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

Checkpoint Inhibitors ◽

Standard Of Care ◽

Phase Iii ◽

Medical Community ◽

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.

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

Future Oncology ◽

10.2217/fon-2020-0283 ◽

2020 ◽

Vol 16 (21) ◽

pp. 1525-1536 ◽

Cited By ~ 2

Author(s):

Robin Kate Kelley ◽

Jennifer W Oliver ◽

Saswati Hazra ◽

Fawzi Benzaghou ◽

Thomas Yau ◽

...

Keyword(s):

Kinase Inhibitor ◽

Checkpoint Inhibitors ◽

Single Agent ◽

Phase Iii ◽

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

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

Frontiers in Oncology ◽

10.3389/fonc.2021.803133 ◽

2021 ◽

Vol 11 ◽

Author(s):

Alessandro Rizzo ◽

Angela Dalia Ricci ◽

Alessandro Di Federico ◽

Giorgio Frega ◽

Andrea Palloni ◽

...

Keyword(s):

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.

Real-World Efficacy and Safety of Lenvatinib in Korean Patients with Advanced Hepatocellular Carcinoma: A Multicenter Retrospective Analysis

Liver Cancer ◽

10.1159/000508901 ◽

2020 ◽

Vol 9 (5) ◽

pp. 613-624 ◽

Cited By ~ 2

Author(s):

Jaekyung Cheon ◽

Hong Jae Chon ◽

Yeonghak Bang ◽

Neung Hwa Park ◽

Jung Woo Shin ◽

...

Keyword(s):

Retrospective Analysis ◽

Real World ◽

Checkpoint Inhibitors ◽

Clinical Trial Data ◽

Progression Free Survival ◽

Phase Iii ◽

Efficacy And Safety ◽

First Line

Introduction/Objective: Lenvatinib demonstrated efficacy and safety in patients with advanced hepatocellular carcinoma (HCC) in the randomized phase III REFLECT trial. Considering the discrepancies in patients between clinical trial data and daily practice, an account of practical experience is needed. Methods: We conducted a multicenter retrospective analysis in which 3 tertiary referral centers participated. A total of 92 patients with advanced HCC treated with lenvatinib between September 2018 and January 2020 were analyzed. Results: Lenvatinib was used as the first-line therapy for 67 (72.8%) patients, and for 25 (27.2%) patients previously treated with other systemic therapy including immune checkpoint inhibitors. At the time of initiation of lenvatinib, 74 (80.4%) and 18 (19.6%) patients were classified as Child-Pugh A and B, respectively. Thirty-five patients (38.0%) had extensive disease that would have excluded them from the REFLECT trial. In the Child-Pugh A group, the response rate graded according to the Response Evaluation Criteria in Solid Tumors v1.1 was 21.1%, median progression-free survival (PFS) was 4.6 (95% confidence interval [CI] 3.1–6.1) months, and overall survival (OS) was 10.7 (95% CI 4.8–16.5) months for patients treated with first-line lenvatinib (n = 57). With second- or later-line lenvatinib (n = 17), median PFS and OS were 4.1 (95% CI 3.1–5.1) and 6.4 (95% CI 5.1–7.7) months, respectively. In the Child-Pugh B group (n = 18), median PFS and OS were 2.6 (95% CI 0.6–4.6) and 5.3 (95% CI 2.0–8.5) months, respectively. The most common grade 3–4 toxicities were hyperbilirubinemia (n = 8; 8.7%), AST elevation (n = 6; 6.5%), and diarrhea (n = 5; 5.4%) across all study patients. Conclusions: In this real-world study, lenvatinib was found to be well tolerated and effective in more heterogeneous HCC patient populations.

Immunotherapy for advanced hepatocellular carcinoma: a focus on special subgroups

Gut ◽

10.1136/gutjnl-2020-321702 ◽

2020 ◽

Vol 70 (1) ◽

pp. 204-214 ◽

Cited By ~ 4

Author(s):

Matthias Pinter ◽

Bernhard Scheiner ◽

Markus Peck-Radosavljevic

Keyword(s):

Solid Organ Transplantation ◽

Progression Free Survival ◽

Standard Of Care ◽

The United States ◽

Phase Iii ◽

Solid Organ ◽

United States Food ◽

Phase Iii Trials

Following the success of immune checkpoint blockers (ICBs) in different cancer types, a large number of studies are currently investigating ICBs in patients with hepatocellular carcinoma (HCC), alone or in combination with other treatments. Both nivolumab and pembrolizumab, as well as the combination of nivolumab plus ipilimumab have been granted accelerated approval by the United States Food and Drug Administration for sorafenib-pretreated patients. While nivolumab and pembrolizumab both failed to meet their primary endpoints in phase III trials, the combination of atezolizumab plus bevacizumab eventually improved overall and progression-free survival compared with sorafenib in a front-line phase III trial, and thus, will become the new standard of care in this setting. Despite this breakthrough, there are patient populations with certain underlying conditions that may not be ideal candidates for this new treatment either due to safety concerns or potential lack of efficacy. In this review, we discuss the safety of ICBs in patients with pre-existing autoimmune disease, IBD or a history of solid organ transplantation. Moreover, we summarise emerging preclinical and clinical data suggesting that ICBs may be less efficacious in patients with underlying non-alcoholic steatohepatitis or HCCs with activated Wnt/β-catenin signalling.

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

Zeitschrift für Gastroenterologie ◽

10.1055/a-1190-5681 ◽

2020 ◽

Vol 58 (08) ◽

pp. 773-777 ◽

Cited By ~ 2

Author(s):

Nadine Schulte ◽

Moying Li ◽

Tianzuo Zhan ◽

Lena Dreikhausen ◽

Janina Sollors ◽

...

Keyword(s):

Combination Therapy ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Standard Of Care ◽

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.

The Role of Immunotherapy in a Tolerogenic Environment: Current and Future Perspectives for Hepatocellular Carcinoma

Cells ◽

10.3390/cells10081909 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1909

Author(s):

Liliana Montella ◽

Federica Sarno ◽

Annamaria Ambrosino ◽

Sergio Facchini ◽

Maria D'Antò ◽

...

Keyword(s):

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Special Focus ◽

Future Perspectives ◽

Immune Organ ◽

Systemic Treatments ◽

Healthy Liver

In contrast to several tumors whose prognoses are radically affected by novel immunotherapeutic approaches and/or targeted therapies, the outcomes of advanced hepatocellular carcinoma (HCC) remain poor. The underlying cirrhosis that is frequently associated with it complicates medical treatment and often determines survival. The landscape of HCC treatment had included sorafenib as the only drug available for ten years, until 2018, when lenvatinib was approved for treatment. The second-line systemic treatments available for hepatocellular carcinoma include regorafenib, cabozantinib, ramucirumab, and, more recently, immune checkpoint inhibitors. However, the median survival remains below 15 months. The results obtained in clinics should be interpreted whilst considering the peculiar role of the liver as an immune organ. A healthy liver microenvironment ordinarily experiences stimulation by gut-derived antigens. This setup elucidates the response to chronic inflammation and the altered balance between tolerance and immune response in HCC development. This paper provides an overview of the mechanisms involved in HCC pathogenesis, with a special focus on the immune implications, along with current and future clinical perspectives.

Use of Antibiotics during Immune Checkpoint Inhibitor Treatment Is Associated with Lower Survival in Hepatocellular Carcinoma

Liver Cancer ◽

10.1159/000518090 ◽

2021 ◽

pp. 1-9

Author(s):

Ka Shing Cheung ◽

Lok Ka Lam ◽

Wai Kay Seto ◽

Wai K. Leung

Keyword(s):

Immune Checkpoint ◽

Checkpoint Inhibitors ◽

Antibiotic Use ◽

Adverse Outcomes ◽

Advanced Hcc ◽

Concurrent Use ◽

All Cause Mortality

Background: Recent studies suggested that use of antibiotics may interfere with treatment responses to immune checkpoint inhibitors (ICIs). We determined whether concurrent use of antibiotics during ICI therapy was associated with adverse outcomes in patients with advanced hepatocellular carcinoma (HCC). Methods: This is a territory-wide retrospective cohort study including all advanced HCC patients who received ICIs (nivolumab, pembrolizumab, or ipilimumab) between January 2014 and December 2019. Exclusion criteria included prior liver transplantation and use of cabozantinib, regorafenib, or ramucirumab. The exposure of interest was concurrent antibiotic use within 30 days before or after the commencement of ICI. The adjusted hazard ratio (aHR) of cancer-related mortality and all-cause mortality with antibiotic use was derived by propensity score (PS) matching in 1:2 ratio of covariates including baseline characteristics, causes of cirrhosis, Child-Pugh status, prior HCC treatment, comorbidities, concurrent medications, and laboratory results including alpha fetoprotein. Results: A total of 395 HCC patients who had received ICIs were included. During a median follow-up of 16.5 months (interquartile range [IQR]: 5.6–44.3), there were 286 (72.4%) deaths including 231 cancer-related deaths. The median time from the first ICI to event was 7.7 months (IQR: 4.0–16.8). PS matching of 56 antibiotic users with 99 nonusers showed that concurrent antibiotic use with ICI was associated with higher cancer-related (aHR: 1.66; 95% CI: 1.08–2.54) and all-cause mortality (aHR: 1.63; 95% CI: 1.17–2.28). Conclusions: Concurrent antibiotic use during immunotherapy was associated with higher mortality in patients with advanced HCC. Further studies should examine the role of gut dysbiosis on responses to ICI.

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

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.3_suppl.316 ◽

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):

Overall Survival ◽

Hong Kong ◽

Checkpoint Inhibitors ◽

Single Agent ◽

Objective Response ◽

Real Life ◽

Phase Iii ◽

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

Annual Review of Medicine ◽

10.1146/annurev-med-042220-021121 ◽

2021 ◽

Vol 73 (1) ◽

Author(s):

Rubens Copia Sperandio ◽

Roberto Carmagnani Pestana ◽

Beatriz Viesser Miyamura ◽

Ahmed O. Kaseb

Keyword(s):

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.

Molecular targeted and immune checkpoint therapy for advanced hepatocellular carcinoma

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-019-1412-8 ◽

2019 ◽

Vol 38 (1) ◽

Cited By ~ 20

Author(s):

Ziyu Liu ◽

Yan Lin ◽

Jinyan Zhang ◽

Yumei Zhang ◽

Yongqiang Li ◽

...

Keyword(s):

Phase Ii ◽

Checkpoint Inhibitors ◽

Phase Iii ◽

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.