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Purpose: Transarterial chemoembolization (TACE) may prime adaptive immunity and enhance immunotherapy efficacy. PETAL evaluated safety, preliminary activity of TACE plus pembrolizumab and explored mechanisms of efficacy., Patients and Methods: Patients with liver-confined hepatocellular carcinoma (HCC) were planned to receive up to two rounds of TACE followed by pembrolizumab 200 mg every 21 days commencing 30 days post-TACE until disease progression or unacceptable toxicity for up to 1 year. Primary endpoint was safety, with assessment window of 21 days from pembrolizumab initiation. Secondary endpoints included progression-free survival (PFS) and evaluation of tumor and host determinants of response., Results: Fifteen patients were included in the safety and efficacy population: 73% had nonviral cirrhosis; median age was 72 years. Child-Pugh class was A in 14 patients. Median tumor size was 4 cm. Ten patients (67%) received pembrolizumab after one TACE; 5 patients after two (33%). Pembrolizumab yielded no synergistic toxicity nor dose-limiting toxicities post-TACE. Treatment-related adverse events occurred in 93% of patients, most commonly skin rash (40%), fatigue, and diarrhea (27%). After a median follow-up of 38.5 months, objective response rate 12 weeks post-TACE was 53%. PFS rate at 12 weeks was 93% and median PFS was 8.95 months [95% confidence interval (CI): 7.30-NE (not estimable)]. Median duration of response was 7.3 months (95% CI: 6.3-8.3). Median overall survival was 33.5 months (95% CI: 11.6-NE). Dynamic changes in peripheral T-cell subsets, circulating tumor DNA, serum metabolites, and in stool bacterial profiles highlight potential mechanisms of action of multimodal therapy., Conclusions: TACE plus pembrolizumab was tolerable with no evidence of synergistic toxicity, encouraging further clinical development of immunotherapy alongside TACE., (©2024 The Authors; Published by the American Association for Cancer Research.)

Introduction: While essential for cost-effectiveness analyses, there are no current resource use and cost data available for advanced hepatocellular carcinoma (HCC) and selective internal radiation therapy (SIRT). The study aims to assess current resource use and costs in HCC and for SIRT compared to historical survey data., Areas Covered: To address this data gap, resource use was elicited via surveys and interviews with medical professionals experienced with HCC and SIRT in the United Kingdom. Unit costs were from publicly available databases. Resource use and costs were estimated and compared to prior surveys., Expert Opinion: From eleven responses, pre-progression costs for SIRT and systemic therapy were £256.77 and £292.27/month, respectively. One-off progression and post-progression costs were £209.98 and £522.84/month. Monthly costs were 54%-79% lower than in previous surveys, due to reduction in hospitalizations and funded social care. Furthermore, substantial differences in resource use associated with SIRT between clinical practice and clinical trials were found. In conclusion, increased availability and familiarity with systemic treatments has led to important changes in HCC care and SIRT administration. The uncertainty from the use of expert opinion and the limited number of hospitals with SIRT experience can be addressed with future research using large databases, registries.

Purpose: To study the impact of transarterial Yttrium-90 radioembolization (TARE) in combination with second-line systemic chemotherapy for colorectal liver metastases (CLM)., Methods: In this international, multicenter, open-label phase III trial, patients with CLM who progressed on oxaliplatin- or irinotecan-based first-line therapy were randomly assigned 1:1 to receive second-line chemotherapy with or without TARE. The two primary end points were progression-free survival (PFS) and hepatic PFS (hPFS), assessed by blinded independent central review. Random assignment was performed using a web- or voice-based system stratified by unilobar or bilobar disease, oxaliplatin- or irinotecan-based first-line chemotherapy, and KRAS mutation status., Results: Four hundred twenty-eight patients from 95 centers in North America, Europe, and Asia were randomly assigned to chemotherapy with or without TARE; this represents the intention-to-treat population and included 215 patients in the TARE plus chemotherapy group and 213 patients in the chemotherapy alone group. The hazard ratio (HR) for PFS was 0.69 (95% CI, 0.54 to 0.88; 1-sided P = .0013), with a median PFS of 8.0 (95% CI, 7.2 to 9.2) and 7.2 (95% CI, 5.7 to 7.6) months, respectively. The HR for hPFS was 0.59 (95% CI, 0.46 to 0.77; 1-sided P < .0001), with a median hPFS of 9.1 (95% CI, 7.8 to 9.7) and 7.2 (95% CI, 5.7 to 7.6) months, respectively. Objective response rates were 34.0% (95% CI, 28.0 to 40.5) and 21.1% (95% CI, 16.2 to 27.1; 1-sided P = .0019) for the TARE and chemotherapy groups, respectively. Median overall survival was 14.0 (95% CI, 11.8 to 15.5) and 14.4 months (95% CI, 12.8 to 16.4; 1-sided P = .7229) with a HR of 1.07 (95% CI, 0.86 to 1.32) for TARE and chemotherapy groups, respectively. Grade 3 adverse events were reported more frequently with TARE (68.4% v 49.3%). Both groups received full chemotherapy dose intensity., Conclusion: The addition of TARE to systemic therapy for second-line CLM led to longer PFS and hPFS. Further subset analyses are needed to better define the ideal patient population that would benefit from TARE., Competing Interests: Mary F. MulcahyResearch Funding: BTG Armeen MahvashHonoraria: Sirtex MedicalConsulting or Advisory Role: Sirtex Medical, Boston Scientific, AbbiskoSpeakers' Bureau: SIR-TexResearch Funding: BTG, Sirtex MedicalTravel, Accommodations, Expenses: BTG, SIR-TexOpen Payments Link: https://openpaymentsdata.cms.gov/physician/1192235 Marc PrachtTravel, Accommodations, Expenses: MSD Steve BandulaHonoraria: Varian Medical Systems Robert C. G. MartinConsulting or Advisory Role: Angiodynamics Ken HerrmannLeadership: Sofibio, Theragnostics, Pharma15Stock and Other Ownership Interests: Sofibio, Theragnostics, Pharma15, Aktis OncologyConsulting or Advisory Role: Novartis, Bain Capital, Bayer, Advanced Accelerator Applications, Amgen, BTG, Ipsen, ITG, ROTOP Pharmaka, Siemens Healthineers, GE Healthcare Ewan BrownResearch Funding: MSD Oncology Gregory WilsonStock and Other Ownership Interests: Tandem Diabetes Care, Regeneron, Novacyt, Spire Hospital GroupConsulting or Advisory Role: Delcath Systems Paul RossStock and Other Ownership Interests: Perci Health LtdHonoraria: Sirtex Medical, Eisai, Servier, Pierre Fabre, Shire, Roche, AstraZeneca, MerckConsulting or Advisory Role: Sirtex Medical, Eisai, Servier, Roche, AstraZeneca, AmgenSpeakers' Bureau: Amgen, Merck, Servier, Boston ScientificResearch Funding: Sanofi, BayerTravel, Accommodations, Expenses: Roche, Ipsen William P. HarrisConsulting or Advisory Role: Neo Therma, Eisai, Exelixis, Bristol Myers Squibb, QED Therapeutics, Zymeworks, BD Medical, MerckResearch Funding: ArQule, Exelixis, Halozyme, Bristol Myers Squibb, MedImmune, Agios, Bayer, Merck, BTG, Boston Scientific, Koo Foundation, ZymeworksTravel, Accommodations, Expenses: Eisai Janet GrahamHonoraria: Merck Serono, Bristol Myers Squibb, Nucana, BayerConsulting or Advisory Role: Merck KGaATravel, Accommodations, Expenses: Nucana Jamie MillsTravel, Accommodations, Expenses: GenesisCare UK Matthew S. JohnsonStock and Other Ownership Interests: Endoshape, FluidXConsulting or Advisory Role: Argon Medical Devices, Boston Scientific, Cook MedicalResearch Funding: Argon Medical Devices, Boston Scientific, Black SwanExpert Testimony: Argon Medical Devices Constantinos T. SofocleousHonoraria: Ethicon/Johnson & JohnsonConsulting or Advisory Role: Varian Medical Systems, BTG, Sirtex Medical, TerumoSpeakers' Bureau: Ethicon/Johnson & JohnsonResearch Funding: BTG, Ethicon, Sirtex MedicalTravel, Accommodations, Expenses: Ethicon/Johnson & Johnson, Terumo Siddharth A. PadiaConsulting or Advisory Role: Boston Scientific, Bristol Meyer Squibb, Johnson & Johnson, Teleflex Medical, Varian Medical SystemsResearch Funding: Varian Medical Systems Robert J. LewandowskiConsulting or Advisory Role: Boston Scientific, BD Bard, Varian Medical Systems, ABKSpeakers' Bureau: Boston Scientific Etienne GarinHonoraria: BTG/Boston ScientificConsulting or Advisory Role: BTG/Boston ScientificTravel, Accommodations, Expenses: BTG/Boston Scientific Philip SinclairEmployment: Boston ScientificStock and Other Ownership Interests: Boston Scientific Riad SalemConsulting or Advisory Role: Eisai, Bard Medical, Cook Medical, Boston Scientific, Sirtex Medical, AstraZeneca, QED Therapeutics, Genentech/Roche, SiemensResearch Funding: Boston ScientificNo other potential conflicts of interest were reported.

Background: Advanced hepatocellular carcinoma (HCC) is commonly diagnosed using non-invasive radiological criteria (NIRC) defined by the European Association for the Study of the Liver or the American Association for the Study of Liver Diseases. In 2017, The National Institute for Clinical Excellence mandated histological confirmation of disease to authorise the use of sorafenib in the UK., Methods: This was a prospective multicentre audit in which patients suitable for sorafenib were identified at multidisciplinary meetings. The primary analysis cohort (PAC) was defined by the presence of Child-Pugh class A liver disease and performance status 0-2. Clinical, radiological and histological data were reported locally and collected on a standardised case report form., Results: Eleven centres reported 418 cases, of which 361 comprised the PAC. Overall, 76% had chronic liver disease and 66% were cirrhotic. The diagnostic imaging was computed tomography in 71%, magnetic resonance imaging in 27% and 2% had both. Pre-existing histology was available in 45 patients and 270 underwent a new biopsy, which confirmed HCC in 93.4%. Alternative histological diagnoses included cholangiocarcinoma (CC) and combined HCC-CC. In cirrhotic patients, NIRC criteria had a sensitivity of 65.4% and a positive predictive value of 91.4% to detect HCC. Two patients (0.7%) experienced mild post-biopsy bleeding., Conclusion: The diagnostic biopsy is safe and feasible for most patients eligible for systemic therapy., (© 2021. The Author(s).)

Background: The study assessed the cost-utility of selective internal radiation therapy (SIRT) with Y-90 resin microspheres versus sorafenib in UK patients with unresectable hepatocellular carcinoma ineligible for transarterial chemoembolization. Materials & methods: A lifetime partitioned survival model was developed for patients with low tumor burden (≤25%) and good liver function (albumin-bilirubin grade 1). Efficacy, safety and quality of life data were from a European Phase III randomized controlled trial and published studies. Resource use was from registries and clinical surveys. Results: Discounted quality-adjusted life-years were 1.982 and 1.381, and discounted total costs were £29,143 and 30,927, for SIRT and sorafenib, respectively. Conclusion: SIRT has the potential to be a dominant (more efficacious/less costly) or cost-effective alternative to sorafenib in patients with unresectable hepatocellular carcinoma.

Aim: To determine whether a liver tumor burden ≤25% and well-preserved liver function (albumin-bilirubin grade 1) are appropriate criteria for identifying patients with unresectable hepatocellular carcinoma who may benefit from selective internal radiation therapy (SIRT) using 90 yttrium resin microspheres versus sorafenib. Patients & methods: Post-hoc analysis of patients in the intention-to-treat population of the SARAH trial (SIRT vs sorafenib) with ≤25% tumor burden and albumin-bilirubin grade 1. Primary end point: overall survival. Results: Median overall survival was 21.9 months (95% CI: 15.2-32.5, n = 37) with SIRT and 17.0 months (11.6-20.8, n = 48) with sorafenib (hazard ratios: 0.73; 95% CI: 0.44-1.21; p = 0.22). Conclusion: A combination of good liver function and low tumor burden may be relevant for selection of hepatocellular carcinoma patients for SIRT.

Purpose: Refametinib, an oral MEK inhibitor, has demonstrated antitumor activity in combination with sorafenib in patients with RAS -mutated hepatocellular carcinoma (HCC). Two phase II studies evaluated the efficacy of refametinib monotherapy and refametinib plus sorafenib in patients with RAS -mutant unresectable or metastatic HCC. Patients and Methods: Eligible patients with RAS mutations of cell-free circulating tumor DNA (ctDNA) determined by beads, emulsion, amplification, and magnetics technology received twice-daily refametinib 50 mg ± sorafenib 400 mg. Potential biomarkers were assessed in ctDNA via next-generation sequencing (NGS). Results: Of 1,318 patients screened, 59 (4.4%) had a RAS mutation, of whom 16 received refametinib and 16 received refametinib plus sorafenib. With refametinib monotherapy, the objective response rate (ORR) was 0%, the disease control rate (DCR) was 56.3%, overall survival (OS) was 5.8 months, and progression-free survival (PFS) was 1.9 months. With refametinib plus sorafenib, the ORR was 6.3%, the DCR was 43.8%, OS was 12.7 months, and PFS was 1.5 months. In both studies, time to progression was 2.8 months. Treatment-emergent toxicities included fatigue, hypertension, and acneiform rash. Twenty-seven patients had ctDNA samples available for NGS. The most frequently detected mutations were in TERT (63.0%), TP53 (48.1%), and β-catenin ( CTNNB1 ; 37.0%). Conclusions: Prospective testing for RAS family mutations using ctDNA was a feasible, noninvasive approach for large-scale mutational testing in patients with HCC. A median OS of 12.7 months with refametinib plus sorafenib in this small population of RAS -mutant patients may indicate a synergistic effect between sorafenib and refametinib-this preliminary finding should be further explored. Clin Cancer Res; 24(19); 4650-61. ©2018 AACR ., (©2018 American Association for Cancer Research.)

This report describes a case of hepatocellular carcinoma in an adolescent with perinatally acquired HIV and hepatitis B virus coinfection, arising despite more than a decade of suppressive antiretroviral therapy for both HIV and hepatitis B virus. This case raises important questions regarding optimal hepatocellular carcinoma screening in this high-risk group and the oncogenic potential of even very well-controlled viral infection.

Combined hepatocellular-cholangiocarcinoma (cHCC-CC) is a rare and aggressive primary liver cancer with both hepatocellular and cholangiocellular differentiation. Due to its bi-phenotypic component, cHCC-CC is a heterogeneous tumour and histopathological analysis of metastatic deposits is poorly characterized. In this retrospective study, we describe four patients in whom the histology from resected specimens of both primary and recurrent and/or metastatic tumour was available for comparison and immunohistochemical characterization. Our study shows that recurrent or metastatic deposits replicate the heterogeneity of the primary cHCC-CC, that even originally small foci of divergent differentiation can become predominant later on and that hepatocellular and cholangiocellular components can show different tropism in distant organs. In our experience, the behaviour of recurrent/metastatic cHCC-CC is unpredictable and histological examination is necessary to guide treatment options at present.

Hepatocellular carcinoma is one of the fastest growing causes of cancer-related mortality worldwide. Sorafenib was the first and only drug to improve survival for patients with advanced disease, and has been the cornerstone of treatment for nearly a decade. Regorafenib is a multikinase inhibitor that has recently been shown to significantly improve survival in patients who have progressed on first-line sorafenib. In this review, we discuss the pharmacokinetic and pharmacodynamics properties of regorafenib and its efficacy and tolerability in patients with advanced hepatocellular carcinoma.

Metabolic syndrome (MetS) is associated with non-alcoholic fatty liver disease, which may progress to cirrhosis, a significant risk factor of hepatocellular carcinoma (HCC), the commonest malignant primary liver cancer (PLC). We investigated the association between the individual components of MetS (lipids, apolipoproteins, raised glucose, diabetes and obesity), PLC and cirrhosis. A total of 509,436 participants from the Swedish AMORIS cohort, recruited between January 1985 and December 1996 (end-date December 2011), aged ≥20 with baseline triglycerides (TG), total cholesterol (TC), glucose and liver enzymes were included. Those with baseline benign liver tumours, PLC or cirrhosis were excluded. Multivariate Cox regression, adjusted for age, gender, socio-economic status, liver disease (excluding cirrhosis) and MetS factors were used to estimate the association with PLC and cirrhosis. There were 766 PLC and 2,775 cirrhosis cases over 13 years. Raised TG, low TC, raised glucose, diabetes and low HDL were associated with an increased risk of developing PLC and cirrhosis. ApoB/ApoA-I ratio were also associated with PLC, whilst low LDL, raised TG/HDL, low ApoA-I and low ApoB were associated with cirrhosis. Obesity was significantly associated with PLC but not cirrhosis. Raised TG, low TC, raised glucose and diabetes showed stronger associations with PLC in participants with cirrhosis but many participants developed PLC without cirrhosis. Individual components of MetS (lipids, apolipoproteins, raised glucose, diabetes and obesity) were associated with an increased risk of developing PLC or cirrhosis. MetS components were more strongly associated with PLC with preceding cirrhosis history but many participants developed PLC without cirrhosis., (© 2017 UICC.)

Background: Transarterial chemoembolisation (TACE) is the standard of care for patients with intermediate stage hepatocellular carcinoma, while the multikinase inhibitor sorafenib improves survival in patients with advanced disease. We aimed to determine whether TACE with sorafenib improves progression-free survival versus TACE with placebo., Methods: We did a multicentre, randomised, placebo-controlled, phase 3 trial (TACE 2) in 20 hospitals in the UK for patients with unresectable, liver-confined hepatocellular carcinoma. Patients were eligible if they were at least aged 18 years, had Eastern Cooperative Oncology Group performance status of 1 or less, and had Child-Pugh A liver disease. Patients were randomised 1:1 by computerised minimisation algorithm to continuous oral sorafenib (400 mg twice-daily) or matching placebo combined with TACE using drug-eluting beads (DEB-TACE), which was given via the hepatic artery 2-5 weeks after randomisation and according to radiological response and patient tolerance thereafter. Patients were stratified according to randomising centre and serum α-fetoprotein concentration (<400 ng/mL and ≥400 ng/mL). Only the trial coordinator was unmasked to treatment allocation before patient progression during the study. The primary endpoint was progression-free survival defined as the interval between randomisation and progression according to Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1) or death due to any cause, and was analysed by intention-to-treat. Safety was analysed by intention-to-treat. The trial has been completed and the final results are reported. The trial is registered at EudraCT, number 2008-005073-36, and ISRCTN, number ISRCTN93375053., Findings: Between Nov 4, 2010, and Dec 7, 2015, the trial enrolled 399 patients and was terminated after a planned interim futility analysis. 86 patients failed screening and 313 remaining patients were randomly assigned: 157 to sorafenib and 156 to placebo. The median daily dose was 660 mg (IQR 389·2-800·0) sorafenib versus 800 mg (758·2-800·0) placebo, and median duration of therapy was 120·0 days (IQR 43·0-266·0) for sorafenib versus 162·0 days (70·0-323·5) for placebo. There was no evidence of difference in progression-free survival between the sorafenib group and the placebo group (hazard ratio [HR] 0·99 [95% CI 0·77-1·27], p=0·94); median progression-free survival was 238·0 days (95% CI 221·0-281·0) in the sorafenib group and 235·0 days (209·0-322·0) in the placebo group. The most common grade 3-4 adverse events were fatigue (29 [18%] of 157 patients in the sorafenib group vs 21 [13%] of 156 patients in the placebo group), abdominal pain (20 [13%] vs 12 [8%]), diarrhoea (16 [10%] vs four [3%]), gastrointestinal disorders (18 [11%] vs 12 [8%]), and hand-foot skin reaction (12 [8%] and none). At least one serious adverse event was reported in 65 (41%) of 157 patients in the sorafenib group and 50 (32%) of 156 in the placebo group, and 181 serious adverse events were reported in total, 95 (52%) in the sorafenib group and 86 (48%) in the placebo group. Three deaths occurred in each group that were attributed to DEB-TACE. Four deaths were attributed to study drug; three in the sorafenib group and one in the placebo group., Interpretation: The addition of sorafenib to DEB-TACE does not improve progression-free survival in European patients with hepatocellular carcinoma. Alternative systemic therapies need to be assessed in combination with TACE to improve patient outcomes., Funding: Bayer PLC and BTG PLC., (Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: There are no systemic treatments for patients with hepatocellular carcinoma (HCC) whose disease progresses during sorafenib treatment. We aimed to assess the efficacy and safety of regorafenib in patients with HCC who have progressed during sorafenib treatment., Methods: In this randomised, double-blind, parallel-group, phase 3 trial done at 152 sites in 21 countries, adults with HCC who tolerated sorafenib (≥400 mg/day for ≥20 of last 28 days of treatment), progressed on sorafenib, and had Child-Pugh A liver function were enrolled. Participants were randomly assigned (2:1) by a computer-generated randomisation list and interactive voice response system and stratified by geographical region, Eastern Cooperative Oncology Group performance status, macrovascular invasion, extrahepatic disease, and α-fetoprotein level to best supportive care plus oral regorafenib 160 mg or placebo once daily during weeks 1-3 of each 4-week cycle. Investigators, patients, and the funder were masked to treatment assignment. The primary endpoint was overall survival (defined as time from randomisation to death due to any cause) and analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01774344., Findings: Between May 14, 2013, and Dec 31, 2015, 843 patients were screened, of whom 573 were enrolled and randomised (379 to regorafenib and 194 to placebo; population for efficacy analyses), and 567 initiated treatment (374 received regorafenib and 193 received placebo; population for safety analyses). Regorafenib improved overall survival with a hazard ratio of 0·63 (95% CI 0·50-0·79; one-sided p<0·0001); median survival was 10·6 months (95% CI 9·1-12·1) for regorafenib versus 7·8 months (6·3-8·8) for placebo. Adverse events were reported in all regorafenib recipients (374 [100%] of 374) and 179 (93%) of 193 placebo recipients. The most common clinically relevant grade 3 or 4 treatment-emergent events were hypertension (57 patients [15%] in the regorafenib group vs nine patients [5%] in the placebo group), hand-foot skin reaction (47 patients [13%] vs one [1%]), fatigue (34 patients [9%] vs nine patients [5%]), and diarrhoea (12 patients [3%] vs no patients). Of the 88 deaths (grade 5 adverse events) reported during the study (50 patients [13%] assigned to regorafenib and 38 [20%] assigned to placebo), seven (2%) were considered by the investigator to be related to study drug in the regorafenib group and two (1%) in the placebo group, including two patients (1%) with hepatic failure in the placebo group., Interpretation: Regorafenib is the only systemic treatment shown to provide survival benefit in HCC patients progressing on sorafenib treatment. Future trials should explore combinations of regorafenib with other systemic agents and third-line treatments for patients who fail or who do not tolerate the sequence of sorafenib and regorafenib., Funding: Bayer., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: Sorafenib is the standard of care for patients with advanced hepatocellular carcinoma (HCC), but data on its use in the elderly are inconclusive., Methods: All consecutive HCC patients who were treated in our institution with sorafenib since its licensing were included in the analysis. Patients were divided into two groups: (A) up to 75 and (B) older than 75 years old. Our endpoints were overall survival (OS) and time to treatment failure (TTF) because of disease progression or toxicity. Safety parameters and the prognostic effect of HCC characteristics were also investigated., Results: Data from 190 patients (157 men), median age 66 (26-87) years, were studied (A=151 and B=39). No significant difference in OS and TTF was detected between the two groups [7.1 (5.5-8.7) vs. 10.4 (6.5-14.3) months, P=0.360 and 4.2 (2.3-6.2) vs. 5.6 (3.1-8.1) months, P=0.369, respectively]. Incidence of toxicities at all grades and dose reductions were comparable between groups A and B. In a multivariate setting, patients with Child-Pugh B score at baseline were associated with a higher risk of death (adjusted hazard ratio=2.17, 95% confidence interval:1.24-3.79, P=0.007) and treatment failure (adjusted hazard ratio=4.64, 95% confidence interval: 2.55-8.42, P=0.001) and had shorter OS and TTF compared with patients with a Child-Pugh A (P=0.004 and P<0.001, respectively)., Conclusion: Elderly patients with advanced HCC, when treated with sorafenib, have an equivalent clinical outcome with similar toxicity rates as their younger counterparts. Age alone should not be a discriminating factor for the management of advanced HCC with sorafenib.

Background & Aims: The Albumin-Bilirubin (ALBI) grade was proposed as an objective means to evaluate liver function in patients with Hepatocellular Carcinoma (HCC). ALBI grade 1 vs 2 were proposed as stratification factors within the Child Pugh (CP) A class. However, the original publication did not provide comparison with the subclassification by points (5-15) within the CP classification., Methods: We retrospectively analysed data from patients treated with sorafenib for HCC from 17 centres in United Kingdom and France. Overall survival (OS) was analysed using the Kaplan-Meier method and a Cox regression model. Discriminatory abilities of the classifications were assessed with the log likelihood ratio, Harrell's C statistics and Akaike information criterion., Results: Data from 1019 patients were collected, of which 905 could be assessed for both scores. 92% of ALBI grade 1 were CP A5 while ALBI 2 included a broad range of CP scores of which 44% were CP A6. Median OS was 10.2, 7.0 and 3.6 months for CP scores A5, A6 and >A6, respectively (P < 0.001), Hazard Ratio (HR) = 1.60 (95%CI: 1.35-1.89, P < 0.001) for A6 vs A5. Median OS was 10.9, 6.6 and 3.0 months for ALBI grade 1, 2 and 3, respectively (P < 0.001), HR = 1.68 (1.43-1.97, P < 0.001) for grade 2 vs 1. Discriminatory abilities of CP and ALBI were similar in the CP A population, but better for CP in the overall population., Conclusions: Our findings support the use CP class A as an inclusion criterion, and ALBI as a stratification factor in trials of systemic therapy., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: Sorafenib is the current standard therapy for advanced hepatocellular carcinoma, but validated biomarkers predicting clinical outcomes are lacking. This study aimed to identify biomarkers predicting prognosis and/or response to sorafenib, with or without erlotinib, in hepatocellular carcinoma patients from the phase III SEARCH trial., Experimental Design: A total of 720 patients were randomized to receive oral sorafenib 400 mg twice daily plus erlotinib 150 mg once daily or placebo. Fifteen growth factors relevant to the treatment regimen and/or to hepatocellular carcinoma were measured in baseline plasma samples., Results: Baseline plasma biomarkers were measured in 494 (69%) patients (sorafenib plus erlotinib, n = 243; sorafenib plus placebo, n = 251). Treatment arm-independent analyses showed that elevated hepatocyte growth factor [HGF; HR, 1.687 (high vs. low expression); endpoint multiplicity adjusted (e-adj) P = 0.0001] and elevated plasma VEGFA (HR, 1.386; e-adj P = 0.0377) were significantly associated with poor overall survival (OS) in multivariate analyses, and low plasma KIT [HR, 0.75 (high vs. low); P = 0.0233; e-adj P = 0.2793] tended to correlate with poorer OS. High plasma VEGFC independently correlated with longer TTP (HR, 0.633; e-adj P = 0.0010) and trended toward associating with improved disease control rate (univariate: OR, 2.047; P = 0.030; e-adj P = 0.420). In 67% of evaluable patients (339/494), a multimarker signature of HGF, VEGFA, KIT, EPGN, and VEGFC correlated with improved median OS in multivariate analysis (HR, 0.150; P < 0.00001). No biomarker predicted efficacy from erlotinib., Conclusions: Baseline plasma HGF, VEGFA, KIT, and VEGFC correlated with clinical outcomes in hepatocellular carcinoma patients treated with sorafenib with or without erlotinib. These biomarkers plus EPGN constituted a multimarker signature for improved OS. Clin Cancer Res; 22(19); 4870-9. ©2016 AACR., (©2016 American Association for Cancer Research.)

Background & Aims: Codrituzumab, a humanized monoclonal antibody against Glypican-3 (GPC3) that is expressed in hepatocellular carcinoma (HCC), interacts with CD16/FcγRIIIa and triggers antibody-dependent cytotoxicity. Codrituzumab was studied vs. placebo in a randomized phase II trial in advanced HCC patients who had failed prior systemic therapy., Methods: Patients with advanced HCC who had failed prior systemic therapy, ⩾18years, Eastern cooperative oncology group (ECOG) 0-1, Child-Pugh A were randomized 2:1 to biweekly codrituzumab 1600mg vs. placebo. Patients were stratified based on GPC3 immunohistochemical expression: 2+/3+, 1+, and 0. Primary endpoint was progression free survival. Secondary endpoints include overall survival (OS), tolerability, pharmacokinetics, and an exploratory endpoint in biomarkers analysis., Results: 185 patients were enrolled: 125 received codrituzumab and 60 placebo: Median age 64/63, 85/75% male, 46/42% Asian, ECOG 0 65/63%, 74/77% having vascular invasion and/or extra-hepatic metastasis. 84%/70% had prior sorafenib. Drug exposure was 98.4% of planned dose, with an identical adverse events profile between the 2 groups. The median progression free survival and overall survival in the codrituzumab vs. placebo groups in months were: 2.6 vs. 1.5 (hazard ratios 0.97, p=0.87), and 8.7 vs. 10 (hazard ratios 0.96, p=0.82). Projected Ctrough at cycle 3day 1 based exposure, high CD16/FcγRIIIa on peripheral immune cells, and GPC3 expression in the tumor, were all associated with prolonged progression free survival and overall survival., Conclusions: Codrituzumab did not show clinical benefit in this previously treated HCC population. Whether higher codrituzumab drug exposure or the use of CD16 and GPC3 as potential biomarkers would improve outcome remain unanswered questions., Lay Summary: Codrituzumab is a manufactured antibody against a liver cancer protein called glypican-3. In this clinical trial, codrituzumab was not found be effective against liver cancer. It was suggested though that a higher dose of codrituzumab or selecting patients with high level of glypican-3 or its mediator CD16 might improve outcome., Clinical Trial Registration: This trial is registered at Clinicaltrials.gov (NCT01507168)., (Copyright © 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Purpose: To compare the clinical outcomes of sorafenib plus either erlotinib or placebo in patients with advanced hepatocellular carcinoma (HCC) in a multicenter, multinational, randomized, phase III trial., Patients and Methods: Patients with advanced HCC and underlying Child-Pugh class A cirrhosis, who were naive to systemic treatment (N = 720), were randomly assigned to sorafenib plus either erlotinib (n = 362) or placebo (n = 358). The primary end point was overall survival (OS)., Results: Median OS was similar in the sorafenib plus erlotinib and sorafenib plus placebo groups (9.5 v 8.5 months, respectively; hazard ratio [HR], 0.929; P = .408), as was median time to progression (3.2 v 4.0 months, respectively; HR, 1.135; P = .18). In the sorafenib/erlotinib arm versus the sorafenib/placebo arm, the overall response rate trended higher (6.6% v 3.9%, respectively; P = .102), whereas the disease control rate was significantly lower (43.9% v 52.5%, respectively; P = .021). The median durations of treatment with sorafenib were 86 days in the sorafenib/erlotinib arm and 123 days in the sorafenib/placebo arm. In the sorafenib/erlotinib and sorafenib/placebo arms, the rates of treatment-emergent serious AEs (58.0% v 54.6%, respectively) and drug-related serious AEs (21.0% v 22.8%, respectively) were similar. AEs matched the known safety profiles of both agents, but rates of rash/desquamation, anorexia, and diarrhea were higher in the sorafenib/erlotinib arm, whereas rates of alopecia and hand-foot skin reaction were higher in the sorafenib/placebo arm. Withdrawal rates for AEs during cycles 1 to 3 were higher in the sorafenib/erlotinib arm., Conclusion: Adding erlotinib to sorafenib did not improve survival in patients with advanced HCC., (© 2014 by American Society of Clinical Oncology.)

Objectives: To identify the pattern of the risk of death over long-term in unresectable hepatocellular carcinoma by determining the appropriate distribution to extrapolate overall survival and to assess the role of the Weibull distribution as the standard survival model in oncology., Research Design and Methods: To select the appropriate distribution, three types of data sources have been analysed. Patient level data from two randomized controlled trials and published Kaplan-Meier curves from a systematic literature review provided short term follow-up data. They were supplemented with patient level data, with long-term follow-up from the Cancer Institute New South Wales, Australia. Published Kaplan-Meier curves were read in and a time-to-event dataset was created. Distributions were fitted to the data from the different sources separately. Their fit was assessed visually and compared using statistical criteria based on log-likelihood, the Akaike information criterion (AIC), and the Bayesian information criterion (BIC)., Results: Based on both published and patient-level, and both short- and long-term follow-up data, the Weibull distribution, used very often in cost-effectiveness models in oncology, does not seem to offer a good fit in hepatocellular carcinoma among the different survival models. The best fitting distribution appears to be the lognormal, with loglogistic as the second-best fitting function. Results were consistent between the different sources of data., Conclusions: In unresectable hepatocellular carcinoma, the Weibull model, which is often treated at the gold standard, does not appear to be appropriate based on different sources of data (two clinical trials, a retrospective database and published Kaplan-Meier curves). Lognormal distribution seems to be the most appropriate distribution for extrapolating overall survival.

Sorafenib, a small molecule multikinase inhibitor, is the standard of care in the USA and Europe for the treatment of advanced hepatocellular carcinoma. This article reviews its development from the basis of molecular hepatocarcinogenesis to phase III trials and discusses the future for sorafenib in hepatocellular carcinoma.