scholarly journals Molecular targeted and immune checkpoint therapy for advanced hepatocellular carcinoma

2019 ◽  
Vol 38 (1) ◽  
Author(s):  
Ziyu Liu ◽  
Yan Lin ◽  
Jinyan Zhang ◽  
Yumei Zhang ◽  
Yongqiang Li ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Phase Ii ◽  
Checkpoint Inhibitors ◽  
Phase Iii ◽  
Advanced Hepatocellular Carcinoma ◽  
Line Treatment ◽  
Phase Ii Trials ◽  
Advanced Hcc ◽  
Phase Iii Trials ◽  
Asian Pacific

Abstract Molecular targeted therapy for advanced hepatocellular carcinoma (HCC) has changed markedly. Although sorafenib was used in clinical practice as the first molecular targeted agent in 2007, the SHARPE and Asian-Pacific trials demonstrated that sorafenib only improved overall survival (OS) by approximately 3 months in patients with advanced HCC compared with placebo. Molecular targeted agents were developed during the 10-year period from 2007 to 2016, but every test of these agents from phase II or phase III clinical trial failed due to a low response rate and high toxicity. In the 2 years after, 2017 through 2018, four successful novel drugs emerged from clinical trials for clinical use. As recommended by updated Barcelona Clinical Liver cancer (BCLC) treatment algorithms, lenvatinib is now feasible as an alternative to sorafenib as a first-line treatment for advanced HCC. Regorafenib, cabozantinib, and ramucirumab are appropriate supplements for sorafenib as second-line treatment for patients with advanced HCC who are resistant, show progression or do not tolerate sorafenib. In addition, with promising outcomes in phase II trials, immune PD-1/PD-L1 checkpoint inhibitors nivolumab and pembrolizumab have been applied for HCC treatment. Despite phase III trials for nivolumab and pembrolizumab, the primary endpoints of improved OS were not statistically significant, immune PD-1/PD-L1 checkpoint therapy remains to be further investigated. This review summarizes the development and progression of molecular targeted and immune-based checkpoint therapies in HCC.

Capecitabine and irinotecan (XELIRI) in first-line treatment of metastatic colorectal cancer (mCRC): A systematic review of controlled clinical trials

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15100-e15100
Author(s):  
S. Sukumaran ◽  
N. Pavlakis ◽  
K. B. Pittman ◽  
K. Patterson ◽  
T. J. Price
Keyword(s):  
Phase Ii ◽  
Phase Iii ◽  
Line Treatment ◽  
Phase Ii Trials ◽  
First Line ◽  
Hand Foot Syndrome ◽  
Phase Iii Trials ◽  
Grade 3 ◽  
Phase Ii And Iii ◽  
First Line Treatment

e15100 Background: Irinotecan and 5-Fluorouracil based combination is an effective regimen for mCRC. Capecitabine, an oral fluoropyrimidine, is a convenient alternative to intravenous 5- Fluorouracil. This study aims to systematically review all published and unpublished controlled phase II and III trials of XELIRI combination, used in first line treatment of mCRC, reported from 2000–2008, to describe its efficacy and safety. Methods: A literature search of MEDLINE, EMBASE, CINAHL and proceedings from ASCO, ESMO and WGIC was conducted. The primary end point was response rate (RR), secondary endpoints include: time to progression (TTP), overall survival (OS) and toxicity. Results: Thirty non-randomised phase II trials (n = 1380) along with 6 randomised phase II and 3 phase III trials, were included (pooled n = 1478). The daily dose of capecitabine ranged from 1,800 mg/m2 to 2,500 mg/m2 for 7 to 14 days per cycle and the dose of irinotecan varied from 180mg/m2 to 350 mg/m2, over a 3 week period per cycle. Amongst the non-randomised studies, the median patient age was 61 years (53–72).The median RR was 46.75% (25–78%). The median reported TTP was 7.9 months (mo) (5- 9.9 mo) and the median OS was 15.6 months (7–24.8 mo). Grade 3–4 toxicity incidence was: diarrhoea (21.5%), neutropenia (12%), vomiting (12.5%), fatigue (6%) and Hand-foot syndrome (6%). The pooled incidence of febrile neutropenia was 2.5%. Amongst the randomised trials, the comparator regimens were XELOX or FOLFIRI. Median age was 65 years (61–74). RR for XELIRI was 39% (34–56%) compared to 47% (27–61.8%) for the non XELIRI comparator arms. Median reported TTP was 8.2 mo (5.7–12.5 mo) for the XELIRI arms and 9.2 mo for the comparator arms. Conclusions: XELIRI is an effective and feasible regime in the first line management of mCRC. However the optimal role of this combination remains to be established. No significant financial relationships to disclose.

The use of cabozantinib in advanced hepatocellular carcinoma (HCC): Hong Kong multi-center experience.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 316-316
Author(s):  
Yawen Dong ◽  
Thomas Wai-Tong Leung ◽  
Gin Wai Kwok ◽  
Vikki Tang ◽  
Bryan Li ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Overall Survival ◽  
Hong Kong ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Objective Response ◽  
Real Life ◽  
Phase Iii ◽  
Advanced Hepatocellular Carcinoma ◽  
Advanced Hcc

316 Background: In the phase III CELESTIAL trial, cabozantinib showed significant improvement in overall survival with good tolerability in advanced HCC population. We aimed to evaluate the efficacy, survival and tolerability of cabozatinib in advanced hepatocellular carcinoma (HCC) patients in a real life setting. Methods: Between February 2018 and October 2019, consecutive advanced HCC patients who received cabozatinib alone or in combination at University of Hong Kong Health System hospitals were analysed. Cabozantinib was administered at 60 mg continuously daily. Objective response rate (ORR), time-to-progression (TTP), overall survival (OS), and tolerability were evaluated. Results: Overall, 22 patients were included. The median age was 57.1 years (range 48.5-58.6). All patients except one were hepatitis B carriers. More than 80% of the patients had underlying Child-Pugh A cirrhosis. Most patients had metastatic disease (95.5%). More than 70% of patients received cabozantinib beyond second-line, and most of the patients had prior exposure to tyrosine kinase inhibitor (TKI) and/or immunotherapy. The median time from the start of first-line systemic treatment to the start of cabozantinib was 11.2 months. Cabozantinib was administered to 11 patients (50%) as single agent, while the other half received cabozantinib in combination with mostly immune checkpoint inhibitors. The median follow-up was 7.6 months. The table below shows the ORR. The overall median TTP and OS were 4.2 and 8.90 months, respectively. Interestingly, among those who received single agent cabozantinib, the median OS was 5.36 months in contrast to 12.32 months in the patients received combination. Overall, 90.9% of patients experienced treatment related adverse events (TRAEs) with transient liver function occurred in nearly 50% patients. Nevertheless, Grade 3/4 TRAEs was only 12%. Conclusions: Our present study showed that the use of cabozatinib in advanced HCC patients had good anti-tumour activity and survival benefits with acceptable toxicity profile. [Table: see text]

scholarly journals Immunotherapy and Targeted Therapy for Hepatocellular Carcinoma: A Literature Review and Treatment Perspectives

2020 ◽  
Vol 14 (1) ◽  
pp. 28
Author(s):  
Daniel M. Girardi ◽  
Jana Priscila M. Pacífico ◽  
Fernanda P. L. Guedes de Amorim ◽  
Gustavo dos Santos Fernandes ◽  
Marcela C. Teixeira ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Clinical Trials ◽  
Targeted Therapies ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Phase Iii ◽  
Advanced Hepatocellular Carcinoma ◽  
Line Treatment ◽  
Sorafenib Treatment

Advanced hepatocellular carcinoma is a prevalent and potentially aggressive disease. For more than a decade, treatment with sorafenib has been the only approved therapeutic approach. Moreover, no agent has been proven to prolong survival following the progression of disease after sorafenib treatment. However, in recent years, this scenario has changed substantially with several trials being conducted to examine the effects of immunotherapy and novel targeting agents. Several immune checkpoint inhibitors have shown promising results in early-stage clinical trials. Moreover, phase III trials with large cohorts have demonstrated remarkable improvement in survival with the use of new targeted therapies in second-line treatment. Treatment regimens involving the combination of two immune checkpoint inhibitors as well as immune checkpoint inhibitors and anti-angiogenic targeted therapies have shown potential to act synergistically in clinical trials. Recently, the combination of atezolizumab and bevacizumab evaluated in a phase III clinical trial has demonstrated survival superiority in the first-line treatment; it is the new considered standard of care. In this manuscript, we aimed to review the latest advances in the systemic treatment of advanced hepatocellular carcinoma focusing on immunotherapy and targeted therapies.

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.

Biofeedback

2016 ◽  
Vol 4 (1) ◽  
pp. 57-63 ◽  
Author(s):  
Paul Lehrer
Keyword(s):  
Phase Ii ◽  
Real Life ◽  
Phase Iii ◽  
Controlled Trials ◽  
Clinical Environment ◽  
Phase Ii Trials ◽  
Research Support ◽  
Phase Iii Trials ◽  
Psychosomatic Problems ◽  
Biofeedback Research

Although evidence supports the efficacy of biofeedback for treating a number of disorders and for enhancing performance, significant barriers block both needed research and payer support for this method. Biofeedback has demonstrated effects in changing psychophysiological substrates of various emotional, physical, and psychosomatic problems, but payers are reluctant to reimburse for biofeedback services. A considerable amount of biofeedback research is in the form of relatively small well-controlled trials (Phase II trials). This article argues for greater payer support and research support for larger trials in the “real life” clinical environment (Phase III trials) and meta-analytic reviews.

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 Targeting Angiogenesis in Prostate Cancer

2019 ◽  
Vol 20 (11) ◽  
pp. 2676 ◽  
Author(s):  
Zsombor Melegh ◽  
Sebastian Oltean
Keyword(s):  
Prostate Cancer ◽  
Phase Ii ◽  
Phase Iii ◽  
Refractory Disease ◽  
Phase Ii Trials ◽  
Angiogenic Activity ◽  
Angiogenic Therapy ◽  
Resistant Refractory ◽  
Castration Resistant ◽  
Phase Iii Trials

Prostate cancer is the most commonly diagnosed cancer among men in the Western world. Although localized disease can be effectively treated with established surgical and radiopharmaceutical treatments options, the prognosis of castration-resistant advanced prostate cancer is still disappointing. The objective of this study was to review the role of angiogenesis in prostate cancer and to investigate the effectiveness of anti-angiogenic therapies. A literature search of clinical trials testing the efficacy of anti-angiogenic therapy in prostate cancer was performed using Pubmed. Surrogate markers of angiogenic activity (microvessel density and vascular endothelial growth factor A (VEGF-A) expression) were found to be associated with tumor grade, metastasis, and prognosis. Six randomizedstudies were included in this review: two phase II trials on localized and hormone-sensitive disease (n = 60 and 99 patients) and four phase III trials on castration-resistant refractory disease (n = 873 to 1224 patients). Although the phase II trials showed improved relapse-free survival and stabilisation of the disease, the phase III trials found increased toxicity and no significant improvement in overall survival. Although angiogenesis appears to have an important role in prostate cancer, the results of anti-angiogenic therapy in castration-resistant refractory disease have hitherto been disappointing. There are various possible explanations for this lack of efficacy in castration-resistant refractory disease: redundancy of angiogenic pathways, molecular heterogeneity of the disease, loss of tumor suppressor protein phosphatase and tensin homolog (PTEN) expression as well as various VEGF-A splicing isoforms with pro- and anti-angiogenic activity. A better understanding of the molecular mechanisms of angiogenesis may help to develop effective anti-angiogenic therapy in prostate cancer.

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.

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