Trials Of Advanced Hepatocellular Carcinoma Research Articles

Clinical outcomes by Child-Pugh Class in patients with advanced hepatocellular carcinoma in a community oncology setting.

Many pivotal trials in advanced hepatocellular carcinoma (HCC) require participants to have Child-Pugh A disease. However, many patients in real-world practice are Child-Pugh B or C. This study examined treatment patterns and clinical outcomes in patients with advanced HCC treated with first-line systemic therapy. In this retrospective study, patients with HCC treated with first-line systemic therapy (2010-2017) were identified from US Oncology Network records. Outcomes included overall survival and progression-free survival, by Child-Pugh Class and prior liver-directed therapy. Of 352 patients, 78.7% were Child-Pugh A or B, 96.6% received first-line sorafenib, and 33.8% received first-line-prior liver-directed therapy. Survival outcomes were similar for Child-Pugh A or B, and longer after first-line prior liver-directed therapy. First-line systemic therapy is beneficial in patients with Child-Pugh A or B, and after first-line prior liver-directed therapy. These findings may help position systemic therapy in the community setting.

Abstract IA14: Lessons learned from phase III trials in HCC: OS, PFS and ORR

Abstract Through well conducted phase III trials, recent development of molecularly targeted agents, immune checkpoint inhibitors, and combination strategies in advanced hepatocellular carcinoma (HCC) has significantly improved the treatment outcome in this disease. The median overall survival (OS) for patients receiving the new standard treatment, atezolizumab plus bevacizumab, has approached to 20 months in IMbrave150 trial. While OS remains the gold standard and main endpoint for phase III trials in advanced HCC, there is an increasing need to define surrogate endpoints including progression free survival (PFS) and overall response rate (ORR) that can reliably predict the survival benefits. The author will discuss the rationale and current status of using PFS and ORR as surrogate endpoints in HCC, and the strengths and limitations of PFS and ORR as surrogate endpoints to predict survival. Citation Format: Andrew X. Zhu. Lessons learned from phase III trials in HCC: OS, PFS and ORR [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA14.

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.

Advanced hepatocellular carcinoma: Impact of systemic treatments on health‐related quality of life and patient‐reported outcomes

AbstractIn the past years, treatment options for advanced hepatocellular carcinoma (HCC) have thriven. Although globally recognised, the patient‐reported outcomes (PROs) are often underused and quality of life (QoL) results are underreported in many phase III trials. We performed a systematic review to describe the prevalence of QoL inclusion and heterogeneity in QoL reporting in published phase III trials of systemic treatment in advanced HCC. Twenty‐one publications were identified: 12 (57.1%) in first line setting, eight (38.1%) in second line and only one (4.7%) in second and further lines. In 14 trials (66.6%), Qol was included in the analysis as a secondary or tertiary endpoint but only in nine (47.4%) cases Qol results were published in the main paper. QoL data are lacking in a significant proportion of published phase III trials in advanced HCC. The methodology of QoL analysis is heterogeneous for type of instruments, analysis and presentation of results.

Meta-analysis of surrogate endpoints for survival in patients with unresectable hepatocellular carcinoma treated with immune checkpoint inhibitor-based regimens.

483 Background: Overall survival (OS) remains the gold standard for demonstrating clinical benefit in advanced hepatocellular carcinoma (HCC). While surrogate radiology-based endpoints for OS, such as progression-free survival (PFS) and objective response rate (ORR) are commonly used in the field of oncology, they remain controversial in the setting of HCC where antiangiogenic agents were the mainstay of treatment until recently. Immune checkpoint inhibitors (CPIs) as monotherapy or in combination have shifted the treatment paradigm in HCC. We investigated the surrogacy of radiology-based endpoints from CPI clinical trials in advanced HCC. Methods: Study level data were collected for disclosures published in EMBASE, PubMed, Clinicaltrials.gov and conference abstracts. Keywords used included (abbreviated here): immune CPIs, advanced or metastatic HCC and ORR, PFS and OS. Key inclusion criteria included: Phase I, II and III trial data, and patients with advanced or metastatic HCC who received CPI monotherapy or in a combination regimen. The endpoints investigated were median OS (mOS), median PFS (mPFS) and ORR (RECIST v1.1). A weighted Pearson correlation coefficient, with weights corresponding to the number of patients in the different treatment arms of the trials, was calculated between ORR/mOS, ORR/mPFS and mPFS/mOS in all arms, arms that included only patients with Child-Pugh A liver function, and arms in the first-line therapy setting. 95% confidence intervals (CIs) based on the empirical bootstrap re-sampling method are also reported. Results: Eighteen clinical trials (8 randomized trials and 10 multi-cohort trials) published between 2017 and 2021, including 3,246 patients across 32 treatment arms, were selected for inclusion in this meta-analysis. Ten trials included CPI monotherapy arms, 5 trials included CPI + TKI arms, 4 trials included CPI + anti-angiogenic monoclonal antibody arms, and 2 trials included CPI + CPI arms. There was 1 CPI + chemotherapy arm and 1 CPI + CPI + TKI arm in separate trials. Weighted Pearson correlation coefficients and corresponding 95% CIs are presented in the table. Conclusions: Our analysis suggests ORR/mOS, ORR/mPFS, and mPFS/mOS are positively correlated, with ORR/mPFS more strongly correlated compared to the other pairs, in patients with advanced HCC who were treated with CPI-based regimens. [Table: see text]

Trends in treatment for hepatocellular carcinoma in Japan

Hepatocellular carcinoma (HCC) is the fifth leading cause of cancer deaths in Japan, and it has gradually decreased in the last quarter century. The reason for the decrease in HCC patients is the decrease of patients with hepatitis C virus due to avoiding unnecessary blood transfusions and development of direct-acting antiviral agents (DAAs), which have been available since 2014, along with interferon and oral antiviral agents in Japan. On the other hand, the numbers of HCC patients with non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD) are increasing. In the treatment strategy for HCC in the Japanese guideline, the algorithm involves five clinicopathological factors: liver function (assessed using the Child-Pugh classification, liver damage score, and the ICG-R15 value), presence of extrahepatic metastases, presence of vascular invasion, number of tumors (within 3 or more than 4), and tumor size (within 3 cm or over 3 cm). Surgical resection is sometimes indicated for extrahepatic metastases in patients with well-controlled intrahepatic HCC, and for advanced HCC with vascular invasion, hepatectomy is also recommended as one of the treatment options according to the results of a nationwide survey in Japan. In the latest Japanese guideline, the recommended chemotherapy for advanced HCC is lenvatinib or sorafenib as first-line and regorafenib as second-line therapy. Currently, based on the results of various clinical trials for advanced HCC, the therapeutic options for advanced HCC have increased, such as combination therapy of atezolizumab and bevacizumab, ramucirumab, and cabozantinib. Reports of conversion surgery after chemotherapy have also increased, and the development of multidisciplinary treatment for advanced HCC will be of further interest in the future.

SO-9 Outcomes for patients with advanced hepatocellular carcinoma and Child-Pugh B liver function in the phase 3 CELESTIAL study of cabozantinib vs placebo

Patients with advanced hepatocellular carcinoma (HCC) and Child-Pugh B liver cirrhosis have poor prognosis, limited treatment options, and are underrepresented in clinical trials. In the CELESTIAL trial (NCT01908426), cabozantinib improved overall survival (OS) and progression-free survival (PFS) versus placebo in previously treated patients with advanced HCC. Like other phase 3 trials in advanced HCC, CELESTIAL limited eligibility to patients with Child-Pugh A liver function. We retrospectively analyzed data from patients in CELESTIAL whose cirrhosis evolved to Child-Pugh B by Week 8, the time of the first Child-Pugh assessment post-randomization.

Surrogacy of Time to Progression for Overall Survival in Advanced Hepatocellular Carcinoma Treated with Systemic Therapy: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Time to progression (TTP) is widely used as the endpoint in early-phase trials of advanced hepatocellular carcinoma (HCC). However, the relevance of using TTP as a surrogate marker for overall survival (OS) in pivotal trials remains uncertain. The PubMed database and ASCO Meeting Library were searched for reports of randomized controlled trials that investigated patients with advanced HCC, included data for both OS and TTP, and were launched between 2009 and 2016. The correlation between hazard ratios (HRs) for TTP and OS was determined using weighted linear regression. Correlations between median OS and TTP, and between median OS and postprogression survival (PPS), defined as the period obtained by subtracting the median TTP from the median OS, were also evaluated. The database search yielded 24 trials with 50 arms. Overall, TTP HR correlated with OS HR (R = 0.73); however, the coefficient in the regression equation was 0.48. The correlation between median OS and median TTP was not so strong (R = 0.50), whereas the correlation between median OS and median PPS was strong (R = 0.78). In advanced HCC, the OS HR can be predicted from the TTP HR, which is useful when considering whether to proceed to a pivotal trial based on the results of early-phase trials. TTP may be a better endpoint than OS for evaluating a novel agent in a pivotal trial, because an improvement in antitumor effect cannot fully reflect an improvement in OS due to the strong impact of PPS on OS.

Surrogacy of time to prgression for overall survival in advanced hepatocellular carcinoma treated with systemic therapy: A systematic review and meta-analysis of randomized controlled trials.

403 Background: Time to progression (TTP) is widely used as the endpoint in early-phase trials for advanced hepatocellular carcinoma (HCC). However, the relevance of using TTP as a surrogate marker for overall survival (OS) in pivotal trials remains uncertain. Methods: The PubMed database and ASCO meeting library were searched for reports of randomized controlled trials that investigated patients with advanced HCC, included data for both OS and TTP, and were launched between 2009 and 2016. Correlation between hazard ratios (HRs) for TTP and OS was determined using weighted linear regression. Correlations between median OS and TTP, and between median OS and post-progression survival (PPS), defined as the period obtained by subtracting median TTP from median OS, were also evaluated. Results: The database search yielded 24 trials with 50 arms. Overall, TTP HR correlated with OS HR (R = 0.73); however, the coefficient in the regression equation was 0.48. When trials were stratified by treatment line, TTP HR was more strongly correlated with OS HR in second-line (R = 0.91) than in first-line (R = 0.77) settings. Correlation between median OS and median TTP was weak (R = 0.50), whereas the correlation between median OS and median PPS was strong (R = 0.78). Conclusions: In advanced HCC, the OS HR can be predicted from the TTP HR, especially in second-line trials, which is useful when considering whether to proceed to a pivotal trial based on the results of early-phase trials. However, TTP may not be appropriate as a primary endpoint in a pivotal trial if the trial aims to evaluate the survival benefit of novel agents because improvement of TTP cannot fully reflect improvement of OS because of the impact of PPS on OS.

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

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

Tumor biopsy and patient enrollment in clinical trials for advanced hepatocellular carcinoma.

Tumor biopsies may help to reliably distinguish hepatocellular carcinoma (HCC) from other tumors, mostly cholangiocarcinoma as well as to identify the patient populations who most benefit from target-driven HCC treatments, in order to improve the success rate of experimental therapies. Clarifying tumor biology may also lead to identify biomarkers with prognostic role and/or enabling to predict response or resistance to therapies. Recently, clinical trials have more efficiently included biomarker endpoints and increasingly collected tumor tissue from enrolled patients. Due to their frail status and sometimes fast-progressing disease, the performance status of patients with HCC progressing on first-line therapy can deteriorate quickly, preventing their enrollment in clinical trials. However, the challenge of identifying the proper patient at the proper time can be overcome by periodic inter-department meetings involving the key specialists taking care of HCC patients, and solid networks between research centers and referring institutions. An early planned biopsy would also facilitate timely inclusion of patients in biology-driven clinical trials. Ultimately, institution of multidisciplinary teams can optimize treatment choice, biopsy timing, and quick enrollment of patients in clinical trials, before their performance status deteriorates.

Current trends and recent advances in diagnosis, therapy, and prevention of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) has been one of the most fatal malignant tumors worldwide and its associated morbidity and mortality remain of significant concern. Based on in-depth reviews of serological diagnosis of HCC, in addition to AFP, there are other biomarkers: Lens culinaris agglutinin-reactive AFP (AFP-L3), des- carboxyprothrombin (DCP), tyrosine kinase with Ig and eprdermal growth factor (EGF) homology domains 2 (TIE2)-espressing monocytes (TEMs), glypican-3 (GPC3), Golgi protein 73 (GP73), interleukin-6 (IL-6), and squamous cell carcinoma antigen (SCCA) have been proposed as biomarkers for the early detection of HCC. The diagnosis of HCC is primarily based on noninvasive standard imaging methods, such as ultrasound (US), dynamic multiphasic multidetector-row CT (MDCT) and magnetic resonance imaging (MRI). Some experts advocate gadolinium diethyl-enetriamine pentaacetic acid (Gd-EOB-DTPA) MRI and contrast-enhanced US as the promising imaging madalities of choice. With regard to recent advancements in tissue markers, many cuting-edge technologies using genome-wide DNA microarrays, qRT-PCR, and proteomic and inmunostaining studies have been implemented in an attempt to identify markers for early diagnosis of HCC. Only less than half of HCC patients at initial diagnosis are at an early stage treatable with curative options: local ablation, surgical resection, or liver transplant. Transarterial chemoembolization (TACE) is considered the standard of care with palliation for intermediate stage HCC. Recent innovative procedures using drug-eluting-beads and radioembolization using Yttrium-90 may exhibit beneficial effects in HCC treatment. During the past few years, several molecular targeted agents have been evaluated in clinical trials in advanced HCC. Sorafenib is currently the only approved systemic treatment for HCC. It has been approved for the therapy of asymptomatic HCC patients with well-preserved liver function who are not candidates for potentially curative treatments, such as surgical resection or liver transplantation. In the USA, Europe and particularly Japan, hepatitis C virus (HCV) related HCC accounts for most liver cancer, as compared with Asia-Pacific regions, where hepatitis B virus (HBV) may play a more important role in HCC development. HBV vaccination, while a vaccine is not yet available against HCV, has been recognized as a best primary prevention method for HBV-related HCC, although in patients already infected with HBV or HCV, secondary prevention with antiviral therapy is still a reasonable strategy. In addition to HBV and HCV, attention should be paid to other relevant HCC risk factors, including nonalcoholic fatty liver disease due to obesity and diabetes, heavy alcohol consumption, and prolonged aflatoxin exposure. Interestingly, coffee and vitamin K2 have been proven to provide protective effects against HCC. Regarding tertiary prevention of HCC recurrence after surgical resection, addition of antiviral treatment has proven to be a rational strategy.

Somatostatin receptor expression in hepatocellular carcinoma: prognostic and therapeutic considerations.

Sorafenib is the only systemic therapy to demonstrate a significant survival benefit over supportive care in robust randomised controlled trials for advanced hepatocellular carcinoma (HCC). In the context of an intense search for prognostic and predictive factors for response and efficacy of different systemic therapies (including sorafenib), a number of molecular targets have been identified, paving new avenues for potential therapeutic opportunities. Such molecular targets include somatostatin receptor (SSTR)-related alterations. In this review, we provide an overview of the various considerations relating to SSTRs as potentially novel prognostic and predictive biomarkers for HCC with special emphasis on the therapeutic potential of somatostatin analogues in HCC management.

A comparative study of circulating biomarkers of anti-VEGF therapy in phase II trials in advanced hepatocellular carcinoma (HCC) patients (pts).

2543 Background: Sorafenib, a multikinase inhibitor of VEGFR, remains the only approved systemic therapy in HCC. Several other anti-VEGFR agents have either failed or continued in phase III trials....

Emerging Targeted Strategies in Advanced Hepatocellular Carcinoma

Treatment of advanced-stage hepatocellular carcinoma (HCC) remains a challenge because of the complex nature of the disease and the lack of available therapies. The antiangiogenic multikinase inhibitor sorafenib is the first therapy to demonstrate a significant overall survival benefit in advanced HCC. However, new agents for both first- and second-line treatment of advanced HCC are needed. The multiple pathways involved in HCC oncogenesis, proliferation, and survival provide many opportunities for the development of molecularly targeted therapies. Many novel agents are under investigation in phase III trials in advanced HCC, including antiangiogenic multikinase inhibitors (e.g., brivanib, sunitinib, linifanib) and inhibitors of the mammalian target of rapamycin (mTOR) pathway (e.g., everolimus). Although these therapies have demonstrated some utility as single agents in advanced HCC, rational combinations of therapies are likely to provide greater success. Current research efforts are directed at combining agents targeting different molecular pathways (e.g., sorafenib in combination with erlotinib) and combining molecularly targeted agents with systemic chemotherapy or transarterial chemoembolization (TACE). Therapies targeting other molecular pathways in HCC are in early development; future research will focus on discovering additional targets for therapy and identifying biomarkers that predict the success of current therapies.

Prognosis of advanced hepatocellular carcinoma patients enrolled in clinical trials can be classified by current staging systems

Background:Patients enrolled in clinical trials of advanced hepatocellular carcinoma (HCC) are usually required to have good liver reserve and organ function. However, their outcomes are still highly variable. We aimed to examine whether current staging systems can predict the survival of these highly selected patients.Methods:Patients from clinical trials involving first-line anti-angiogenic therapy were assigned to different stage groups using the American Joint Committee on Cancer (AJCC), Barcelona Clinic Liver Cancer (BCLC), China integrated score, Cancer of the Liver Italian Program (CLIP) score, Chinese University Prognostic Index (CUPI), Groupe d’Etude et de Traitement du Carcinome Hepatocellulaire (GETCH), Japan Integrated Staging (JIS) score, Okuda, Tokyo score, and a new staging system recently proposed. Survival prediction by the 10 systems was then compared by both univariate and multivariate analyses.Results:A total of 157 patients were selected for this study. In univariate analysis, all staging systems can predict patient survival except AJCC, BCLC, and JIS score. Concordance indexes for CLIP score, CUPI, and GETCH (0.752, 0.775, and 0.791, respectively) were significantly higher than those obtained for other staging systems. In multivariate analysis, the CLIP score and CUPI (P<0.001 and 0.009, respectively) predicted survival more accurately than did the other tested staging systems. Hepatitis B infection and poor performance status were also associated with poor survival.Conclusion:Several HCC staging systems, especially the CLIP score and CUPI, can predict prognosis of patients who are enrolled in clinical trials of advanced HCC.

Sorafenib for the treatment of hepatocellular carcinoma across geographic regions

Sorafenib is an oral multikinase inhibitor targeting Raf, VEGF receptor, PDGF receptor, c-kit, Flt-3 and rearranged during transfection (RET). Two randomized, placebo-controlled trials for Western and Asian patients, respectively, demonstrated that sorafenib significantly prolongs overall survival and time to progression in patients with advanced hepatocellular carcinoma (HCC). These have become the reference treatment for future clinical trials of advanced HCC. Sorafenib is well tolerated in patients with Child–Pugh liver function class A, but limited data are available in Child–Pugh class B and C patients. Clinical trials are ongoing to test the efficacy of sorafenib-based combination therapy and sorafenib adjuvant therapy for HCC.

Assessment of health‐related quality of life and patient benefit as outcome measures for clinical trials in hepatocellular carcinoma

AbstractAim: The purpose of the study was to determine the feasibility and validity of using health‐related quality of life (HRQL) and patient benefit as outcome measures in a phase II trial of octreotide long acting release (LAR) for hepatocellular carcinoma (HCC); and, to determine aspects of HRQL that were most impaired and aspects that changed.Methods: Sixty‐three patients with advanced HCC were treated with octreotide LAR. HRQL was assessed monthly with the Functional Assessment of Cancer Therapy – Hepatobiliary Questionnaire (FACT‐Hep) and the Patient Disease and Treatment Assessment Form (Patient DATA Form). Benefit was assessed directly by asking subjects at 1 month about change from baseline using the Patient Benefit Form. Convergent, discriminative and predictive validity were assessed by testing a priori hypotheses.Results: Seventy‐three percent completed a baseline assessment of HRQL. Compliance decreased over time. Fatigue, energy, anxiety, pain, insomnia, and emotional well‐being were the most impaired aspects of HRQL on the Patient DATA Form. Convergent validity was supported by 52 of 57 hypothesized correlations. Predictive validity was supported by associations between survival and four aspects of HRQL. Patients' direct assessments of benefit for common symptoms were moderately associated with changes in their scores on the Patient DATA Form.Conclusion: Use of the FACT Hep and Patient DATA Form is feasible in trials of advanced HCC. The validity of the direct measure of patient benefit was questionable, despite its intuitive attraction. Fatigue, anxiety, insomnia, and impaired emotional well‐being were prominent, are probably under‐recognized in practice, and are worthy of future research.