Systemic Therapy For Advanced Hepatocellular Carcinoma Research Articles

Assessment of Macrovascular Invasion in Advanced Hepatocellular Carcinoma: Clinical Implications and Treatment Outcomes with Systemic Therapy

<b><i>Introduction:</i></b> Macrovascular invasion (MVI) is a strong prognostic factor for advanced hepatocellular carcinoma (HCC). The current criteria for radiological assessment are unclear in evaluating the impact of MVI on systemic therapy. In this study, we standardized the assessment of MVI and validated its clinical relevance. <b><i>Methods:</i></b> Clinical data were collected from patients with advanced HCC and MVI who received first-line systemic therapy at four medical centers in Japan. First, we used MVI progressive disease (MVI-PD) to track MVI progression and Response Evaluation Criteria in Solid Tumors version 1.1 progressive disease (RECIST v1.1-PD) to evaluate tumor enlargement other than MVI and the appearance of new lesions. Next, we assessed the prognostic value of MVI-PD and RECIST v1.1-PD. <b><i>Results:</i></b> Of the 207 advanced HCC patients with MVI, 189 received appropriate imaging evaluation. Forty (21.2%) patients had MVI-PD and RECIST v1.1-PD, 51 (27.0%) had prior MVI-PD, and 61 (32.3%) had prior RECIST v1.1-PD. In a landmark analysis, the prognosis of 163 patients who survived more than 3 months was analyzed based on the assessment of imaging response during the first 3 months. The median overall survival (OS) was 5.4 months in those who had MVI-PD and RECIST v1.1-PD, 7.4 months in those who had RECIST v1.1-PD only, 7.2 months in those who had MVI-PD only, and 19.7 months in patients who had neither (<i>p</i> < 0.001). The correlation coefficients between progression-free survival and OS in patients with appropriate imaging assessments were similar for MVI-PD (0.515) and RECIST v1.1-PD (0.498). <b><i>Conclusion:</i></b> Our findings demonstrate the link between MVI progression and poor OS in systemic therapy for advanced HCC, emphasizing the importance of an accurate method for assessing MVI progression.

Hepatocellular Carcinoma: Advances in Systemic Therapy.

Hepatocellular carcinoma (HCC) is a prevalent primary liver cancer, representing over 90% of cases globally and ranking as the third leading cause of cancer-related death. This article reviews the evolving landscape of systemic therapies for advanced HCC, emphasizing recent advancements and their impact on patient outcomes. The advent of molecular targeted therapies has transformed HCC management, with sorafenib being the first FDA-approved molecular targeted therapy, setting a standard for a decade. However, recent breakthroughs involve the combination of atezolizumab and bevacizumab, demonstrating superior outcomes over sorafenib, leading to FDA approval in 2020. Another notable combination is tremelimumab and durvalumab, showing efficacy in a multinational phase III trial. Beyond these combinations, this article explores the role of other first-line treatments and subsequent therapies after progression. The evolving landscape of systemic therapies for HCC reflects a paradigm shift, with immunotherapy combinations emerging as key players alongside targeted therapies. This article highlights the complexity of treatment decisions, considering individual patient characteristics and disease etiology, and underscores the ongoing quest to optimize both systemic and local-regional therapies for improved long-term outcomes in HCC patients.

SLC7A11 in hepatocellular carcinoma: potential mechanisms, regulation, and clinical significance.

Exploring novel early detection biomarkers and developing more efficacious treatments remain pressing tasks in the current research landscape for hepatocellular carcinoma (HCC). Morphologically and molecularly separate from apoptosis, cell death, and autophagy, ferroptosis is a recently discovered, unique, controlled form of cell death. SLC7A11 (also known as xCT) represents a subunit of the cystine-glutamate antiporter (also known as system Xc(-)). A growing body of research suggests that induction of ferroptosis through SLC7A11 can effectively eliminate hepatocellular carcinoma (HCC) cells, particularly those exhibiting resistance to alternative forms of cell death. Thus, targeting ferroptosis via SLC7A11 may become a new direction for the design of therapeutic strategies for HCC. Although many research articles have investigated the possible roles of SLC7A11 in HCC, a study that summarizes the main findings, including the regulators and mechanisms of action of SLC7A11 in HCC is not available. Therefore, we present a comprehensive overview of the functions of ferroptosis, particularly SLC7A11, in the identification, development, and management of HCC in this review. In addition, we discuss how this knowledge can be translated into treatment by providing a systemic therapy in advanced HCC using sorafenib, the first-line drug targeting multiple kinases and SLC7A11. We further dissect the possible barriers as well as the corresponding solutions and provide insights on how to navigate effective treatment using this knowledge.

Comparative analysis of disease modelling for health economic evaluations of systemic therapies in advanced hepatocellular carcinoma.

The objective of this study was to systematically analyse methodological and structural assumptions utilised in model-based health economic evaluations of systemic advanced hepatocellular carcinoma (HCC) therapies, discuss the existing challenges, and develop methodological recommendations for future models in advanced HCC. We performed literature searches using five databases (Embase, PubMed, Web of Science, Econlit, and CNKI) up to December 4, 2022. Technology appraisals from Canada, England, Australia, and the United States were also considered. Model-based full economic evaluations of systemic advanced HCC therapies in English or Chinese met the eligibility criteria. The reporting quality was assessed by using the Consolidated Health Economic Evaluation Reporting Standards 2022 checklist. Of 12,863 records retrieved, 55 were eligible for inclusion. Markov model (n = 29, 53%) and partitioned survival model (n = 27, 49%) were the most commonly used modelling techniques. Most studies were based on health-state-driven structure (n = 51, 93%), followed by treatment-line-driven structure (n = 2, 4%) and combination structure (n = 1, 2%). Only three studies (5%) adopted external real-world data to extrapolate the overall survival or calibrate the extrapolation. Few studies reported the assumptions of transition probabilities. Utility modelling approaches were state-based (n = 51, 93%) and time-to-death (n = 1, 2%). Only 13 studies (24%) reported five types of model validation. Economic evaluation results of specific treatment strategies varied among studies. Disease modelling for health economic evaluations of systemic therapies in advanced HCC has adopted various modelling approaches and assumptions, leading to marked uncertainties in results. By proposing methodological recommendations, we suggest that future model-based studies for health economic evaluation of HCC therapies should follow good modelling practice guidelines and improve modelling methods to generate reliable health and economic evidence.

Combined radiotherapy and immune checkpoint inhibition for the treatment of advanced hepatocellular carcinoma.

Hepatocellular Carcinoma (HCC) is one of the most common cancers and a leading cause of cancer related death worldwide. Until recently, systemic therapy for advanced HCC, defined as Barcelona Clinic Liver Cancer (BCLC) stage B or C, was limited and ineffective in terms of long-term survival. However, over the past decade, immune check point inhibitors (ICI) combinations have emerged as a potential therapeutic option for patients with nonresectable disease. ICI modulate the tumor microenvironment to prevent progression of the tumor. Radiotherapy is a crucial tool in treating unresectable HCC and may enhance the efficacy of ICI by manipulating the tumor microenvironment and decreasing tumor resistance to certain therapies. We herein review developments in the field of ICI combined with radiotherapy for the treatment of HCC, as well as look at challenges associated with these treatment modalities, and review future directions of combination therapy.

Cabozantinib for Advanced Hepatocellular Carcinoma in the Latest Real-World Practice: A Multicenter Retrospective Analysis.

Cabozantinib was found to be effective as a second- or third-line treatment after sorafenib in patients with advanced hepatocellular carcinoma (HCC) in the phase 3 CELESTIAL trial. So far, as immunotherapy has substituted molecular target agents as the primary systemic therapy for advanced HCC, cabozantinib is extensively used in the latest real-world clinical practice in a greatly different position than that shown by the CELESTIAL trial. In the current analysis, we examined the safety and effectiveness of cabozantinib administration in real-life settings for patients with advanced HCC. We retrospectively obtained data from patients with advanced HCC who received cabozantinib in three institutions in Japan between 14 September 2018 and 30 November 2021. During the study period, 23 patients with advanced HCC received cabozantinib. Our cohort included 21.7% of patients with Child-Pugh class B, and 52.2% of patients in fourth line or later. The median progression-free survival of patients given cabozantinib was 3.7months. Regarding patients with Child-Pugh class B or administration in fourth line or later, the discontinuation rate due to adverse events in patients who initialized at 40 or 20mg was lower than those who initialized at 60mg (42.9% versus 75.0%). Patients who were able to continue treatment with cabozantinib for more than 3months were more likely to undergo dose reduction than those who did not (85.7% versus 25.0%). Cabozantinib has recently been administered to a diverse range of patients, including those who were not enrolled in the CELESTIAL trial. Deliberate dose reduction could potentially offer clinical benefits to patients with impaired liver function. Furthermore, managing adverse events by reducing the dose could play a crucial role in extending the duration of treatment with cabozantinib. The preprint version of this work is available on https://www.researchsquare.com/article/rs-2655181/v1 .

The clinical feasibility of circulating tumor DNA alterations in patients with advanced hepatocellular carcinoma.

4110 Background: Need for individualized treatment based on tumor attributes is being reinforced with the rapid development of targeted therapies and immune checkpoint inhibitors for hepatocellular carcinoma (HCC). Lack of mandatory tissue biopsy for the diagnosis of HCC, continues to be a challenge for development of precision medicine for HCC compared to other solid tumors. Liquid biopsy enables comprehensive genomic profiling of circulating tumor DNA (ctDNA) shed from tumors into the circulation. This could compensate for the lack of tissue-based analysis in HCC providing a non-invasive and safer option for genomic profiling. This study aims to address the concordance between commercially available ctDNA and tissue genomic profiling in patients with advanced HCC and to assess the feasibility of liquid biopsy in the treatment of patients with HCC. Methods: Patients subjected to tissue-based next-generation sequencing (NGS) before systemic therapy for advanced HCC at CHA Bundang Medical Center from June 2020 to October 2022 and also had sufficient plasma samples available for ctDNA analysis were included. Oncomine Comprehensive Assay (OCA) ThermoFisher was used for tissue-based NGS and Guardant360 for ctDNA based NGS. For the concordance assessment for the same patient, paired samples of ctDNA and tumor tissue, we investigated the common targeted regions across both the panels. Results: Out of hundred thirty patients included in this study, 98% percent of ctDNA samples for these patients were successfully sequenced; ctDNA were detected in 88% of the samples. For the assessment of concordance between intra-patient ctDNA and tumor tissues, we investigated only clinically important (AMP/ASCO/CAP guidelines tier 1 or 2) variants. When we considered the variants detected in tissues as true positive, the concordance between the mutations detected from ctDNA and tissue samples indicated 68.9% sensitivity and 63.1% positive predictive value (PPV). In ctDNA, targetable alterations were detected in 16.9% of samples, such as ARID1A mutations (7.7%), PTEN mutations (6.9%), PIK3CA hotspot mutations (1.5%), RAS mutations (1.5%), and one RET fusion (0.8%). Regarding the concordance between ctDNA and tumor tissue, the sensitivity for mutation was high for RAS mutation (100.0%), PTEN mutations (100.0%), and ARID1A mutations (75.0%) but low for PIK3CA hotspot mutations (0.0%). One RET fusion was identified only in ctDNA. Conclusions: ctDNA-based genotyping demonstrated clinically acceptable concordance with tissue genomic profiling in patients with advanced HCC. Thus, liquid biopsy using ctDNA help address any challenges associated with the limited use of tissue-based genomic profiling in HCC. Investigation of time between blood and tissue collection and the impact it has on concordance is ongoing.

Beneficial Effect of Combining Radiotherapy and Transarterial Chemoembolization on Patient Survival in Hepatocellular Carcinomas and Macrovascular Invasion Treated with Sorafenib.

Approximately 10-40% of hepatocellular carcinoma (HCC) patients have definite vascular invasion at the time of diagnosis. Without curative treatment options, these patients have an abysmal prognosis with a median survival of only a few months following systemic therapy. However, supportive evidence of combining multiple locoregional treatments with systemic therapy is limited. This study compared the outcomes of sorafenib alone versus multimodality therapy with sorafenib, radiotherapy (RT), and transarterial chemoembolization (TACE) in advanced HCC patients with macrovascular invasion (MaVI). The process took place over a nine-year period between March 2009 and October 2017, wherein 78 HCC patients with MaVI who underwent either sorafenib therapy alone (n = 49) or combined sorafenib/RT/TACE (n = 29) therapy were chosen for the retrospective study. We compared the overall survival (OS) between the two groups using the Cox regression hazard model and adjusted imbalances using propensity score matching (PSM). At the last follow-up, 76 patients had died, with a median follow-up time of 4.8 months for all patients and 31 months for those who were alive. Patients treated with sorafenib/RT/TACE had superior OS compared to those treated with sorafenib alone, showing a median survival of 9.3 vs. 2.7 months and a one-year survival of 37.1% vs. 6.1% (p < 0.001). In the multivariable analysis, new diagnosis or recurrence of HCC and treatment modalities (sorafenib alone vs. sorafenib/RT/TACE) were independent prognostic factors for OS. Compared to patients treated with sorafenib alone, significantly better OS was further verified using PSM (p < 0.001) in patients who received multiple therapeutic modalities. Multimodality therapy with sorafenib/RT/TACE increased OS threefold versus sorafenib therapy alone in HCC patients with MaVI. This study offers promising benefits of combined locoregional and systemic therapy for advanced HCC in current patient management and prospective clinical trials.

Baveno VII Criteria Is an Accurate Risk Stratification Tool to Predict High-Risk Varices Requiring Intervention and Hepatic Events in Patients with Advanced Hepatocellular Carcinoma.

The Baveno VII criteria are used in patients with liver cirrhosis to predict high-risk varices in patients with liver cirrhosis. Yet its use in patients with advanced hepatocellular carcinoma (HCC) has not been validated. HCC alone is accompanied with a higher variceal bleeding risk due to its association with liver cirrhosis and portal vein thrombosis. The use of systemic therapy in advanced HCC has been thought to further augment this risk. Upper endoscopy is commonly used to evaluate for the presence of varices before initiation of treatment with systemic therapy. Yet it is associated with procedural risks, waiting time and limited availability in some localities which may delay the commencement of systemic therapy. Our study successfully validated the Baveno VI criteria with a 3.5% varices needing treatment (VNT) missed rate, also with acceptable <5% VNT missed rates when considering alternative liver stiffness (LSM) and platelet cut-offs. The Baveno VII clinically significant portal hypertension rule-out criteria (LSM < 15 kPa and platelet >150 × 109/L) also revealed a low frequency (2%) of hepatic events, whilst the rule-in criteria (LSM > 25 kPa) was predictive of a higher proportion of hepatic events (14%). Therefore, our study has successfully validated the Baveno VII criteria as a non-invasive stratification of the risk of variceal bleeding and hepatic decompensation in the HCC population.

Sorafenib increases cytochrome P450 lipid metabolites in patient with hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a leading cause of cancer death, and medical treatment options are limited. The multikinase inhibitor sorafenib was the first approved drug widely used for systemic therapy in advanced HCC. Sorafenib might affect polyunsaturated fatty acids (PUFA)-derived epoxygenated metabolite levels, as it is also a potent inhibitor of the soluble epoxide hydrolase (sEH), which catalyzes the conversion of cytochrome-P450 (CYP)-derived epoxide metabolites derived from PUFA, such as omega-6 arachidonic acid (AA) and omega-3 docosahexaenoic acid (DHA), into their corresponding dihydroxy metabolites. Experimental studies with AA-derived epoxyeicosatrienoic acids (EETs) have shown that they can promote tumor growth and metastasis, while DHA-derived 19,20-epoxydocosapentaenoic acid (19,20-EDP) was shown to have anti-tumor activity in mice. In this study, we found a significant increase in EET levels in 43 HCC patients treated with sorafenib and a trend towards increased levels of DHA-derived 19,20-EDP. We demonstrate that the effect of sorafenib on CYP- metabolites led to an increase of 19,20-EDP and its dihydroxy metabolite, whereas DHA plasma levels decreased under sorafenib treatment. These data indicate that specific supplementation with DHA could be used to increase levels of the epoxy compound 19,20-EDP with potential anti-tumor activity in HCC patients receiving sorafenib therapy.

Survival Trends in Sorafenib for Advanced Hepatocellular Carcinoma: A Reconstructed Individual Patient Data Meta-Analysis of Randomized Trials

Background: Emerging data suggest that outcomes for advanced hepatocellular carcinoma (HCC) treated with sorafenib may have improved over time. We aimed to provide robust, time-to-event estimates of survival outcomes for sorafenib in advanced HCC. Summary: In this systematic review and individual patient data meta-analysis of randomized-controlled trials (RCTs), we searched MEDLINE and Embase from inception till September 2022 for RCTs that provided data for overall survival (OS) and progression-free survival (PFS) for sorafenib monotherapy as first-line systemic therapy for advanced HCC. We performed a pooled analysis using reconstructed individual participant data from published Kaplan-Meier curves to obtain robust estimates for OS and PFS. Of 1,599 articles identified, 29 studies (5,525 patients) met the inclusion criteria. Overall, the median OS was 10.4 (95% CI: 9.6–11.4) months. Median OS increased over time, from 9.8 (95% CI: 8.8–10.7) months in studies before 2015 to 13.4 (95% CI: 11.03–15.24) months in studies from 2015 onwards (p < 0.001). OS did not differ by trial phase, geographical region, or study design. The overall median PFS was 4.4 (95% CI: 3.9–4.8) months, but PFS did not improve over time. Sensitivity analysis of studies from 2015 and onwards to account for the introduction of direct-acting antivirals determined that hepatitis C virus was associated with reduced mortality (p < 0.001). There was minimal heterogeneity in the estimates for OS (all I² ≤ 33). Key Messages: Survival outcomes for sorafenib in advanced HCC have improved over time. These data have important implications for clinical trial design.

Updates on Organoid Model for the Study of Liver Cancer.

Liver cancer remains one of the most common cancers worldwide with limited therapy options. The main risk factors for hepatocellular carcinoma (HCC), the most common form of liver cancer, include chronic infection with hepatitis B or hepatitis C viruses, alcohol abuse, and metabolic disease. Current systemic therapies for advanced HCCs have greatly improved in the last decade, but there is still a need to develop more targeted drug therapy for HCCs. The development of liver organoids, a self-organising and self-renewal three-dimensional cell culture model, has greatly improved cancer research, including liver cancer. The generation of liver organoids provides a physiologically relevant model to study cancer drug screening and development, personalized medicine, liver disease modeling, and liver regeneration. However, the advent of organoid development also comes with few shortcomings that must be overcome, including the high cost of the model, the availability of origin tissues, and the need for multilineage liver organoids to replicate the true cellular heterogeneity of the liver. Despite all the limitations, liver organoids provide a reliable in vitro model for translational applications to develop more effective HCC therapy and to understand the underlying pathogenic mechanism in various liver diseases.

Risk of Variceal Bleeding in Patients With Advanced Hepatocellular Carcinoma Receiving Atezolizumab/Bevacizumab

Risk of Variceal Bleeding in Patients With Advanced Hepatocellular Carcinoma Receiving Atezolizumab/Bevacizumab

Drug Treatment for Advanced Hepatocellular Carcinoma: First-Line and Beyond.

Hepatocellular carcinoma (HCC) has high mortality. The option of systemic therapy has increased significantly over the past five years. Sorafenib was the first multikinase inhibitor, introduced in 2007, as a treatment option for HCC, and it was the only effective systemic treatment for more than ten years. It was not until 2017 that several breakthroughs were made in the development of systemic strategies. Lenvatinib, another multikinase inhibitor, stood out successfully after sorafenib, and has been applied to clinical use in the first-line setting. Other multikinase inhibitors such as regorafenib, ramucirumab and cabozantinib, were approved in quick succession as second-line therapies. Concurrently, immune checkpoint inhibitors (ICIs) have readily become established treatments for many solid tumors, including HCC. The most studied ICIs to date, target programmed cell death-1 (PD-1), its ligand PD-L1, and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). These ICIs have demonstrated efficacy in treating advanced HCC. More recently, combination of bevacizumab and atezolizumab (ICI targeting PD-L1) was approved as the gold-standard first-line therapy. Combination of ICIs with nivolumab and ipilimumab was also approved in the second-line setting for those who failed sorafenib. At the moment, numerous clinical trials in advanced HCC are underway, which will bring continuous change to the management, and increase the survival, for patients with advanced HCC. Our review article: (1) summarizes United States Food and Drug Administration (US FDA) approved systemic therapies in advanced HCC, (2) reports the evidence of currently approved treatments, (3) discusses potential drugs/drug combinations being currently tested in phase III clinical trials, and (4) proposes possible future directions in drug development for advanced HCC.

Conversion resection for patients with hepatocellular carcinoma and inferior vena cava tumor thrombus: a consecutive case series

Conversion resection for patients with hepatocellular carcinoma and inferior vena cava tumor thrombus: a consecutive case series

Clinical outcomes associated with tislelizumab in patients (pts) with advanced hepatocellular carcinoma (HCC) who have been previously treated with sorafenib (SOR) or lenvatinib (LEN) in RATIONALE-208.

4072 Background: Tislelizumab, an anti-PD-1 monoclonal antibody, demonstrated clinical activity and was well tolerated in pts with previously treated advanced HCC in the Phase 2 RATIONALE-208 study (NCT03419897). At the time of this study, SOR and LEN were recommended first-line treatments for pts with advanced HCC and continue to have an important role in the first-line treatment of HCC despite the recent approval of new immuno-oncology-based combinations (atezolizumab and bevacizumab) in some regions. We report the clinical outcomes of pts with advanced HCC who were previously treated with SOR/LEN. Methods: Pts who had received ≥ 1 prior line of systemic therapy for advanced HCC received tislelizumab 200 mg intravenously once every three weeks. Objective response rate (ORR) by independent review committee (IRC) (ORRIRC), duration of response by IRC (DORIRC), progression-free survival by IRC (PFSIRC), overall survival (OS), and safety were evaluated in pts who had been previously treated with SOR/LEN. Results: As of February 2020, 249 pts were enrolled and 235 pts had received prior treatment with SOR/LEN, of whom 126 and 109 pts had received 1 or ≥ 2 prior lines of systemic therapy, respectively. At study entry, 211 (89.8%) pts had BCLC stage C and 187 (79.6%) pts had extrahepatic spread. Median follow-up duration for pts previously treated with SOR/LEN was 12.5 months and ORRIRC was 13.6% (95% CI: 9.5, 18.7), including 2 complete responses and 30 partial responses. Median DORIRC was not reached. Median PFSIRC and OS of pts previously treated with SOR/LEN was 2.7 months (95% CI: 1.6, 2.8) and 13.5 months (95% CI: 10.9, 15.8), respectively. Tislelizumab was generally well tolerated in pts previously treated with SOR/LEN (Table), and the most common treatment-emergent adverse events were increased aspartate aminotransferase (n=70; 28.1%) and alanine aminotransferase (n=52; 20.9%). Conclusions: Tislelizumab was investigated beyond the first-line setting, as effective second- and third-line treatment options are limited for pts with advanced HCC and there is an unmet medical need. This analysis indicates that tislelizumab is clinically active and well tolerated in pts with advanced HCC who have received prior systemic treatment with SOR/LEN. Clinical trial information: NCT03419897. [Table: see text]

Clinical outcomes in patients (pts) with previously treated advanced hepatocellular carcinoma (HCC) experiencing hepatitis B virus (HBV) DNA increases during tislelizumab (TIS) treatment in RATIONALE-208.

e16181 Background: The effect of checkpoint inhibitor therapy on HBV infection is uncertain. TIS, an anti-PD-1 antibody, was clinically active and well tolerated in pts with previously treated advanced HCC in the Phase 2 RATIONALE-208 study (NCT03419897). Objective response rate by independent committee review (IRC) in pts with a history of HBV infection was consistent with the overall population (12.5% vs 13.3%, respectively). We explored whether TIS treatment was associated with increased HBV DNA and the clinical significance of HBV DNA elevations. Methods: Pts with ≥ 1 prior systemic therapy for advanced HCC received TIS 200 mg IV Q3W. Pts with inactive, chronic, or active HBV were eligible if HBV DNA levels were &lt; 500 IU/mL at screening (pts with detectable hepatitis B surface antigen [HBsAg] or detectable HBV DNA were required to be managed per treatment guidelines). HBV DNA testing was conducted every 4 cycles if HBV DNA was detectable at screening, or when clinically indicated. Results: Among 249 enrolled pts, 128 had a history of HBV infection. Of these pts, 114 were HBsAg positive at baseline (BL), 36 had detectable HBV DNA at BL, and 32 had detectable HBV DNA and HBsAg at BL. Clinically significant increases in HBV DNA levels from BL were reported in 7 pts, with no pattern relative to the time of TIS initiation (Table). All 7 pts were HBsAg positive at BL and had been receiving antiviral treatment for ≥ 3 months before the first dose of TIS. Six out of the 7 pts had increases in alanine transaminase (ALT) from BL during the study (Table), 4 of whom had ≥ 3-fold increases in ALT which were observed concurrently or soon after HBV DNA increases. IRC-assessed best overall response (BOR) was partial response (PR) for 1 pt with increased HBV DNA and progressive disease for the remaining 6. HBV-related treatment-emergent adverse events (TEAEs) were reported in 6 of the 7 pts (2 pts had a Grade 3 TEAE of hepatitis B; 2 pts had a Grade 2 TEAE of HBV reactivation; 2 pts had a TEAE of increased HBV DNA, with one Grade 1 and one Grade 3 event). All HBV-related TEAEs were non-serious and did not result in discontinuation of TIS. Conclusions: Clinically significant increases in HBV DNA from BL were reported in a small number of pts, which does not suggest that TIS is associated with increased HBV DNA. Tumor responses in these pts were consistent with the overall population and HBV-related TEAEs were manageable and did not require discontinuation of TIS, demonstrating that HBV DNA increases did not impact treatment. The effects of TIS in pts with HBV infection will be further investigated in an ongoing Phase 3 trial (NCT03412773). Clinical trial information: NCT03419897. [Table: see text]

Systemic Therapy in Metastatic Hepatocellular Carcinoma

Multiple new tyrosine kinase inhibitors, immunotherapies and anti-angiogenic therapies are now available for the treatment of advanced hepatocellular carcinoma (HCC). In this article, we reviewed the evidence supporting these new therapies. The combination of atezolizumab and bevacizumab has become a new standard of care for initial systemic therapy in eligible patients, replacing sorafenib in the first line for many patients. Lenvatinib, a multikinase inhibitor, is also a new first line treatment option for patients who are not eligible for immunotherapy. Several additional options for second line treatment were also reviewed in detail in this paper. New systemic therapies for advanced HCC have prolonged overall survival. However, these new therapies are primarily approved for patients with Child-Pugh A classification with few options for patients with Child-Pugh B disease. Further work is needed to expand options for patients with more advanced liver disease and to optimize the sequencing of these new therapies.

Rapidly Evolving Landscape and Future Horizons in Hepatocellular Carcinoma in the Era of Immuno-Oncology.

Hepatocellular carcinoma (HCC) is a serious global health problem as one of the leading causes of cancer-related death worldwide. Systemic therapy for advanced HCC has progressed with the development of molecular targeted agents, however survival benefits remain modest. More recently, immune checkpoint inhibitors (ICI) have emerged and exhibited promising therapeutic benefits in a subset of patients. Physiologically, the intrinsic microenvironment in the liver is immunosuppressive, which represents a major obstacle for effective immune therapies in primary and secondary liver malignancies. For this reason, combination therapies that can overcome immune inhibitory mechanisms and enhance the immune response are a rationale approach for drug development in HCC. A recent example is the combination of the anti-PD-L1 antibody (atezolizumab) and anti-VEGF-A antibody (bevacizumab), which has shown significant improvement in survival as compared to standard of care in the first-line treatment for HCC. Other immunotherapy approaches including cancer vaccines and adoptive cell therapy are also under investigation. This review summarizes the key trials leading to our current HCC treatment options and provides an overview of future immune-based strategies in development.

Conversion surgery after preoperative therapy for advanced hepatocellular carcinoma in the era of molecular targeted therapy and immune checkpoint inhibitors.

Optimal strategies for advanced hepatocellular carcinoma (HCC) tumors, such as those with vascular tumor thrombus and those with extrahepatic metastases are unclear. A literature review was conducted focusing on conversion surgery for HCC after molecular targeted therapy and therapy using immune checkpoint inhibitors. Upfront surgical resection of advanced HCC tumors has been challenged at some institutions because of lack of promising therapeutic options. Preoperative transcatheter arterial chemoembolization, hepatic arterial infusion chemotherapy, and radiotherapy in patients with unresectable HCC were developed to improve long-term outcome, but the results were not promising. Nonetheless, the recent advent of molecular targeted therapies and immune check-point inhibitors, enabling frequent tumor responses, has accelerated the use of conversion surgery after these therapies in patients with initially unresectable HCC. Increasing numbers of conversion surgeries after lenvatinib therapy has been reported, and the first prospective clinical trial assessing conversion surgery after lenvatinib therapy in initially unresectable HCC has been commenced. Furthermore, the superiority of combination therapy using atezolizumab and bevacizumab over sorafenib, a conventional first-line drug for unresectable HCC, in terms of overall survival and tumor response has been demonstrated, and the use of this regimen alongside conversion surgery is expected in addition to lenvatinib. The literature demonstrated the feasibility of conversion surgery after systemic therapy. Further clinical investigation of surgery after systemic therapy for advanced HCC may be undertaken by clearly distinguishing the tumor status as technically unresectable or oncologically unresectable but technically resectable.