Adverse events of immune checkpoint inhibitors in advanced hepatocellular carcinoma and their prognostic significance

2021 ◽  
Author(s):  
Markus Wilhelmi
Keyword(s):  
Hepatocellular Carcinoma ◽  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Prognostic Significance ◽  
Advanced Hepatocellular Carcinoma

scholarly journals Impact of Immune-Related Adverse Events on Efficacy of Immune Checkpoint Inhibitors in Patients with Advanced Hepatocellular Carcinoma

Liver Cancer ◽  
2021 ◽  
pp. 1-13
Author(s):  
Kennedy Yao Yi Ng ◽  
Sze Huey Tan ◽  
Jack Jie En Tan ◽  
Desiree Shu Hui Tay ◽  
Ailica Wan Xin Lee ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Multivariable Analysis ◽  
Primary Study ◽  
Advanced Hepatocellular Carcinoma ◽  
Systemic Corticosteroids ◽  
Grade 3

<b><i>Introduction:</i></b> Development of immune-related adverse events (irAEs) has been associated with enhanced efficacy with the use of immune checkpoint inhibitors (ICIs). It remains unknown whether such an association exists in advanced hepatocellular carcinoma (aHCC). This study aims to evaluate the association between irAEs and ICI efficacy in patients with aHCC. <b><i>Methods:</i></b> We performed a retrospective cohort study on patients with aHCC who received at least one dose of an ICI between May 2015 and November 2019 at the National Cancer Centre Singapore. The primary study objectives were to compare the overall survival (OS) and progression-free survival (PFS) between patients with and without irAEs. Complementary multivariable landmark analyses were performed at the 6-week and 12-week landmarks. Data cutoff was December 31, 2020. <b><i>Results:</i></b> One hundred and sixty-eight patients were included. Median age was 69 years, 85.7% were male, 57.7% had hepatitis B infection, 60.7% had ECOG 0, and 78.0% had Child-Pugh A liver cirrhosis. 82.7% received ICI monotherapy, while 17.3% received ICI in combination. Development and severity of irAE were correlated with survival. The median PFS for grade ≥3 irAE versus grades 1–2 irAE versus no irAE was 8.5 versus 3.6 versus 1.3 mths (<i>p</i> &#x3c; 0.001). The median OS for grade ≥3 irAE versus grades 1–2 irAE versus no irAE was 26.9 versus 14.0 versus 4.6 mths (<i>p</i> &#x3c; 0.001). Patients with ≥2 irAEs had a significantly longer OS on multivariable analysis (adjusted hazard ratio [aHR]0.35, <i>p</i> &#x3c; 0.001). The presence of grade ≥3 irAEs was associated with a significantly longer OS on the multivariable analysis at the 6-week landmark (aHR0.34, <i>p</i> = 0.030) and 12-week landmark (aHR0.28, <i>p</i> = 0.011). The use of systemic corticosteroids in patients with irAE was associated with a trend toward a longer OS (20.7 vs. 14.3 mths, <i>p</i> = 0.064). <b><i>Conclusion:</i></b> Our study suggests that the presence of all-grade irAEs may be a potential prognostic biomarker in patients with aHCC treated with ICI. Patients with more severe irAEs and multisystem involvement have better prognosis. The prompt use of systemic corticosteroids to treat patients with irAEs is key to ensure the best long-term outcomes for these patients.

scholarly journals Ipilimumab and nivolumab/pembrolizumab in advanced hepatocellular carcinoma refractory to prior immune checkpoint inhibitors

2021 ◽  
Vol 9 (2) ◽  
pp. e001945 ◽  
Author(s):  
Jeffrey Sum Lung Wong ◽  
Gerry Gin Wai Kwok ◽  
Vikki Tang ◽  
Bryan Cho Wing Li ◽  
Roland Leung ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Acquired Resistance ◽  
Survival Rates ◽  
Advanced Hepatocellular Carcinoma ◽  
Primary Resistance ◽  
Advanced Hcc

BackgroundProgrammed cell death protein 1 (PD-1) pathway blockade with immune checkpoint inhibitors (ICIs) is a standard therapy in advanced hepatocellular carcinoma (HCC) nowadays. No strategies to overcome ICI resistance have been described. We aimed to evaluate the use of ipilimumab and anti-PD-1 ICIs (nivolumab or pembrolizumab) combinations in patients with advanced HCC with progression on prior ICIs.MethodsPatients with advanced HCC with documented tumor progression on prior ICIs and subsequently received ipilimumab with nivolumab/pembrolizumab were analyzed. Objective response rate (ORR), median duration of response (DOR), time-to-progression (TTP), overall survival (OS), and treatment-related adverse events (TRAEs) were assessed.ResultsTwenty-five patients were included. The median age was 62 (range: 51–83). About 68% were of Child-Pugh (CP) Grade A and 48% had primary resistance to prior ICI. At median follow-up of 37.7 months, the ORR was 16% with a median DOR of 11.5 months (range: 2.76–30.3). Three patients achieved complete response. The median TTP was 2.96 months (95% CI: 1.61 to 4.31). Median OS was 10.9 months (95% CI: 3.99 to 17.8) and the 1 year, 2 year and 3 year survival rates were 42.4%, 32.3% and 21.6%, respectively. The ORR was 16.7% in primary resistance group and 15.4% in acquired resistance group (p=1.00). All responders were of CP A and Albumin-Bilirubin (ALBI) Grade 1 or 2. CP and ALBI Grades were significantly associated with OS (p=0.006 and p<0.001, respectively). Overall, 52% of patients experienced TRAEs and 12% experienced Grade 3 or above TRAEs.ConclusionsIpilimumab and nivolumab/pembrolizumab can achieve durable antitumor activity and encouraging survival outcomes with acceptable toxicity in patients with advanced HCC who had prior treatment with ICIs.

Serum neutrophil/lymphocyte ratio as a potential predictor of treatment response for immune checkpoint inhibitors in patients with advanced hepatocellular carcinoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16156-e16156
Author(s):  
Jian He ◽  
Zhiqiang Mo ◽  
Qicong Mai ◽  
Xiaoming Chen
Keyword(s):  
Hepatocellular Carcinoma ◽  
Treatment Response ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Post Treatment ◽  
Advanced Hepatocellular Carcinoma ◽  
Advanced Hcc ◽  
Lymphocyte Ratio ◽  
Pre Treatment

e16156 Background: Neutrophil to lymphocyte ratio (NLR) has been shown to associate with tumor progression. The present study was to investigate the role of NLR on predicting the treatment response for immune checkpoint inhibitors (ICIs) therapy in patients with advanced hepatocellular carcinoma (HCC). Methods: We retrospectively reviewed 81 patients received ICIs for advanced HCC from January 2017 to July 2019. We analyzed whether pre- and first 3 weeks post- treatment serum NLR level was associated with ICIs outcome. Results: In this study, the pre-treatment NLR level ranged from 0.64 to 14.93 among 81 patients. The cut-off level of NLR was set as the median value of 2.79. The objective response rate (ORR) in the patients with NLR＜2.79 (low NLR) was 25.0%, which was significantly better than that of patients with NLR ≥2.79 (high NLR) (7.3%, P ＝0.03). Compared to patients with high NLR, patients with low NLR exhibited significantly longer median progression-free survival (PFS) (3.7 vs 3.0 months, P ＝0.004) and median overall survival (OS) (10.3 vs 7.5 months, P ＝0.001). Multivariate analysis revealed high NLR was an independent unfavourable prognostic factor for PFS (hazard ratio [HR] = 1.857, 95% confidence interval [CI] = 1.093-3.154; P = 0.022) and OS (HR = 2.267, 95% CI = 1.221-4.207; P = 0.009). For the patients with high pre-treatment NLR level, ICIs outcome was stratified more clearly by first 3 weeks post- treatment NLR level. Conclusions: The pre- and first 3 weeks post- treatment serum NLR level could be considered as a predictive factor of treatment response for ICIs in patients with advanced HCC.

scholarly journals Immune Checkpoint Inhibitors as Monotherapy or Within a Combinatorial Strategy in Advanced Hepatocellular Carcinoma

2020 ◽  
Vol 21 (17) ◽  
pp. 6302
Author(s):  
Michela Guardascione ◽  
Giuseppe Toffoli
Keyword(s):  
Hepatocellular Carcinoma ◽  
Clinical Trials ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Target Therapy ◽  
Antiangiogenic Agents ◽  
Advanced Hepatocellular Carcinoma ◽  
Advanced Hcc

In advanced-stage hepatocellular carcinoma (HCC), systemic treatment represents the standard therapy. Target therapy has marked a new era based on a greater knowledge of molecular disease signaling. Nonetheless, survival outcomes and long-term response remain unsatisfactory, mostly because of the onset of primary or acquired resistance. More recently, results from clinical trials with immune targeting agents, such as the immune checkpoint inhibitors (ICIs), have shown a promising role for these drugs in the treatment of advanced HCC. In the context of an intrinsic tolerogenic liver environment, since HCC-induced immune tolerance, it is supported by multiple immunosuppressive mechanisms and several clinical trials are now underway to evaluate ICI-based combinations, including their associations with antiangiogenic agents or multikinase kinase inhibitors and multiple ICIs combinations. In this review, we will first discuss the basic principles of hepatic immunogenic tolerance and the evasive mechanism of antitumor immunity in HCC; furthermore we will elucidate the consistent biological rationale for immunotherapy in HCC even in the presence of an intrinsic tolerogenic environment. Subsequently, we will critically report and discuss current literature on ICIs in the treatment of advanced HCC, including a focus on the currently explored combinatorial strategies and their rationales. Finally, we will consider both challenges and future directions in this field.

Early alpha‐foetoprotein response associated with treatment efficacy of immune checkpoint inhibitors for advanced hepatocellular carcinoma

2019 ◽  
Vol 39 (11) ◽  
pp. 2184-2189 ◽  
Author(s):  
Yu‐Yun Shao ◽  
Tsung‐Hao Liu ◽  
Chiun Hsu ◽  
Li‐Chun Lu ◽  
Yin‐Chung Shen ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Immune Checkpoint ◽  
Treatment Efficacy ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Advanced Hepatocellular Carcinoma

scholarly journals Transarterial Chemoembolization Improves Survival in Advanced Hepatocellular Carcinoma Patients Treated with Tyrosine Kinase Inhibitors Plus Immune Checkpoint Inhibitors

2021 ◽  
Author(s):  
Yue Hu ◽  
Tao Pan ◽  
Xi Cai ◽  
Quansheng He ◽  
Yubao Zheng ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tyrosine Kinase ◽  
Immune Checkpoint ◽  
Transarterial Chemoembolization ◽  
Immune Checkpoint Inhibitors ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Advanced Hepatocellular Carcinoma ◽  
Advanced Hcc ◽  
Tace Group

Abstract BackgroundThe survival benefit and safety of transarterial chemoembolization (TACE) for advanced Hepatocellular Carcinoma (HCC) patients treated with tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) is unclear. We aimed to investigate the efficacy and safety of TACE combined with TKIs and ICIs the treatment of advanced HCC. MethodsIn this study, the conditions of 147 patients with advanced HCC who underwent TKIs plus ICIs treatment between July 2017 and April 2020 were evaluated. We divided these patients into the TACE group and non-TACE group based on whether they were treated with TACE during TKIs plus ICIs treatment, and compared their survival outcomes, especially overall survival (OS), and whether they were exposed to unexpected toxicities. ResultsIn this study, a total of 98 patients who underwent TACE during TKIs plus ICIs treatment were included in the TACE group, while the other 49 patients were included in the non-TACE group. According to the Modified Response Evaluation Criteria in Solid Tumors (mRECIST), the objective response rate (ORR) of the TACE group was higher than that of the non-TACE group (ORR 74.5% vs. 40.8%, p ＜0.001). The OS of the TACE group was significantly longer than the non-TACE group (OS 19.3 months vs. 10.8 months, p = 0.010). The incidence of grade 3-4 toxicities in the TACE group was similar to that in the non-TACE group (33.7% vs. 28.6%, p = 0.532). ConclusionsThe TACE treatment combined with TKIs plus ICIs resulted in longer OS compared to the treatment of systemic TKIs plus ICIs without TACE during the process of advanced HCC.

scholarly journals Clinical Benefits of Immune Checkpoint Inhibitors and Predictive Value of Tumor Mutation Burden in Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis

2022 ◽  
Author(s):  
Jiaxi Zheng ◽  
◽  
Haihua Yang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Clinical Trials ◽  
Clinical Outcomes ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Kinase Inhibitor ◽  
Checkpoint Inhibitors ◽  
Advanced Hepatocellular Carcinoma ◽  
Tumor Mutation Burden ◽  
Mutation Burden

Review question / Objective: Is immunotherapy associated with beneficial clinical outcomes for hepatocellular carcinoma (HCC) and how can combination immunotherapy be deployed to produce the best benefit? Is tumor mutation burden (TMB) a predictive biomarker for immune‐checkpoint inhibitors? Condition being studied: To this date, about 50 single-arm clinical trials and several randomized control trials (RCTs) presented final or interim results of investigations on the efficacy of PD-1/PD-L1 inhibitors for advanced HCC. In the CheckMate 459, IMbrave 050, and ORIENT-32, immunotherapies were found to significantly improve progression-free survival (PFS) and overall survival (OS) compared with sorafenib (a tyrosine-kinase inhibitor, as standard systemic treatment) in patients with advanced hepatocellular carcinoma. However, these clinical trials were different on clinical phases, sample size, and response evaluation criteria, and inconsistent clinical outcomes were shown in several trials.

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