scholarly journals Selective Inhibitor of the c-Met Receptor Tyrosine Kinase in Advanced Hepatocellular Carcinoma: No Beneficial Effect With the Use of Tivantinib?

2021 ◽  
Vol 12 ◽  
Author(s):  
Shankun Zhao ◽  
Weizhou Wu ◽  
Hao Jiang ◽  
Lei Ma ◽  
Chengyi Pan ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Clinical Trials ◽  
Sample Size ◽  
Distant Metastases ◽  
European Population ◽  
Advanced Hepatocellular Carcinoma ◽  
Phase 2 ◽  
Phase 3 ◽  
Two Phase ◽  
Advanced Hcc

Advanced hepatocellular carcinoma (HCC) remains a formidable health challenge worldwide, with a 5-year survival rate of 2.4% in patients with distant metastases. The hepatocyte growth factor/cellular-mesenchymal-epithelial transition (HGF/c-Met) signaling pathway represents an encouraging therapeutic target for progressive HCC. Tivantinib, a non-adenosine triphosphate-competitive c-Met inhibitor, showed an attractive therapeutic effect on advanced HCC patients with high MET-expression in phase 2 study but failed to meet its primary endpoint of prolonging the overall survival (OS) in two phase 3 HCC clinical trials. Seven clinical trials have been registered in the “ClinicalTrials.gov” for investigating the safety and efficacy of tivantinib in treating advanced or unresectable HCC. Eight relevant studies have been published with results. The sample size ranged from 20 to 340 patients. The methods of tivantinib administration and dosage were orally 120/240/360 mg twice daily. MET overexpression was recorded at 34.6% to 100%. Two large sample phase 3 studies (the METIV-HCC study of Australia and European population and the JET-HCC study of the Japanese population) revealed that tivantinib failed to show survival benefits in advanced HCC. Common adverse events with tivantinib treatment include neutropenia, ascites, rash, and anemia, etc. Several factors may contribute to the inconsistency between the phase 2 and phase 3 studies of tivantinib, including the sample size, drug dosing, study design, and the rate of MET-High. In the future, high selective MET inhibitors combined with a biomarker-driven patient selection may provide a potentially viable therapeutic strategy for 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.

scholarly journals Phase I studies of peptide vaccine cocktails derived from GPC3, WDRPUH and NEIL3 for advanced hepatocellular carcinoma

Immunotherapy ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 371-385
Author(s):  
Masafumi Ikeda ◽  
Takuji Okusaka ◽  
Izumi Ohno ◽  
Shuichi Mitsunaga ◽  
Shunsuke Kondo ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Phase I ◽  
Peptide Vaccine ◽  
Complete Response ◽  
Advanced Hepatocellular Carcinoma ◽  
Two Phase ◽  
Good Tolerability ◽  
Clinical Trial Registration ◽  
Phase I Studies ◽  
Advanced Hcc

Aim: Two peptide cocktail vaccines using glypican-3, WD-repeat-containing protein up-regulated in hepatocellular carcinoma (HCC) and nei endonuclease VIII-like three epitopes were evaluated in advanced HCC in two Phase I studies. Patients & methods: Study 1 evaluated dose-limiting toxicities (DLTs) of peptides 1–3 (HLA-A24-restricted) and study 2 evaluated DLTs of peptides 1–6 (HLA-A24 or A02-restricted). Results: Overall, 18 and 14 patients were enrolled in studies 1 and 2, respectively. No DLTs were observed up to 7.1 mg of the vaccine cocktail. No complete response/partial response was observed. Stable disease was reported in nine and five patients with a disease control rate of 52.9% and 35.7% in studies 1 and 2, respectively. Conclusion: Both vaccines showed good tolerability and potential usefulness against HCC. Clinical trial registration: JapicCTI-121933 ; JapicCTI-142477

scholarly journals Overview of Current Progress in Immune Checkpoint Inhibitor Therapy for Advanced Hepatocellular Carcinoma

2020 ◽  
Vol 19 ◽  
pp. 153303382094748
Author(s):  
Xinlun Dai ◽  
Shupeng Wang ◽  
Chunyuan Niu ◽  
Bai Ji ◽  
Yahui Liu
Keyword(s):  
Hepatocellular Carcinoma ◽  
Clinical Trials ◽  
Immune Checkpoint ◽  
Current Knowledge ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoint Blockade ◽  
Immune Checkpoints ◽  
Advanced Hepatocellular Carcinoma ◽  
Advanced Hcc ◽  
Inhibitory Signaling

Hepatocellular carcinoma (HCC) remains to a common cause of tumor mortality worldwide and represents the most common type of lethal hepatic malignancy. The incidence of HCC is swiftly increasing in western countries and southeast Asia. Despite poor prognosis, traditional treatments for advanced HCC appear to be minimally effective or even useless since patients are usually diagnosed in the advanced stage of disease. In recent years, immune checkpoint blockade has shown promising results in multiple pre-clinical and clinical trials of different solid tumors, including advanced HCC. Novel drugs targeting immune checkpoints, such as nivolumab (anti-PD-1), durvalumab (anti-PD-L1), and tremelimumab (anti-CTLA-4) have been shown to be highly effective and relatively safe in monotherapy or in combination treatment of advanced liver cancer. Unlike other immunotherapies, this approach can rouse human anti-tumor immunity by relieving T-cell exhaustion and inhibiting the evasion of HCC by blocking co-inhibitory signaling transduction accurately. In this review, we will provide current knowledge of several major immune checkpoints and summarize recent data from clinical trials that applied immune checkpoint inhibitors alone or in combination. In addition, this review will discuss the limitations and future prospective of immune checkpoint-targeted therapy for advanced HCC.

Surrogate endpoint in advanced hepatocellular carcinoma treated with molecular targeted therapy: Meta-analysis of randomized controlled trials.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 454-454
Author(s):  
Kyung-Hun Lee ◽  
Dae-Won Lee ◽  
Myoung-Jin Jang ◽  
Tae-Yong Kim ◽  
Sae-Won Han ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Clinical Trials ◽  
Targeted Therapy ◽  
Molecular Targeted Therapy ◽  
Treatment Effects ◽  
Phase Iii ◽  
Advanced Hepatocellular Carcinoma ◽  
Advanced Hcc ◽  
Incremental Benefit ◽  
Randomized Controlled

454 Background: Time to progression (TTP) is suggested as a reliable endpoint compared to progression free survival (PFS) in the clinical trials of hepatocellular carcinoma (HCC). However, the correlation between TTP and overall survival (OS) has never been studied. Methods: We searched Pubmed and Embase data to obtain data source. Eligible studies were randomized controlled phase III trials which evaluated the efficacy of systemic chemotherapy or molecular targeted therapy in advanced HCC. The association of treatment effects as shown by the hazard ratio (HR) of TTP and OS in each trial was assessed by Spearman rank correlation coefficient ( rs) and linear regression analysis. The association between median TTP and OS was also investigated. Results: Nine studies with a total of 18 treatment arms and 6318 patients were included. Incremental benefit from the study treatment in TTP from each trial was correlated with incremental benefit in OS. The rs value and R2 value between log (HRTTP) and log (HROS) was 0.73 (95% CI 0.12 – 0.94, p = 0.024) and 0.57. The minimum TTP effect to predict a treatment effect on OS was 0.63. Median TTP was associated with median OS. The rs value between TTP and OS was 0.73 (95% confidence interval (CI) 0.40 – 0.89, p < 0.001) and the corresponding R2 was 0.42. Conclusions: Our study results suggest that TTP could be used as a surrogate marker for OS in the clinical trials of advanced HCC. However, the results suggest modest correlation between treatment effects on TTP and OS. Along with individual-level analysis more evidences are needed to confirm our finding.

Systemic targeted and immunotherapy for advanced hepatocellular carcinoma

2020 ◽  
Author(s):  
Robert J Cersosimo
Keyword(s):  
Hepatocellular Carcinoma ◽  
Overall Survival ◽  
Adverse Effects ◽  
Median Overall Survival ◽  
Checkpoint Inhibitors ◽  
Advanced Hepatocellular Carcinoma ◽  
Targeted Agents ◽  
Phase 3 ◽  
Advanced Hcc ◽  
Sorafenib Therapy

Abstract Purpose The activity of targeted agents and immunotherapy in the management of advanced hepatocellular carcinoma (HCC) is reviewed. Summary The first drug approved by the Food and Drug Administration for advanced HCC, sorafenib, was approved in 2007. Regorafenib, the second drug, was approved 10 years later. Six additional drugs have been approved since. Targeted agents and checkpoint inhibitors are the only agents approved for systemic therapy of advanced HCC. Sorafenib and lenvatinib are approved as first-line agents, with regorafenib, cabozantinib, ramucirumab, nivolumab (used alone or with ipilimumab), and pembrolizumab approved for patients who have received prior sorafenib therapy. Most patients in phase 3 studies had Child-Pugh class A cirrhosis, and data on the use of these agents in patients with more advanced hepatic dysfunction are limited. All of the targeted agents improve survival in patients with advanced disease. Median overall survival durations of up to 12.3 and 13.6 months were reported with use of sorafenib and lenvatinib, respectively, in phase 3 trials. Overall survival durations of 10.6, 10.2, and 9.2 months have been achieved with use of regorafenib, cabozantinib, and ramucirumab as second-line therapy after sorafenib. A median overall survival of 13.2 months was reported in 1 cohort of a dose-expansion study of nivolumab in which all patients received prior sorafenib therapy. Median survival durations of 12.9 months and 13.9 months were reported with use of pembrolizumab in patients with a history of sorafenib therapy. The most common adverse effects associated with targeted agents are dermatological effects, diarrhea, fatigue, and hypertension. Immune-mediated adverse effects are associated with checkpoint inhibitors. Conclusion Targeted agents and checkpoint inhibitors are the standard of therapy for patients who need systemic therapy for advanced HCC.

Prognostic factors of survival in 236 advanced hepatocellular carcinoma patients enrolled in prospective clinical trials of systemic therapy

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15632-e15632 ◽  
Author(s):  
Z. Lin ◽  
D. Chang ◽  
Y. Shao ◽  
C. Hsu ◽  
C. Hsu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Overall Survival ◽  
Clinical Trials ◽  
Prognostic Factors ◽  
Systemic Therapy ◽  
Objective Response ◽  
Advanced Hepatocellular Carcinoma ◽  
Phase Ii Trials ◽  
Advanced Hcc ◽  
Staging Systems

e15632 Background: Hepatocellular carcinoma (HCC) is a common malignant disease. Promising results of prospective clinical trials using systemic therapy for patients with advanced HCC are emerging. The aim of this study was to explore prognostic factors of survival in advanced HCC patients eligible for clinical trials of systemic therapy. Methods: From December 1990 to July 2005, 236 patients with unresectable HCC were enrolled into 6 phase II trials of systemic therapy using the following regimens: (1) oral etoposide + tamoxifen, (2)doxorubicin + tamoxifen, (3)IFN-α2b + doxorubicin + tamoxifen, (4)pegylated liposomal doxorubicin, (5)thalidomide, and (6)arsenic trioxide. Univariate and multivariate analyses of 23 relevant clinical characteristics/staging systems were used to identify prognostic factors of survival. Results: Baseline characteristics: median age 55; male/female: 192/44; HBsAg(+) 71%; anti-HCV(+) 30%; Okuda stage I/II/III: 42%/55%/3%; AJCC stage III/IV: 30%/61%; BCLC stage B/C/D: 1%/94%/5%; CLIP score 0–3/4–6: 70%/30%; portal vein thrombosis 53%; extrahepatic metastasis 59%; prior chemoembolization 46%. The objective response rate according to WHO criteria was 11.4%. The median overall survival was 118 days (95% CI, 103–133). In the multivariate analysis, significant predictors of a shorter overall survival were: HBsAg(+) with a hazard ratio (HR) = 1.808 (95% CI, 1.121–2.916; P= 0.015), symptomatic with HR = 1.745 (95% CI, 1.072–2.840; P= 0.025), ECOG≥2 with HR = 1.763 (95% CI, 1.040–2.988; P= 0.035), and high BCLC stage with HR = 3.282 (95% CI, 1.129–9.541; P= 0.029). Conclusions: Patients with advanced HCC who are eligible for systemic therapeutic trials have patient- and disease-related prognostic factors. Positive HBsAg, symptomatic, ECOG performance≥2, and high BCLC stage predict a shorter overall survival. No significant financial relationships to disclose.

Phase 3 randomized, double-blind, controlled study of cabozantinib (XL184) versus placebo in subjects with hepatocellular carcinoma who have received prior sorafenib (CELESTIAL; NCT01908426).

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. TPS496-TPS496 ◽  
Author(s):  
Ghassan K. Abou-Alfa ◽  
Ann-Lii Cheng ◽  
Tim Meyer ◽  
Anthony B. El-Khoueiry ◽  
Masafumi Ikeda ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Objective Response ◽  
Controlled Study ◽  
Clinical Activity ◽  
Double Blind Study ◽  
Advanced Hepatocellular Carcinoma ◽  
Phase 3 ◽  
Double Blind ◽  
Advanced Hcc ◽  
Systemic Treatments

TPS496 Background: Currently, there are no approved systemic therapies for patients with advanced hepatocellular carcinoma (HCC) who fail sorafenib. Cabozantinib is an oral receptor tyrosine kinase inhibitor (TKI) with activity against tyrosine kinases including MET, RET and VEGFRs. MET and VEGFR signaling have been implicated in tumor neo-angiogenesis and invasion. MET is overexpressed in HCC compared with non-tumor liver tissue, with higher MET expression linked to poor prognosis. Cabozantinib prolonged survival in a MET-driven transgenic mouse model of HCC, and has demonstrated clinical activity in multiple solid tumor types, including 41 subjects with advanced HCC treated in a phase 2 randomized discontinuation study. Methods: This phase 3, randomized, double-blind study evaluates the efficacy and safety of cabozantinib compared with placebo in subjects with advanced HCC previously treated with sorafenib and have progressed following 1-2 prior systemic treatments for HCC. Subjects must be ≥ 18 year old, have Child-Pugh Score of A and ECOG PS ≤ 1. Subjects are randomized 2:1 to receive either cabozantinib or placebo. Stratification factors are etiology of disease, geographic region and the presence of extrahepatic spread of disease and/or macrovascular invasion. The primary endpoint is overall survival. Secondary endpoints are progression-free survival and objective response rate by RECIST 1.1. Additional endpoints include safety, tolerability, circulating tumor cells, serum bone markers and plasma biomarkers, effects on bony disease assessed by bone scan and health-related quality of life (HRQoL) using the EuroQol Health questionnaire (EQ-5D-5L). Enrollment was initiated in September 2013. Target recruitment is 760 subjects. A total of 621 events planned with 2 interim analyses (at 311 and 466 events) would provide 90% power to detect a 31.6% increase in OS (HR=0.76). Clinical trial information: NCT01908426.

scholarly journals Optimizing Sequential Systemic Therapies for Advanced Hepatocellular Carcinoma: A Decision Analysis

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2132
Author(s):  
Giuseppe Cabibbo ◽  
Ciro Celsa ◽  
Marco Enea ◽  
Salvatore Battaglia ◽  
Giacomo Emanuele Maria Rizzo ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Clinical Trials ◽  
Cancer Progression ◽  
Large Scale ◽  
Single Agent ◽  
Health Benefit ◽  
Advanced Hepatocellular Carcinoma ◽  
Advanced Hcc ◽  
The Difference ◽  
Sequential Treatments

Background: An optimal sequential systemic therapy for advanced hepatocellular carcinoma (HCC) has not been discovered. We developed a decision model based on available clinical trials to identify an optimal risk/benefit strategy for sequences of novel systemic agents. Methods: A Markov model was built to simulate overall survival (OS) among patients with advanced HCC. Three first-line (single-agent Sorafenib or Lenvatinib, and combination of Atezolizumab plus Bevacizumab) followed by five second-line treatments (Regorafenib, Cabozantinib, Ramucirumab, Nivolumab, Pembrolizumab) were compared in fifteen sequential strategies. The likelihood of transition between states (initial treatment, cancer progression, death) was derived from clinical trials. Life-year gained (LYG) was the main outcome. Rates of severe adverse events (SAEs) (≥grade 3) were calculated. The innovative measure, called incremental safety-effectiveness ratio (ISER), of the two best sequential treatments was calculated as the difference in probability of SAEs divided by LYG. Results: Lenvatinib followed by Nivolumab (median OS, 27 months) was the most effective sequence, producing a LYG of 0.75, while Atezolizumab plus Bevacizumab followed by Nivolumab was the safest sequence (SAEs 40%). Accordingly, the net health benefit assessed by ISER favored Lenvatinib followed by Nivolumab, compared to Atezolizumab plus Bevacizumab, followed by Nivolumab in 52% of cases. Conclusion: Further sequential clinical trials or large-scale real-world studies may prove useful to evaluate the net health benefit of the best sequential treatment for advanced HCC.

Trends of clinical outcomes with sorafenib in randomized controlled trials for patients with treatment-naïve advanced hepatocellular carcinoma.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 327-327
Author(s):  
Timothy J Brown ◽  
Arjun Gupta ◽  
Ramy Sedhom ◽  
Thomas Benjamin Karasic ◽  
Mark Yarchoan
Keyword(s):  
Hepatocellular Carcinoma ◽  
Clinical Trials ◽  
Median Duration ◽  
Systemic Therapy ◽  
Phase Iii ◽  
Advanced Hepatocellular Carcinoma ◽  
Advanced Hcc ◽  
Duration Of Therapy ◽  
Recist 1.1 ◽  
Over Time

327 Background: Sorafenib was first approved by the US FDA to treat patients with advanced hepatocellular carcinoma (HCC) after two landmark trials (SHARP and Asia-Pacific) showed improved overall survival (OS). Since those two landmark trials, median OS has increased in the sorafenib arms in several recent phase III trials in HCC. We analyzed trends in OS, progression-free survival (PFS), and objective response rates (ORR) in published randomized clinical trials of sorafenib in HCC to better understand factors underlying the improvements. Methods: We searched PubMed for all published trials of sorafenib in advanced HCC. Trials were included if the patients were naïve to systemic therapy and had a comparison arm that was active systemic therapy or placebo. We extracted demographic and trial-level outcome data to correlate outcomes such as OS, PFS, ORR, and duration of therapy. T-tests were used to compare outcomes and linear regression was used to identify temporal trends with significance set at p£0.05. Results: The PubMed search returned 100 studies. A total of 15 studies met inclusion criteria with a total of 3755 patients treated with sorafenib (9 phase III and 6 phase II). Included trials enrolled patients from 2005-2019. The median OS in all trials was 10.0 mos (range: 6.5-14.8 mos). OS has significantly improved since the first trial began accruing (p = 0.04). A total of 12 studies provided data on PFS using RECIST 1.1, with a median PFS of 4.0 months (range: 2.7-6.6 mos). PFS has not changed over time (p = 0.99). However, ORR assessed by RECIST 1.1 have trended toward improvement over time (p = 0.08). Median duration of therapy with sorafenib has decreased by 53% since the enrollment of the first clinical trial in 2005, from 23.1 weeks to 12.2 weeks (p = 0.02). Despite this, no significant correlations were observed with the interaction of duration of therapy and OS (p = 0.92). Further, there was no significant change in the age of patients included, proportion of patients with Childs-Pugh A, Barcelona Clinic Liver Cancer (BCLC) B, BCLC C, ECOG performance status 0, HBV or HCV, proportion of patients with extrahepatic spread or vascular invasion at time of enrollment, or proportion of patients who have undergone prior locoregional therapies to explain the OS findings. Conclusions: The OS of patients with advanced HCC on the sorafenib arm in published trials has been increasing, however the reasons for this increase are not apparent from data available in the published literature. At the same time, the median duration of treatment with sorafenib has been decreasing over time and PFS is unchanged, suggesting improvements in sorafenib delivery may not be the primary factor. It is possible these trends represent heretofore unquantified changes in patient selection for systemic therapy, improvements in supportive care, or post-progression treatment for patients on HCC clinical trials.

scholarly journals Molecular Targets, Pathways, and Therapeutic Implications for Hepatocellular Carcinoma

2020 ◽  
Vol 21 (15) ◽  
pp. 5232
Author(s):  
Jun Gong ◽  
Jeremy Chuang ◽  
May Cho ◽  
Kyra Toomey ◽  
Andrew Hendifar ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Clinical Trials ◽  
Targeted Therapies ◽  
Cancer Mortality ◽  
Molecular Targets ◽  
Advanced Hepatocellular Carcinoma ◽  
Advanced Hcc ◽  
Therapeutic Implications ◽  
The Past ◽  
Selection Of

Hepatocellular carcinoma (HCC) represents one of the leading causes of cancer mortality worldwide. While significant advances have been made for the treatment of advanced hepatocellular carcinoma in the past few years, the prognosis remains poor and effective biomarkers to guide selection of therapies remain noticeably absent. However, several targeted therapies have been approved in the past few years that have improved the outlook for this disease. In this review, we will highlight the recent therapies approved for the treatment of advanced HCC and discuss promising therapeutic options, targets, and pathways for drug development and consideration for future clinical trials.

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