scholarly journals Predictive Biomarkers for Checkpoint Inhibitor-Based Immunotherapy in Hepatocellular Carcinoma: Where Do We Stand?

2021 ◽  
Vol 11 ◽  
Author(s):  
Alessandro Rizzo ◽  
Angela Dalia Ricci ◽  
Alessandro Di Federico ◽  
Giorgio Frega ◽  
Andrea Palloni ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Anticancer Agents ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Predictive Biomarkers ◽  
Standard Of Care ◽  
Phase Iii ◽  
Cochrane Library ◽  
Advanced Hcc ◽  
Treatment Naïve

Hepatocellular carcinoma (HCC) remains the sixth most commonly diagnosed malignancy worldwide, still representing an important cause of cancer-related death. Over the next few years, novel systemic treatment options have emerged. Among these, immune checkpoint inhibitors (ICIs) have been widely evaluated and are under assessment, as monotherapy or in combination with other anticancer agents in treatment-naïve and previously treated patients. In particular, the approval of the PD-L1 inhibitor atezolizumab plus the antiangiogenic agent bevacizumab as front-line treatment for advanced HCC has led to the adoption of this combination in this setting, and the IMbrave 150 phase III trial has established a novel standard of care. However, several questions remain unanswered, including the identification of reliable predictors of response to ICIs in HCC patients. In the current paper, we will provide an updated overview of potentially useful predictive biomarkers of response to immunotherapy in advanced HCC. A literature search was conducted in September 2021 of Pubmed/Medline, Cochrane library and Scopus databases.

Atezolizumab in advanced hepatocellular carcinoma: good things come to those who wait

Immunotherapy ◽  
2021 ◽  
Author(s):  
Alessandro Rizzo ◽  
Angela Dalia Ricci ◽  
Giovanni Brandi
Keyword(s):  
Hepatocellular Carcinoma ◽  
Checkpoint Inhibitors ◽  
Standard Of Care ◽  
Phase Iii ◽  
Medical Community ◽  
Advanced Hepatocellular Carcinoma ◽  
Novel Treatments ◽  
Treatment Naïve ◽  
The Impact

Advanced hepatocellular carcinoma (HCC) patients present poor prognosis. However, recent years have seen the advent of several novel treatments in this setting, where the role of immune checkpoint inhibitors has been investigated. Among these, the PD-L1 inhibitor atezolizumab in combination with bevacizumab has reported unprecedented results in treatment-naive patients with unresectable disease, with the recently published IMbrave150 Phase III trial showing the superiority of the combination over sorafenib monotherapy, and after having attended more than a decade of ‘stagnation’, the HCC medical community has a new standard of care. Herein, we examine the development and the impact of atezolizumab in advanced HCC, summarizing the mechanism of action, pharmacokinetics and recent evidence from Phase I to III clinical trials.

scholarly journals Cabozantinib in combination with atezolizumab versus sorafenib in treatment-naive advanced hepatocellular carcinoma: COSMIC-312 Phase III study design

2020 ◽  
Vol 16 (21) ◽  
pp. 1525-1536 ◽  
Author(s):  
Robin Kate Kelley ◽  
Jennifer W Oliver ◽  
Saswati Hazra ◽  
Fawzi Benzaghou ◽  
Thomas Yau ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Kinase Inhibitor ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Phase Iii ◽  
Advanced Hepatocellular Carcinoma ◽  
Single Agent Therapy ◽  
Treatment Naïve ◽  
Phase Iii Study ◽  
Immunomodulatory Properties

Cabozantinib is an oral tyrosine kinase inhibitor that targets VEGFR, MET and the TAM (TYRO3, AXL, MER) family of kinase receptors. In addition to their role in tumor growth and angiogenesis, cabozantinib targets promote an immune-suppressive microenvironment. Cabozantinib is approved as single-agent therapy for patients with advanced hepatocellular carcinoma who received prior sorafenib. Owing to its antitumor and immunomodulatory properties, cabozantinib is being developed in combination with immune checkpoint inhibitors. Early studies of these combinations have shown promising antitumor activity and tolerability in patients with solid tumors. Here, we describe the rationale and design of COSMIC-312, a Phase III study evaluating the safety and efficacy of cabozantinib in combination with atezolizumab (anti–PD-L1 monoclonal antibody) versus sorafenib for treatment-naive patients with advanced hepatocellular carcinoma. ClinicalTrial.gov Registration: NCT03755791

Response of advanced HCC to pembrolizumab and lenvatinib combination therapy despite monotherapy failure

2020 ◽  
Vol 58 (08) ◽  
pp. 773-777 ◽  
Author(s):  
Nadine Schulte ◽  
Moying Li ◽  
Tianzuo Zhan ◽  
Lena Dreikhausen ◽  
Janina Sollors ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Combination Therapy ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Standard Of Care ◽  
Advanced Hepatocellular Carcinoma ◽  
Advanced Hcc ◽  
The World ◽  
Vegf Inhibition ◽  
Tki Treatment

AbstractIn recent years, immune checkpoint inhibitors (ICIs) were successfully introduced to cancer therapy, and these drugs have already become essential for the treatment of various noncurable tumors. However, monotherapy in advanced hepatocellular carcinoma (aHCC) failed to show statistically significant improvement.Recently, the combination of atezolizumab and bevacizumab demonstrated efficacy of combining ICI and VEGF inhibition, further substantiating previous data on synergistic mechanisms among respective substance classes.As TKI treatment is currently standard of care for aHCC, and ICIs are approved by the FDA and available in many areas of the world, numerous patients may have been treated with monotherapy of those drugs. However, it remains unclear if failure to monotherapy has an impact on combination therapy. We therefore report a patient well responding to combination therapy despite previous failures to TKI and ICI monotherapy.

A randomized phase III study of immune checkpoint inhibition with chemotherapy in treatment-naive metastatic anal cancer patients: A trial of the ECOG-ACRIN cancer research group (EA2176).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS3614-TPS3614
Author(s):  
Marc Thomas Roth ◽  
Paul J. Catalano ◽  
Kristen Keon Ciombor ◽  
Al Bowen Benson ◽  
Xin Yao ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Cancer Progression ◽  
Phase Ii ◽  
Anal Cancer ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Phase Iii ◽  
Curative Intent ◽  
Platinum Based Chemotherapy ◽  
Treatment Naïve

TPS3614 Background: Anal cancer is growing in annual incidence globally and human papillomavirus (HPV) remains the predominant risk factor underlying its development. Due to its relative rarity, clinical trials in anal cancer have historically been difficult to conduct and treatment options for metastatic disease remain limited. Carboplatin/paclitaxel (CP) was compared to cisplatin/5-fluorouracil (historical standard of care) in a recent randomized phase II clinical trial (InterAACT; EA2133) in treatment-naïve metastatic anal cancer, finding that response rates were equivocal, but that overall survival (OS) was significantly longer in the CP arm (20 months vs 12.3 months, p = 0.014). Additionally, reduced grade 3/4 toxicities were seen in the CP arm. NCI9673, a single-arm phase II study, established safety and efficacy of nivolumab in previously-treated metastatic anal cancer. Progression-free survival (PFS) was 4.1 months (95% CI 3.0-7.9) and OS was 11.5 months (95% CI 7.1-not estimable). Multiple randomized trials in lung cancer have demonstrated efficacy of platinum-based chemotherapy combined with checkpoint inhibitors. Together these studies form the rationale behind combining CP and nivolumab in treatment-naïve metastatic anal cancer. Methods: EA2176 (NCT04444921) is the first NCTN phase III randomized clinical trial in treatment-naïve metastatic anal cancer. Stratification factors include HIV status and history of chemoradiation for curative intent. Patients will be randomized to carboplatin (AUC = 5, Day 1) plus paclitaxel (80mg/m2, Days 1, 8, 15) +/- nivolumab 240mg IV (Cycle 1 = Days 1, 15; Cycle ≥2 = Day 1, 480mg) q 28-days until disease progression or treatment intolerance. CP will be given for up to 6 cycles, while nivolumab will be continued as maintenance for up to 2 years. The primary endpoint is PFS. Secondary objectives include OS, response rate, and toxicity. Goal enrollment is 205 patients and the study continues accrual. This sample size will provide 80% power at a two-sided α of 0.05 to detect a 4.8-month improvement in PFS assuming 8 months in the control arm. Novel correlative studies include sequential quantitative tumor-derived cell-free HPV ctDNA levels (serotypes 16 and 18; Sysmex-Inostics SafeSEQ NGS assay). Correlative funding provided in part by the Farrah Fawcett Foundation and Sysmex Inostics, Inc. Clinical trial information: NCT04444921.

scholarly journals Immunotherapy for hepatocellular carcinoma: recent advances and future perspectives

2019 ◽  
Vol 11 ◽  
pp. 175883591986269 ◽  
Author(s):  
Weiqi Xu ◽  
Ken Liu ◽  
Minjiang Chen ◽  
Jin-Yu Sun ◽  
Geoffrey W McCaughan ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Phase I ◽  
Checkpoint Inhibitors ◽  
Killer Cell ◽  
Objective Response ◽  
Phase Iii ◽  
Future Research ◽  
Advanced Hcc

The introduction of immunotherapies has been a major development in the treatment of many advanced cancers, including hepatocellular carcinoma (HCC). We are entering a new era of systemic therapy for advanced HCC associated with an explosion of clinical trial activity. Data from phase I/II studies of checkpoint inhibitors in advanced HCC have been promising, with durable objective response rates of approximately 20% seen (in both first- and second-line settings) and acceptable safety profiles (including immune-mediated hepatitis). Phase III studies evaluating anti-programmed cell death protein 1 (anti-PD-1) and anti-programmed cell death ligand 1 (anti-PD-L1) antibodies compared with sorafenib are already underway. The potential synergistic effects of anti-PD-1/anti-PD-L1 when used in combination with agents against other checkpoint molecules, systemic therapies, as well as conventional surgical and locoregional therapies are also being explored in upcoming clinical trials. Aside from this, other strategies to harness the immune system, including chimeric antigen receptor-engineered T cells, natural killer cell therapies, and peptide vaccines directed against HCC antigens have entered phase I/II studies. Current limitations of immunotherapies and areas of future research include the accurate assessment and prediction of tumor response, overcoming the immunosuppressive effects of a hypoxic microenvironment, and the management of immune-related hepatitis in patients who already have limited liver reserve.

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]

Hepatocellular Carcinoma Immunotherapy

2021 ◽  
Vol 73 (1) ◽  
Author(s):  
Rubens Copia Sperandio ◽  
Roberto Carmagnani Pestana ◽  
Beatriz Viesser Miyamura ◽  
Ahmed O. Kaseb
Keyword(s):  
Hepatocellular Carcinoma ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Phase Iii ◽  
Annual Review ◽  
Publication Date ◽  
Liver Malignancy ◽  
First Line Therapy

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and the third leading cause of cancer-related death worldwide. Single-agent anti-PD-1 immune checkpoint inhibitors (ICIs) demonstrated promising efficacy in early-phase trials, a finding that was not confirmed in phase III studies. The combination of atezolizumab (an anti-PD-L1 ICI) with bevacizumab (an anti-VEGF antibody) was approved as first-line therapy in 2020, however, with significant improvement in response rate, progression-free survival, and overall survival in comparison with the previous standard of care, sorafenib. Numerous ongoing clinical trials are assessing ICIs in combination with each other or with targeted agents, and also in earlier stages with local therapies. This review summarizes the latest concepts in the use of ICIs for the management of HCC. Expected final online publication date for the Annual Review of Medicine, Volume 73 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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.

scholarly journals Recent Advances in Systemic Therapy for Hepatocellular Carcinoma in an Aging Society: 2020 Update

Liver Cancer ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 640-662
Author(s):  
Masatoshi Kudo
Keyword(s):  
Hepatocellular Carcinoma ◽  
Clinical Trials ◽  
Systemic Therapy ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
New Drugs ◽  
Phase Iii ◽  
Second Line ◽  
First Line ◽  
Recent Advances

Systemic therapy for hepatocellular carcinoma (HCC) has changed markedly since the introduction of the molecular targeted agent sorafenib in 2007. Sorafenib increased the available treatment options for patients with extrahepatic spread and vascular invasion and improved survival in patients with advanced HCC; however, various shortcomings such as low response rates and relatively high toxicity (e.g., hand-foot skin reaction) prompted concerted efforts aimed at developing new molecular targeted agents to provide more treatment options and second-line agents for patients with disease progression or intolerance to sorafenib. Despite many attempts to develop new drugs between 2007 and 2016, all first-line and second-line clinical trials conducted during this period failed. However, between 2017 and 2019, 4 drugs (lenvatinib as a first-line agent and regorafenib, cabozantinib, and ramucirumab as second-line agents) emerged in quick succession from clinical trials and became available for clinical use. In addition, nivolumab and pembrolizumab were approved as second-line agents after sorafenib. A recent phase III trial (IMbrave150) showed that combination immunotherapy with atezolizumab plus bevacizumab increases overall survival compared with sorafenib therapy; Food and Drug Agency already approved this combination therapy, and worldwide approval is expected soon. This review describes the recent advances in systemic therapy and the use of tyrosine kinase inhibitors (sorafenib, lenvatinib, regorafenib, and cabozantinib), monoclonal antibodies (ramucirumab and bevacizumab), and immune checkpoint inhibitors (nivolumab, pembrolizumab, and atezolizumab) in elderly patients and the similarity of their efficacy and safety profiles to those in the general population.

scholarly journals Immunotherapy in Hepatocellular Carcinoma

2021 ◽  
Vol 22 (10) ◽  
Author(s):  
Claudia A. M. Fulgenzi ◽  
Thomas Talbot ◽  
Sam M. Murray ◽  
Marianna Silletta ◽  
Bruno Vincenzi ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Cytotoxic T Lymphocyte ◽  
Treatment Options ◽  
Predictive Biomarkers ◽  
Intermediate Stage ◽  
Routine Practice ◽  
Advanced Hcc

Opinion statementPatients with hepatocellular carcinoma (HCC) have been traditionally deprived from highly effective systemic therapy options in the past decades. The multi-targeted tyrosine kinase inhibitor sorafenib, approved in 2008, remained the only treatment option for advanced HCC for over a decade. A number of molecularly targeted therapies such as lenvatinib, regorafenib, cabozantinib, and ramucirumab have significantly widened treatment options in patients with advanced HCC. However, emergence of resistance and long-term toxicity from treatment are barriers to long-term survivorship. Immunotherapy is at the focus of intense research efforts in HCC. Whilst targeting of programmed cell death 1 (PD-1) and cytotoxic T lymphocyte 4 (CTLA-4) is associated with radiologically measurable disease-modulating effects in HCC, monotherapies fell short of demonstrating evidence of significant survival extension in advanced disease. Atezolizumab and bevacizumab were the first immunotherapy regimen to demonstrate clear superiority in improving the survival of patients with unresectable HCC compared to sorafenib, paving the way for immunotherapy combinations. As the treatment landscape of HCC rapidly evolves, with immunotherapy integrating within early- and intermediate-stage disease treatment algorithms, lack of level 1 evidence on sequencing of therapeutic strategies and lack of head-to-head comparisons across immunotherapy combinations will affect prescribing of immunotherapy in routine practice. In the absence of predictive biomarkers, choice of immunotherapy over kinase inhibitors will continue to remain an empirical exercise, guided by balancing anti-tumour efficacy with toxicity considerations in the individual patient.

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