Comparative efficacy of novel combination strategies for unresectable hepatocellular carcinoma: A network metanalysis of phase III trials.

BACKGROUND: Dual programmed cell death-1 and vascular endothelial growth factor pathway inhibition is the novel standard of care for patients with unresectable hepatocellular carcinoma. Direct comparisons between first-line treatments are lacking. METHOD: We conducted a literature search in MEDLINE (https://pubmed.ncbi.nlm.nih.gov), the Cochrane library (https://www.cochranelibrary.com) and Embase (www.embase.com) between January 2007 and February 2022. We included phase III randomised controlled trials that tested immune-checkpoint inhibitors or tyrosine kinase inhibitors, including sorafenib, lenvatinib and donafenib, and evaluated as primary end-point overall survival (OS) or progression-free survival (PFS). Studies testing loco-regional therapies were excluded. The primary end-point was to compare the efficacy of first-line options in terms of OS and PFS. We extracted Hazard ratios (HR) and 95% confidence intervals (95% CI) for OS and PFS and performed a frequentist network meta-analysis with fixed effect multivariable meta-regression models. The research protocol was registered in PROSPERO, an international prospective register of systematic reviews (registration code CRD42022312489). FINDINGS: Literature review yielded 13709 results, after duplicates removal and exclusion of not relevant studies, 70 papers were available for screening. After full-text review, 9 studies were eligible for analysis. Atezolizumab plus bevacizumab reduced the risk of death compared to placebo (HR 0·40; 95% CI 0·28-0·57), sorafenib (HR 0·58; 95% CI 0·42-0·80), lenvatinib (HR 0·63; 95% CI 0·44-0·89), atezolizumab plus cabozantinib (HR 0·64; 95% CI 0·43-0·97), nivolumab (HR 0·68; 95% CI 0·48-0·98) and donafenib (HR 0·69; 95% CI 0·48-0·99). Atezolizumab plus bevacizumab was not statistically superior to durvalumab plus tremelimumab (HR 0·74; 95% CI 0·52-1·06) and sintilimab plus IBI305 (HR 1·02; 95% CI 0·67-1·55) in reducing the risk of death. Efficacy was associated with a higher risk of grade 3 adverse events.

Novel immunotherapy combinations in clinical trials for hepatocellular carcinoma: will they shape the future treatment landscape?

INTRODUCTION: Underlying liver disease and the intrinsic chemoresistance have historically hampered the development of efficacious treatments in HCC. However, in the last few years, immunotherapy-based combinations have emerged as efficacious therapeutic strategy in this setting. This paper critically summarizes the recent therapeutic progress in the systemic treatment of HCC. AREA COVERED: This paper examines the preclinical rationale of the following combinations in HCC: dual checkpoint inhibitors, immune checkpoint inhibitors plus anti-angiogenic agents, and immune checkpoint inhibitors plus tyrosine kinase inhibitors. Results of recent clinical studies are presented, along with a brief overview of ongoing and future trials. EXPERT OPINION: The approval of atezolizumab plus bevacizumab and the positive results of the HIMALAYA trial have broadened the therapeutic scenario for advanced HCC, opening, at the same time, new challenges. First of all, predictive biomarkers to allocate patients to the best treatment are eagerly required; second, specific studies are urgently needed to define the use of new combinations in patients usually excluded from clinical trials, e.g. those with deranged liver function and HIV or transplant recipients. Finally, with new combinations being translated into earlier stages, profound changes are soon expected in the adjuvant and neoadjuvant setting.

New Frontiers in the Medical Therapy of Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common primary liver tumor, and it rates fourth as a cause of cancer-related death. The presence of underlying liver disease and poor chemosensitivity pose major treatment challenges in the management of HCC. However, in the last few years, the therapeutic scenario has substantially changed, and immunotherapy in the form of immune checkpoint inhibitors (ICPIs) has become an essential therapeutic strategy in this field. SUMMARY: After controversial results of monotherapy, ICPIs have been mainly investigated in association with antiangiogenic agents or as dual checkpoint inhibition. The combination of atezolizumab plus bevacizumab has become the new therapeutic standard for unresectable HCC. Currently, a number of ICPI-based combinations are being studied in phase III clinical trials as front-line therapy for advanced HCC, with growing interest in integration of early-stage disease management in the form of adjuvant or neoadjuvant therapies. With most of the trials investigating ICPIs as first-line treatment, the second-line scenario relies mainly on tyrosine kinase inhibitors, which however have not been formally trialed after ICPIs. KEY MESSAGES: In this review, we summarize the main therapeutic advances in the systemic management of HCC focusing on the most relevant ongoing trials. We also discuss the main issues arising from a such rapidly evolving field including therapeutic sequencing and patient stratification.

ALBI grade: Evidence for an improved model for liver functional estimation in patients with hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) usually arises in the context of a chronically damaged liver. Liver functional estimation is of paramount importance in clinical decision making. The Child-Pugh score (CPS) can be used to categorise patients into 3 classes (A to C) based on the severity of liver functional impairment according to 5 parameters (albumin, bilirubin, prothrombin time, presence of ascites and hepatic encephalopathy). The albumin-bilirubin (ALBI) grade has emerged as an alternative, reproducible and objective measure of liver functional reserve in patients with HCC, defining worsening liver impairment across 3 grades (I to III). The ALBI score can identify different subgroups of patients with different prognoses across the diverse Barcelona Clinic Liver Cancer stages and CP classes, making it an appealing clinical predictor. In patients treated with potentially curative approaches (resection, transplantation, radiofrequency ablation, microwave ablation), ALBI grade has been shown to correlate with survival, tumour relapse, and post-hepatectomy liver failure. ALBI grade also predicts survival, toxicity and post-procedural liver failure in patients treated with transarterial chemoembolisation, radioembolisation, external beam radiotherapy as well as multi-kinase inhibitors (sorafenib, lenvatinib, cabozantinib, regorafenib) and immune checkpoint inhibitor therapy. In this review, we summarise the body of evidence surrounding the role of ALBI grade as a biomarker capable of optimising patient selection and therapeutic sequencing in HCC.

Arterial stiffness is associated independently with liver stiffness in biopsy-proven nonalcoholic fatty liver disease: a transient elastography study.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) has been associated with an increased arterial stiffness. However, the question as to whether an association exists between the extent of vascular and liver stiffness in patients with biopsy-proven NAFLD remains open. In this study, we sought to investigate whether pulse wave velocity (PWV) and augmentation index (AIx) - two common indices of arterial stiffness - are associated with (a) liver stiffness measurement (LSM) on transient elastography (TE) and (b) histological liver fibrosis. PATIENTS AND METHODS: We examined 125 patients with biopsy-proven NAFLD and 55 age-matched and sex-matched controls. Arterial stiffness of the brachial artery was measured using a Mobil-O-Graph arteriography system. LSM was assessed using TE, whereas the presence of advanced fibrosis (F ≥ 3) was determined on histology. RESULTS: Patients with NAFLD had higher PWV [median: 7.2 (6.3-8.2) and 6.2 (5.5-6.7) m/s, respectively, P < 0.001] and AIx (mean: 21.3 ± 13.5 and 17.2 ± 11.9%, respectively, P=0.01) compared with the controls. LSM showed positive correlations with both PWV (ρ = 0.300; P<0.01) and AIx (ρ = 0.223, P = 0.02). Both indices of arterial stiffness were higher in patients with advanced fibrosis than in those with nonadvanced fibrosis (F ≤ 2). CONCLUSION: The severity of arterial and liver stiffness increases in parallel in patients with biopsy-proven NAFLD. Systematic risk assessment for reducing arterial stiffness is recommended in the presence of TE-determined advanced fibrosis.