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Asia has a disproportionate share of the world's burden of hepatocellular carcinoma (HCC). However, the highly regarded clinical practice guidelines and recommendations for the design and conduct of clinical trials for HCC largely reflect Western practice. In order to design mutually beneficial international clinical trials of promising targeted therapies, it is imperative to understand how the aetiology, staging and treatment of HCC differ between Asian and Western countries. Our group, comprising experts in oncology and hepatology from countries that constitute the Eastern Asian region, convened to compare and contrast our current practices, evaluate potential compliance with the clinical trial recommendations, and offer suggestions for modifications that would enhance international collaboration. Here, we describe the results of our discussions, including recommendations for appropriate patient stratification based on potentially important differences in HCC aetiology, identification of practices that may confound interpretation of clinical trial outcomes (traditional Chinese medicine; antivirals that target hepatitis B virus; heterogeneous embolization procedures), suggestions for utilizing a common staging system in study protocols, recognition that sorafenib usage is limited by financial constraints and potentially increased toxicity in Asian patients, and expansion of patient populations that should be eligible for initial clinical trials with new agents. [ABSTRACT FROM AUTHOR]

The largest burden of hepatocellular carcinoma (HCC) lies in Asia, secondary to hepatitis B virus (HBV) infection. Improved survival with sorafenib has fostered new research but many challenges remain in designing clinical trials. The disease, its management, and populations affected by it are heterogeneous worldwide and within Asia. An expert conference of Eastern Asian oncologists and hepatologists was convened to foster consensus in clinical trial design. The panel identified key areas that need to be addressed to facilitate clinical trials in Asia. Stratification by viral etiology is desirable within Asia and by region in global trials. Antiviral therapy should also be considered as a stratification factor and incorporated into HCC management in trials. The panel agreed that histological diagnosis is not required for trial entry and that Barcelona-Clinic Liver Cancer (BCLC) staging is acceptable for trials as long as portal hypertension can be better defined with standardized methodology. Consensus in treatment must be sought to allow multi-national trials and it must be recognized that first-line sorafenib is not largely feasible in Asia. Finally, Asian nations must be urged to participate in clinical trials, many of which are ongoing, to advance new treatment options in this challenging disease. [ABSTRACT FROM AUTHOR]

Background Nivolumab (NIVO), a programmed death-1 (PD-1) inhibitor, is approved in several countries for sorafenib-treated patients (pts) with advanced hepatocellular carcinoma (aHCC) based on CheckMate040. We report findings on exploratory biomarker analyses. Methods In CheckMate040, pts with aHCC received NIVO regardless of programmed death ligand 1 (PD-L1) status and HCC etiology. Baseline tumor samples were analyzed by IHC for expression of PD-L1, PD-1, T-cell markers (CD3, CD4, CD8, FOXP3), and macrophages (CD68, CD163), and (in a subset of pts) by RNA sequencing for inflammatory signatures (ISs). Results were correlated with clinical outcomes: response (complete response [CR]/partial response [PR]/stable disease [SD]/progressive disease [PD]) and overall survival (OS). Associations with etiology and geographical region (non-Asia vs Asia) were assessed. Data cutoff: June 2018. Results In 184 pts with evaluable data, increased tumor cell PD-L1 expression was associated with response (CR+PR vs SD [P = 0.00009]; CR+PR vs PD [P = 0.0007]) and OS (P = 0.03), as was increased PD-1 expression (CR+PR vs SD [P = 0.05]; CR+PR vs PD [P = 0.009]; OS [P = 0.05]). Of the T-cell markers assessed, CD3 was associated with response (n = 182, CR+PR vs SD; P = 0.05). In pts positive for CD3 or CD8, there was a trend toward improved OS (P = 0.08). There was no association between CD68 and CD163 expression and clinical outcomes. For 37 pts with RNA sequencing data available, median Bristol-Myers Squibb (BMS) IS score was higher in pts with PR vs SD (P = 0.05) and was correlated with improved OS (P = 0.01). For all inflammation markers assessed, there was no association with etiology or geographical region. Conclusions In pts with aHCC, improved OS and response to NIVO may be associated with higher PD-L1, PD-1, and CD3 expression, and higher BMS IS scores, supporting the role of PD-1 inhibition in HCC treatment. Further investigation of these biomarkers is required. Originally presented at the AACR 2019. [ABSTRACT FROM AUTHOR]

The largest burden of hepatocellular carcinoma (HCC) lies in Asia, secondary to hepatitis B virus (HBV) infection. Improved survival with sorafenib has fostered new research but many challenges remain in designing clinical trials. The disease, its management, and populations affected by it are heterogeneous worldwide and within Asia. An expert conference of Eastern Asian oncologists and hepatologists was convened to foster consensus in clinical trial design. The panel identified key areas that need to be addressed to facilitate clinical trials in Asia. Stratification by viral etiology is desirable within Asia and by region in global trials. Antiviral therapy should also be considered as a stratification factor and incorporated into HCC management in trials. The panel agreed that histological diagnosis is not required for trial entry and that Barcelona-Clinic Liver Cancer (BCLC) staging is acceptable for trials as long as portal hypertension can be better defined with standardized methodology. Consensus in treatment must be sought to allow multi-national trials and it must be recognized that first-line sorafenib is not largely feasible in Asia. Finally, Asian nations must be urged to participate in clinical trials, many of which are ongoing, to advance new treatment options in this challenging disease.

Hepatocellular carcinoma is a highly prevalent disease in many Asian countries, accounting for 75-80% of victims worldwide. The incidence of hepatocellular carcinoma varies enormously across Asia, but tends to follow the incidences of hepatitis B infection and liver cirrhosis. The incidence and etiology of hepatocellular carcinoma in Japan are different from the rest of Asia, but similar to that in Western countries because hepatitis C infection is the main etiological factor in Japan. Hepatitis B virus vaccination programs are showing great success in reducing hepatitis B virus-related hepatocellular carcinoma. Screening program improves detection of early hepatocellular carcinoma and has some positive impact on survival, but the majority of hepatocellular carcinoma patients in Asia still present with advanced hepatocellular carcinoma. Long-term outcomes following treatment of even early/intermediate or advanced disease are often unsatisfactory because of a lack of effective adjuvant and systemic therapies. Various clinical practice guidelines for hepatocellular carcinoma have been established and are in use. Clinical diagnosis of hepatocellular carcinoma by imaging diagnosis is replacing diagnosis of hepatocellular carcinoma by pathological confirmation. New imaging and treatment techniques are continuously being developed and guidelines should be updated every 3 or 4 years, incorporating new evidence. New molecularly targeted therapies hold great promise. Sorafenib is the first systemic therapy to demonstrate prolonged survival vs. the placebo in patients with advanced hepatocellular carcinoma. Various other new molecularly targeted agents are currently under investigation.