab-refractory head and neck cancer: Results from a single-arm, phase II study. J Clin Oncol (2017) 35:1542–9. doi: 10.1200/JCO.2016.70.1524
28
BaumlJMMickRCiunciCAggarwalCDavisCEvansTet al. Pembrolizumab after Completion of Locally Ablative Therapy for Oligometastatic Non-Small Cell Lung Cancer: A Phase 2 Trial. JAMA Oncol (2019) 5:1283–90. doi: 10.1001/jamaoncol.2019.1449
29
BellmuntJDe WitRVaughnDJFradetYLeeJLFongLet al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med (2017) 376:1015–26. doi: 10.1056/NEJMoa1613683
30
BorghaeiHPaz-AresLHornLSpigelDRSteinsMReadyNEet al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med (2015) 373:1627–39. doi: 10.1056/NEJMoa1507643
31
BrahmerJReckampKLBaasPCrinoLEberhardtWEPoddubskayaEet al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med (2015) 373:123–35. doi: 10.1056/NEJMoa1504627
32
BurtnessBHarringtonKJGreilRSoulieresDTaharaMde CastroGJret al. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet (2019) 394:1915–28. doi: 10.1016/S0140-6736(19)32591-7
33
CarboneDPReckMPaz-AresLCreelanBHornLSteinsMet al. First-line nivolumab in stage IV or recurrent non-small-cell lung cancer. N Engl J Med (2017) 376:2415–26. doi: 10.1056/NEJMoa1613493
34
ChungHCRosWDelordJPPeretsRItalianoAShapira-FrommerRet al. Efficacy and safety of pembrolizumab in previously treated advanced cervical cancer: Results from the phase II KEYNOTE-158 study. J Clin Oncol (2019) 37:1470–8. doi: 10.1200/JCO.18.01265
35
CohenEEWSoulièresDLe TourneauCDinisJLicitraLAhnMJet al. Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. Lancet (2019) 393:156–67.
36
D’AngeloSPMahoneyMRVan TineBAAtkinsJMilhemMMJahagirdarBNet al. Nivolumab with or without ipilimumab treatment for metastatic sarcoma (Alliance A091401): two open-label, non-comparative, randomised, phase 2 trials. Lancet Oncol (2018) 19:416–26. doi: 10.1016/S1470-2045(18)30006-8
37
DavisKLFoxEMerchantMSReidJMKudgusRALiuXet al. Nivolumab in children and young adults with relapsed or refractory solid tumours or lymphoma (ADVL1412): a multicentre, open-label, single-arm, phase 1–2 trial. Lancet Oncol (2020) 21:541–50. doi: 10.1016/S1470-2045(20)30023-1
38
EggermontAMMBlankCUMandalaMLongGVAtkinsonVDalleSet al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med (2018) 378:1789–801. doi: 10.1056/NEJMoa1802357
39
EngCKimTWBendellJArgilesGTebbuttNCDi BartolomeoMet al. Atezolizumab with or without cobimetinib versus regorafenib in previously treated metastatic colorectal cancer (IMblaze370): a multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol (2019) 20:849–61. doi: 10.1016/S1470-2045(19)30027-0
40
FehrenbacherLSpiraABallingerMKowanetzMVansteenkisteJMazieresJet al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): A multicentre, open-label, phase 2 randomised controlled trial. Lancet (2016) 387:1837–46. doi: 10.1016/S0140-6736(16)00587-0
41
FehrenbacherLvon PawelJParkKRittmeyerAGandaraDRPonce AixSet al. Updated Efficacy Analysis Including Secondary Population Results for OAK: A Randomized Phase III Study of Atezolizumab versus Docetaxel in Patients with Previously Treated Advanced Non–Small Cell Lung Cancer. J Thorac Oncol (2018) 13:1156–70. doi: 10.1016/j.jtho.2018.04.039
42
FelipEArdizzoniACiuleanuTCoboMLaktionovKSzilasiMet al. CheckMate 171: A phase 2 trial of nivolumab in patients with previously treated advanced squamous non-small cell lung cancer, including ECOG PS 2 and elderly populations. Eur J Cancer (2020) 127:160–72. doi: 10.1016/j.ejca.2019.11.019
43
FerrisRLBlumenscheinGFayetteJGuigayJColevasADLicitraLet al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med (2016) 375:1856–67. doi: 10.1056/NEJMoa1602252
44
FerrisRLHaddadREvenCTaharaMDvorkinMCiuleanuTEet al. Durvalumab with or without tremelimumab in patients with recurrent or metastatic head and neck squamous cell carcinoma: EAGLE, a randomized, open-label phase III study. Ann Oncol (2020) 31:942–50. doi: 10.1016/j.annonc.2020.04.001
45
FeunLGLiYYWuCWangpaichitrMJonesPDRichmanSPet al. Phase 2 study of pembrolizumab and circulating biomarkers to predict anticancer response in advanced, unresectable hepatocellular carcinoma. Cancer (2019) 125:3603–14. doi: 10.1002/cncr.32339
46
FinnRSRyooBYMerlePKudoMBouattourMLimHYet al. Pembrolizumab As Second-Line Therapy in Patients With Advanced Hepatocellular Carcinoma in KEYNOTE-240: A Randomized, Double-Blind, Phase III Trial. J Clin Oncol (2020) 38:193–202. doi: 10.1200/JCO.19.01307
47
FuchsCSDoiTJangRWMuroKSatohTMachadoMet al. Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: Phase 2 clinical KEYNOTE-059 trial. JAMA Oncol (2018) 4:e180013. doi: 10.1001/jamaoncol.2018.0013
48
GadgeelSMPennellNAFidlerMJHalmosBBonomiPStevensonJet al. Phase II Study of Maintenance Pembrolizumab in Patients with Extensive-Stage Small Cell Lung Cancer (SCLC). J Thorac Oncol (2018) 13:1393–9. doi: 10.1016/j.jtho.2018.05.002
49
GalskyMDMortazaviAMilowskyMIGeorgeSGuptaSFlemingMTet al. Randomized Double-Blind Phase II Study of Maintenance Pembrolizumab Versus Placebo After First-Line Chemotherapy in Patients With Metastatic Urothelial Cancer. J Clin Oncol (2020) 38:1797–806. doi: 10.1200/JCO.19.03091
50
GarassinoMCChoBCKimJHMazieresJVansteenkisteJLenaHet al. Durvalumab as third-line or later treatment for advanced non-small-cell lung cancer (ATLANTIC): an open-label, single-arm, phase 2 study. Lancet Oncol (2018) 19:521–36. doi: 10.1016/S1470-2045(18)30144-X
51
GeoergerBKangHJYalon-OrenMMarshallLVVezinaCPappoAet al. Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1–2 trial. Lancet Oncol (2020) 21:121–33. doi: 10.1016/S1470-2045(19)30671-0
52
GeoergerBZwaanCMMarshallLVMichonJBourdeautFCasanovaMet al. Atezolizumab for children and young adults with previously treated solid tumours, non-Hodgkin lymphoma, and Hodgkin lymphoma (iMATRIX): a multicentre phase 1-2 study. Lancet Oncol (2020) 21:134–44. doi: 10.1016/S1470-2045(19)30693-X
53
GiacconeGKimCThompsonJMcGuireCKallakuryBChahineJJet al. Pembrolizumab in patients with thymic carcinoma: a single-arm, single-centre, phase 2 study. Lancet Oncol (2018) 19:347–55. doi: 10.1016/S1470-2045(18)30062-7
54
GoldbergSBSchalperKAGettingerSNMahajanAHerbstRSChiangACet al. Pembrolizumab for management of patients with NSCLC and brain metastases: long-term results and biomarker analysis from a non-randomised, open-label, phase 2 trial. Lancet Oncol (2020) 21:655–63. doi: 10.1016/S1470-2045(20)30111-X
55
HamanishiJMandaiMIkedaTMinamiMKawaguchiAMurayamaTet al. Safety and antitumor activity of Anti-PD-1 antibody, nivolumab, in patients with platinum-resistant ovarian cancer. J Clin Oncol (2015) 33:4015–22. doi: 10.1200/JCO.2015.62.3397
56
HamidOPuzanovIDummerRSchachterJDaudASchadendorfDet al. Final analysis of a randomised trial comparing pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory advanced melanoma. Eur J Cancer (2017) 86:37–45. doi: 10.1016/j.ejca.2017.07.022
57
HellmannMDCiuleanuTEPluzanskiALeeJSOttersonGAAudigier-ValetteCet al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med (2018) 378:2093–104. doi: 10.1056/NEJMoa1801946
58
HerbstRSBaasPKimDWFelipEPerez-GraciaJLHanJYet al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet (2016) 387:1540–50. doi: 10.1016/S0140-6736(15)01281-7
59
HidaTNishioMNogamiNOheYNokiharaHSakaiHet al. Efficacy and safety of nivolumab in Japanese patients with advanced or recurrent squamous non-small cell lung cancer. Cancer Sci (2017) 108:1000–6. doi: 10.1111/cas.13225
60
KangYKBokuNSatohTRyuMHChaoYKatoKet al. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet (2017) 390:2461–71. doi: 10.1016/S0140-6736(17)31827-5
61
KatoKChoBCTakahashiMOkadaMLinCYChinKet al. Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol (2019) 20:1506–17. doi: 10.1016/S1470-2045(19)30626-6
62
KaufmanHLRussellJHamidOBhatiaSTerheydenPD'AngeloSPet al. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. Lancet Oncol (2016) 17:1374–85. doi: 10.1016/S1470-2045(16)30364-3
63
KellyRJLeeJBangYJAlmhannaKBlum-MurphyMCatenacciDVTet al. Safety and efficacy of durvalumab and tremelimumab alone or in combination in patients with advanced gastric and gastroesophageal junction adenocarcinoma. Clin Cancer Res (2020) 26:846–54. doi: 10.1158/1078-0432.CCR-19-2443
64
KimJHKimSYBaekJYChaYJAhnJBKimHSet al. A Phase II Study of Avelumab Monotherapy in Patients with Mismatch Repair-Deficient/Microsatellite Instability-High or POLE-Mutated Metastatic or Unresectable Colorectal Cancer. Cancer Res Treat (2020) 52:1135–44. doi: 10.4143/crt.2020.218
65
KimRDChungVAleseOBEl-RayesBFLiDAl-ToubahTEet al. A Phase 2 Multi-institutional Study of Nivolumab for Patients With Advanced Refractory Biliary Tract Cancer. JAMA Oncol (2020) 6:888–94. doi: 10.1001/jamaoncol.2020.0930
66
KlugerHMChiangVMahajanAZitoCRSznolMTranTet al. Long-term survival of patients with melanoma with active brain metastases treated with pembrolizumab on a phase II trial. J Clin Oncol (2019) 37:52–60. doi: 10.1200/JCO.18.00204
67
KonstantinopoulosPALuoWLiuJFGulhanDCKrasnerCIshizukaJJet al. Phase II study of avelumab in patients with mismatch repair deficient and mismatch repair proficient recurrent/persistent endometrial cancer. J Clin Oncol (2019) 37:2786–94. doi: 10.1200/JCO.19.01021
68
KudoTHamamotoYKatoKUraTKojimaTTsushimaTet al. Nivolumab treatment for oesophageal squamous-cell carcinoma: an open-label, multicentre, phase 2 trial. Lancet Oncol (2017) 18:631–9. doi: 10.1016/S1470-2045(17)30181-X
69
LarkinJMinorDD’AngeloSNeynsBSmylieMMillerWHJr.et al. Overall Survival in Patients With Advanced Melanoma Who Received Nivolumab Versus Investigator’s Choice Chemotherapy in CheckMate 037: A Randomized, Controlled, Open-Label Phase III Trial. J Clin Oncol (2018) 36:383–+. doi: 10.1200/JCO.2016.71.8023
70
LeDTUramJNWangHBartlettBRKemberlingHEyringADet al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med (2015) 372:2509–20. doi: 10.1056/NEJMoa1500596
71
LeeJSLeeKHChoEKKimDWKimSWKimJHet al. Nivolumab in advanced non-small-cell lung cancer patients who failed prior platinum-based chemotherapy. Lung Cancer (2018) 122:234–42. doi: 10.1016/j.lungcan.2018.05.023
72
LevyBPGiacconeGBesseBFelipEGarassinoMCDomine GomezMet al. Randomised phase 2 study of pembrolizumab plus CC-486 versus pembrolizumab plus placebo in patients with previously treated advanced non-small cell lung cancer. Eur J Cancer (2019) 108:120–8. doi: 10.1016/j.ejca.2018.11.028
73
LongGVAtkinsonVLoSSandhuSGuminskiADBrownMPet al. Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases: a multicentre randomised phase 2 study. Lancet Oncol (2018) 19:672–81. doi: 10.1016/S1470-2045(18)30139-6
74
LongGVDummerRHamidOGajewskiTFCaglevicCDalleSet al. Epacadostat plus pembrolizumab versus placebo plus pembrolizumab in patients with unresectable or metastatic melanoma (ECHO-301/KEYNOTE-252): a phase 3, randomised, double-blind study. Lancet Oncol (2019) 20:1083–97. doi: 10.1016/S1470-2045(19)30274-8
75
MaBBYLimWTGohBCHuiEPLoKWPettingerAet al. Antitumor Activity of Nivolumab in Recurrent and Metastatic Nasopharyngeal Carcinoma: An International, Multicenter Study of the Mayo Clinic Phase 2 Consortium (NCI-9742). J Clin Oncol (2018) 36:1412–8. doi: 10.1200/JCO.2017.77.0388
76
MatulonisUAShapira-FrommerRSantinADLisyanskayaASPignataSVergoteIet al. Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: results from the phase II KEYNOTE-100 study. Ann Oncol (2019) 30:1080–7. doi: 10.1093/annonc/mdz135
77
McDermottDFHuseniMAAtkinsMBMotzerRJRiniBIEscudierBet al. Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma. Nat Med (2018) 24:749–57. doi: 10.1038/s41591-018-0053-3
78
MiddletonGBrockKSavageJMantRSummersYConnibearJet al. Pembrolizumab in patients with non-small-cell lung cancer of performance status 2 (PePS2): a single arm, phase 2 trial. Lancet Respir Med (2020) 8:895–904. doi: 10.1016/S2213-2600(20)30033-3
79
MokTSKWuYLKudabaIKowalskiDMChoBCTurnaHZet al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet (2019) 393:1819–30. doi: 10.1016/S0140-6736(18)32409-7
80
MorrisVKSalemMENimeiriHIqbalSSinghPCiomborKet al. Nivolumab for previously treated unresectable metastatic anal cancer (NCI9673): a multicentre, single-arm, phase 2 study. Lancet Oncol (2017) 18:446–53. doi: 10.1016/S1470-2045(17)30104-3
81
MotzerRJEscudierBMcDermottDFGeorgeSHammersHJSrinivasSet al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med (2015) 373:1803–13. doi: 10.1056/NEJMoa1510665
82
MotzerRJRiniBIMcDermottDFAren FronteraOHammersHJCarducciMAet al. Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial. Lancet Oncol (2019) 20:1370–85. doi: 10.1016/S1470-2045(19)30413-9
83
NaingAMeric-BernstamFStephenBKarpDDHajjarJRodon AhnertJet al. Phase 2 study of pembrolizumab in patients with advanced rare cancers. J Immunother Cancer (2020) 8(1):e000347. doi: 10.1136/jitc-2019-000347corr1
84
NathanPAsciertoPAHaanenJEspinosaEDemidovLGarbeCet al. Safety and efficacy of nivolumab in patients with rare melanoma subtypes who progressed on or after ipilimumab treatment: a single-arm, open-label, phase II study (CheckMate 172). Eur J Cancer (2019) 119:168–78. doi: 10.1016/j.ejca.2019.07.010
85
NghiemPBhatiaSLipsonEJSharfmanWHKudchadkarRRBrohlASet al. Durable tumor regression and overall survival in patients with advanced Merkel cell carcinoma receiving pembrolizumab as first-line therapy. J Clin Oncol (2019) 37:693–702. doi: 10.1200/JCO.18.01896
86
NghiemPTBhatiaSLipsonEJKudchadkarRRMillerNJAnnamalaiLet al. PD-1 blockade with pembrolizumab in advanced merkel-cell carcinoma. N Engl J Med (2016) 374:2542–52. doi: 10.1056/NEJMoa1603702
87
NishioMHidaTAtagiSSakaiHNakagawaKTakahashiTet al. Multicentre phase II study of nivolumab in Japanese patients with advanced or recurrent non-squamous non-small cell lung cancer. Esmo Open (2017) 2(4):e000108. doi: 10.1136/esmoopen-2016-000108
88
NomuraMOzeIMasuishiTYokotaTSatakeHIwasawaSet al. Multicenter prospective phase II trial of nivolumab in patients with unresectable or metastatic mucosal melanoma. Int J Clin Oncol (2020) 25:972–7. doi: 10.1007/s10147-020-01618-9
89
O’ReillyEMOhDYDhaniNRenoufDJLeeMASunWet al. Durvalumab with or Without Tremelimumab for Patients with Metastatic Pancreatic Ductal Adenocarcinoma: A Phase 2 Randomized Clinical Trial. JAMA Oncol (2019) 5:1431–8. doi: 10.1001/jamaoncol.2019.1588
90
OkadaMKijimaTAoeKKatoTFujimotoNNakagawaKet al. Clinical efficacy and safety of nivolumab: Results of a multicenter, open-label, single-arm, Japanese phase II study in malignant pleural mesothelioma (MERIT). Clin Cancer Res (2019) 25:5485–92. doi: 10.1158/1078-0432.CCR-19-0103
91
OttPABangYJBerton-RigaudDElezEPishvaianMJRugoHSet al. Safety and Antitumor Activity of Pembrolizumab in Advanced Programmed Death Ligand 1-Positive Endometrial Cancer: Results From the KEYNOTE-028 Study. Obstet Gynecol Surv (2018) 73:26–7. doi: 10.1097/01.ogx.0000527579.58363.20
92
OvermanMJMcDermottRLeachJLLonardiSLenzHJMorseMAet al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol (2017) 18:1182–91. doi: 10.1016/S1470-2045(17)30422-9
93
PalSKHoffman-CensitsJZhengHZKaiserCTayamaDBellmuntJ. Atezolizumab in Platinum-treated Locally Advanced or Metastatic Urothelial Carcinoma: Clinical Experience from an Expanded Access Study in the United States. Eur Urol (2018) 73:800–6. doi: 10.1016/j.eururo.2018.02.010
94
PetersSGettingerSJohnsonMLJannePAGarassinoMCChristophDet al. Phase II Trial of Atezolizumab As First-Line or Subsequent Therapy for Patients With Programmed Death-Ligand 1-Selected Advanced Non-Small-Cell Lung Cancer (BIRCH). J Clin Oncol (2017) 35:2781–+. doi: 10.1200/JCO.2016.71.9476
95
PlanchardDReinmuthNOrlovSFischerJRSugawaraSMandziukSet al. ARCTIC: durvalumab with or without tremelimumab as third-line or later treatment of metastatic non-small-cell lung cancer. Ann Oncol (2020) 31:609–18. doi: 10.1016/j.annonc.2020.02.006
96
PowlesTDuranIvan der HeijdenMSLoriotYVogelzangNJDe GiorgiUet al. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet (2018) 391:748–57. doi: 10.1016/S0140-6736(17)33297-X
97
PowlesTKockxMRodriguez-VidaADuranICrabbSJVan Der HeijdenMSet al. Clinical efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial. Nat Med (2019) 25:1706–14. doi: 10.1038/s41591-019-0628-7
98
PujolJLGreillierLAudigier ValetteCMoro-SibilotDUwerLHureauxJet al. A randomized non-comparative phase II study of anti-PD-L1 ATEZOLIZUMAB or chemotherapy as second-line therapy in patients with small cell lung cancer: Results from the IFCT-1603 trial. Ann Oncol (2018) 29:viii596. doi: 10.1016/j.jtho.2019.01.008
99
RajNZhengYKellyVKatzSSChouJDoRKGet al. PD-1 blockade in advanced adrenocortical carcinoma. J Clin Oncol (2020) 38:71–80. doi: 10.1200/JCO.19.01586
100
ReckMRodríguez-AbreuDRobinsonAGHuiRCsosziTFulopAet al. Updated analysis of KEYNOTE-024: Pembrolizumab versus platinum-based chemotherapy for advanced non–small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J Clin Oncol (2019) 37:537–46. doi: 10.1200/JCO.18.00149
101
RizviNAChoBCReinmuthNLeeKHLuftAAhnMJet al. Durvalumab with or without Tremelimumab vs Standard Chemotherapy in First-line Treatment of Metastatic Non-Small Cell Lung Cancer: The MYSTIC Phase 3 Randomized Clinical Trial. JAMA Oncol (2020), E1–E14. doi: 10.1001/jamaoncol.2020.0237
102
RizviNAMazièresJPlanchardDStinchcombeTEDyGKAntoniaSJet al. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol (2015) 16:257–65. doi: 10.1016/S1470-2045(15)70054-9
103
RobertCLongGVBradyBDutriauxCMaioMMortierLet al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med (2015) 372:320–30. doi: 10.1056/NEJMoa1412082
104
RobertCSchachterJLongGVAranceAGrobJJMortierLet al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med (2015) 372:2521–32. doi: 10.1056/NEJMoa1503093
105
RosenbergJEHoffman-CensitsJPowlesTvan der HeijdenMSBalarAVNecchiAet al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: A single-arm, multicentre, phase 2 trial. Lancet (2016) 387:1909–20. doi: 10.1016/S0140-6736(16)00561-4
106
ScherpereelAMazieresJGreillierLLantuejoulSDoPBylickiOet al. Nivolumab or nivolumab plus ipilimumab in patients with relapsed malignant pleural mesothelioma (IFCT-1501 MAPS2): a multicentre, open-label, randomised, non-comparative, phase 2 trial. Lancet Oncol (2019) 20:239–53. doi: 10.1016/S1470-2045(18)30765-4
107
SegalNHOuSHIBalmanoukianAFuryMGMassarelliEBrahmerJRet al. Safety and efficacy of durvalumab in patients with head and neck squamous cell carcinoma: results from a phase I/II expansion cohort. Eur J Cancer (2019) 109:154–61. doi: 10.1016/j.ejca.2018.12.029
108
ShahMAKojimaTHochhauserDEnzingerPRaimbourgJHollebecqueAet al. Efficacy and Safety of Pembrolizumab for Heavily Pretreated Patients with Advanced, Metastatic Adenocarcinoma or Squamous Cell Carcinoma of the Esophagus: The Phase 2 KEYNOTE-180 Study. JAMA Oncol (2019) 5:546–50. doi: 10.1001/jamaoncol.2018.5441
109
SharmaPCallahanMKBonoPKimJSpiliopoulouPCalvoEet al. Nivolumab monotherapy in recurrent metastatic urothelial carcinoma (CheckMate 032): a multicentre, open-label, two-stage, multi-arm, phase 1/2 trial. Lancet Oncol (2016) 17:1590–8. doi: 10.1016/S1470-2045(16)30496-X
110
SharmaPRetzMSiefker-RadtkeABaronANecchiABedkeJet al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol (2017) 18:312–22. doi: 10.1016/S1470-2045(17)30065-7
111
ShitaraKÖzgüroğluMBangYJDi BartolomeoMMandalaMRyuMHet al. KEYNOTE-061: Phase 3 study of pembrolizumab vs paclitaxel for previously treated advanced gastric or gastroesophageal junction (G/GEJ) cancer. Ann Oncol (2018) 29:v123. doi: 10.1093/annonc/mdy208.004
112
SiuLLEvenCMesiaRRemenarEDasteADelordJPet al. Safety and Efficacy of Durvalumab With or Without Tremelimumab in Patients With PD-L1-Low/Negative Recurrent or Metastatic HNSCC: The Phase 2 CONDOR Randomized Clinical Trial. JAMA Oncol (2019) 5:195–203. doi: 10.1001/jamaoncol.2018.4628
113
SpigelDRChaftJEGettingerSChaoBHDirixLSchmidPet al. FIR: Efficacy, Safety, and Biomarker Analysis of a Phase II Open-Label Study of Atezolizumab in PD-L1–Selected Patients With NSCLC. J Thorac Oncol (2018) 13:1733–42. doi: 10.1016/j.jtho.2018.05.004
114
SternbergCNLoriotYJamesNChoyECastellanoDLopez-RiosFet al. Primary Results from SAUL, a Multinational Single-arm Safety Study of Atezolizumab Therapy for Locally Advanced or Metastatic Urothelial or Nonurothelial Carcinoma of the Urinary Tract. Eur Urol (2019) 76:73–81. doi: 10.1016/j.eururo.2019.03.015
115
StrosbergJRMizunoNDoiTGrandeEDelordJPShapira-FrommerRet al. Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Neuroendocrine Tumors: Results From the Phase 2 KEYNOTE-158 Study. Clin Cancer Res (2020) 26:2124–30. doi: 10.1158/1078-0432.CCR-19-3014
116
TamuraKHasegawaKKatsumataNMatsumotoKMukaiHTakahashiSet al. Efficacy and safety of nivolumab in Japanese patients with uterine cervical cancer, uterine corpus cancer, or soft tissue sarcoma: Multicenter, open-label phase 2 trial. Cancer Science (2019) 110:2894–904. doi: 10.1111/cas.14148
117
TawbiHABurgessMBolejackVVan TineBASchuetzeSMHuJet al. Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial. Lancet Oncol (2017) 18:1493–501. doi: 10.1016/S1470-2045(17)30624-1
118
TheelenWSMEPeulenHMULalezariFvan der NoortVde VriesJFAertsJet al. Effect of Pembrolizumab after Stereotactic Body Radiotherapy vs Pembrolizumab Alone on Tumor Response in Patients with Advanced Non-Small Cell Lung Cancer: Results of the PEMBRO-RT Phase 2 Randomized Clinical Trial. JAMA Oncol (2019) 5:1276–82. doi: 10.1001/jamaoncol.2019.1478
119
VargaAPiha-PaulSOttPAMehnertJMBerton-RigaudDMoroskyAet al. Pembrolizumab in patients with programmed death ligand 1–positive advanced ovarian cancer: Analysis of KEYNOTE-028. Gynecol Oncol (2019) 152:243–50. doi: 10.1016/j.ygyno.2018.11.017
120
VijayvergiaNDasariADengMLitwinSAl-ToubahTAlpaughRKet al. Pembrolizumab monotherapy in patients with previously treated metastatic high-grade neuroendocrine neoplasms: joint analysis of two prospective, non-randomised trials. Br J Cancer (2020) 122:1309–14. doi: 10.1038/s41416-020-0775-0
121
VoorwerkLSlagterMHorlingsHMSikorskaKvan de VijverKKde MaakerMet al. Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial. Nat Med (2019) 25:920–8. doi: 10.1038/s41591-019-0432-4
122
WeberJMandalaMDel VecchioMGogasHJAranceAMCoweyCLet al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med (2017) 377:1824–35. doi: 10.1056/NEJMoa1709030
123
WolchokJDChiarion-SileniVGonzalezRRutkowskiPGrobJJCoweyCLet al. Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med (2017) 377:1345–56. doi: 10.1056/NEJMoa1709684
124
WuYLLuSChengYZhouCWangJMokTet al. Nivolumab Versus Docetaxel in a Predominantly Chinese Patient Population With Previously Treated Advanced NSCLC: CheckMate 078 Randomized Phase III Clinical Trial. J Thorac Oncol (2019) 14:867–75. doi: 10.1016/j.jtho.2019.01.006
125
YamazakiNKiyoharaYUharaHIizukaHUeharaJOtsukaFet al. Cytokine biomarkers to predict antitumor responses to nivolumab suggested in a phase 2 study for advanced melanoma. Cancer Science (2017) 108:1022–31. doi: 10.1111/cas.13226
126
YamazakiNKiyoharaYUharaHUeharaJFujisawaYTakenouchiTet al. Long-term follow up of nivolumab in previously untreated Japanese patients with advanced or recurrent malignant melanoma. Cancer Science (2019) 110:1995–2003. doi: 10.1111/cas.14015
127
ZamarinDBurgerRASillMWPowellDJJr.LankesHAFeldmanMDet al. Randomized Phase II Trial of Nivolumab Versus Nivolumab and Ipilimumab for Recurrent or Persistent Ovarian Cancer: An NRG Oncology Study. J Clin Oncol (2020). 38:1814–23. doi: 10.1200/JCO.19.02059
128
ZandbergDPAlgaziAPJimenoAGoodJSFayetteJBouganimNet al. Durvalumab for recurrent or metastatic head and neck squamous cell carcinoma: Results from a single-arm, phase II study in patients with ≥25% tumour cell PD-L1 expression who have progressed on platinum-based chemotherapy. Eur J Cancer (2019) 107:142–52. doi: 10.1016/j.ejca.2018.11.015
129
ZhuAXFinnRSEdelineJCattanSOgasawaraSPalmerDet al. Pembrolizumab in patients with previously treated advanced hepatocellular carcinoma: Phase 2 KEYNOTE-224 study. Ann Oncol (2016) 27:vi242. doi: 10.1016/S1470-2045(18)30351-6
130
YauTKangYKKimTYEl-KhoueiryABSantoroASangroBet al. Nivolumab (NIVO) plus ipilimumab (IPI) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): Results from CheckMate 040. J Clin Oncol (2019) 37(15_suppl):4012–2. doi: 10.1200/JCO.2019.37.15_suppl.4012
131
YauTParkJWFinnRSChengALMathurinPEdelineJet al. CheckMate 459: A randomized, multi-center phase III study of nivolumab (NIVO) vs sorafenib (SOR) as first-line (1L) treatment in patients (pts) with advanced hepatocellular carcinoma (aHCC). Ann Oncol (2019) 30(Supple_5):V874–5. doi: 10.1093/annonc/mdz394.029
132
El-KhoueiryABSangroBYauTCrocenziTSKudoMHsuCet al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet (2017) 389:2492–502. doi: 10.1016/S0140-6736(17)31046-2
133
MartinsFSofiyaLSykiotisGPLamineFMaillardMFragaMet al. Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat Rev Clin Oncol (2019) 16:563–80. doi: 10.1038/s41571-019-0218-0
134
ShahNPuthiamadathilJSerzanMTBeloualiAKellyWJMaBet al. 1222P - Clinical outcome of immune related hepatitis (IrHep) in patients with advanced melanoma (AM) treated with single agent or combination immune checkpoint inhibitors (ICIs). Ann Oncol (2018) 29:viii433–4. doi: 10.1093/annonc/mdy288.093
135
WangYZhouSYangFQiXWangXGuanXet al. Treatment-Related Adverse Events of PD-1 and PD-L1 Inhibitors in Clinical Trials: A Systematic Review and Meta-analysis. JAMA Oncol (2019) 5:1008–19. doi: 10.1001/jamaoncol.2019.0393
136
DaLTengYWangNZaguirreKLiuYQiYet al. Organ-Specific Immune-Related Adverse Events Associated With Immune Checkpoint Inhibitor Monotherapy Versus Combination Therapy in Cancer: A Meta-Analysis of Randomized Controlled Trials. Front Pharmacol (2019) 10:1671. doi: 10.3389/fphar.2019.01671
137
WeinmannSCPisetskyDS. Mechanisms of immune-related adverse events during the treatment of cancer with immune checkpoint inhibitors. Rheumatology (Oxford) (2019) 58:vii59–67. doi: 10.1093/rheumatology/kez308
138
RosskopfSJahn-SchmidBSchmettererKGZlabingerGJSteinbergerP. PD-1 has a unique capacity to inhibit allergen-specific human CD4+ T cell responses. Sci Rep (2018) 8:13543. doi: 10.1038/s41598-018-31757-z
139
BrownJADorfmanDMMaF-RSullivanELMunozOWoodCRet al. Blockade of Programmed Death-1 Ligands on Dendritic Cells Enhances T Cell Activation and Cytokine Production. J Immunol (2003) 170:1257–66. doi: 10.4049/jimmunol.170.3.1257
140
PostowMASidlowRHellmannMD. Immune-Related Adverse Events Associated with Immune Checkpoint Blockade. N Engl J Med (2018) 378:158–68. doi: 10.1056/NEJMra1703481
Summary
Keywords
immune checkpoint inhibitor, hepatotoxicity, primary liver cancer, PD-1, immune-related hepatitis
Citation
Fu J, Li W-Z, McGrath NA, Lai CW, Brar G, Xiang Y-Q and Xie C (2021) Immune Checkpoint Inhibitor Associated Hepatotoxicity in Primary Liver Cancer Versus Other Cancers: A Systematic Review and Meta‐Analysis. Front. Oncol. 11:650292. doi: 10.3389/fonc.2021.650292
Received
06 January 2021
Accepted
29 March 2021
Published
21 April 2021
Volume
11 - 2021
Edited by
Bastian Schilling, University Hospital Würzburg, Germany
Reviewed by
Othmar Schoeb, Clinic Hirslanden Zurich, Switzerland; Jifeng Zhang, University of Michigan, United States
Updates
Copyright
© 2021 Fu, Li, McGrath, Lai, Brar, Xiang and Xie.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Changqing Xie, changqing.xie@nih.gov
†These authors have contributed equally to this work
This article was submitted to Cancer Immunity and Immunotherapy, a section of the journal Frontiers in Oncology
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.