Therapy For Advanced Hepatocellular Carcinoma Research Articles

The Outcomes of Systemic Treatment in Recurrent Hepatocellular Carcinomas Following Liver Transplants.

Treatment of hepatocellular carcinoma (HCC) recurrences following liver transplant (LT) is challenging. Most clinical trials of systemic therapies for advanced HCC excluded patients with any history of organ transplant. We aimed to assess the outcomes in using various systemic therapies in patients with post-LT recurrence. Consecutive patients with HCC and recurrences following LT at a large tertiary centre from 2005 to 2018 were reviewed. Overall survival (OS), response rates and adverse events (AEs) were analysed. Forty-three consecutive patients with a recurrence of HCC following LT were identified from 2005 to 2018. Median OS from diagnosis of recurrence was 17months (CI 11.3, 22.7). Early recurrence within 12months of transplant was associated with a significantly worse median survival of 10months (CI 8.5, 11.4) compared to 26months (CI 18.8, 33.2) when recurrences occurred after 12months from transplant (p < 0.001) with a hazard ratio of 0.104 (log-rank test, p < 0.001). A total of 41 patients had received systemic therapies and 79.1% of them were on sorafenib as the first-line treatment. Among these patients treated with sorafenib, median OS from recurrence was 14months (CI 7.3, 20.7). Hand-foot syndrome (34.7%) was most common among AEs followed by diarrhoea (26.7%). Overall, AEs led to dose interruptions in 8.8% of patients. Notably, 47.1% of patients received subsequent lines of systemic therapies after sorafenib. Early recurrence within 1year from transplant was the most significant risk factor. Treatment efficacy and adverse events and tolerability of sorafenib were comparable with those in the setting of advanced HCC without transplant.

Adoption of single agent anticancer therapy for advanced hepatocellular carcinoma and impact of facility type, insurance status, and income on survival: Analysis of the national cancer database 2004-2014.

BackgroundThis study analyzes the pattern of use of single agent anticancer therapy (SAACT) in the treatment and survival of advanced hepatocellular carcinoma (aHCC) before and after sorafenib was FDA approved in 2007.MethodsAdult patients diagnosed with HCC and treated with only ACT from 2004 – 2014 were identified in NCDB database. Patients were analyzed during three time frames: 2004–2006 (pre‐sorafenib (PS)), 2007–2010 (early sorafenib (ES)) and 2011–2014 (late sorafenib (LS)). Cox proportional hazards models and Kaplan‐Meier method were used for analyses.ResultsThe NCDB contained 31,107 patients with HCC diagnosed from 2004–2014 and treated with ACT alone. Patients were generally men (78.0%), >50 years of age (92.5%). A significant increase in the rate of adaption of SAACT was observed over time: 6.2% PS, 15.2% ES, and 22.2% LS (p < 0.0001). During this later period, the highest proportion of SAACT is among academic and integrated network facilities (23.3%) as compared to community facilities (17.0%, p < 0.0001). The median overall survival of patients with aHCC treated only with SAACT improved significantly over time from 8.0 months (m) (95% CI: 7.4–8.8) to 10.7 m (10.4–11.2) to 15.6 m (15.2–16.0, p < 0.001). Multivariate analysis indicates worse outcomes for patients treated at community cancer programs (HR 1.28, (5% CI: 1.23–1.32), patients without insurance (HR 1.11, 1.06–1.16) and estimated household income of <$63,000 (HR 1.09, 1.05–1.13).ConclusionaHCC patients treated only with ACT have experienced an overall improvement in survival, but significant differences exist between facility type, insurance status, and income.

Tumor Immune Microenvironment and Immunosuppressive Therapy in Hepatocellular Carcinoma: A Review.

Liver cancer has the fourth highest mortality rate of all cancers worldwide, with hepatocellular carcinoma (HCC) being the most prevalent subtype. Despite great advances in systemic therapy, such as molecular-targeted agents, HCC has one of the worst prognoses due to drug resistance and frequent recurrence and metastasis. Recently, new therapeutic strategies such as cancer immunosuppressive therapy have prolonged patients’ lives, and the combination of an immune checkpoint inhibitor (ICI) and VEGF inhibitor is now positioned as the first-line therapy for advanced HCC. Since the efficacy of ICIs depends on the tumor immune microenvironment, it is necessary to elucidate the immune environment of HCC to select appropriate ICIs. In this review, we summarize the findings on the immune microenvironment and immunosuppressive approaches focused on monoclonal antibodies against cytotoxic T lymphocyte-associated protein 4 and programmed cell death protein 1 for HCC. We also describe ongoing treatment modalities, including adoptive cell transfer-based therapies and future areas of exploration based on recent literature. The results of pre-clinical studies using immunological classification and animal models will contribute to the development of biomarkers that predict the efficacy of immunosuppressive therapy and aid in the selection of appropriate strategies for HCC treatment.

Selection of first-line systemic therapies for advanced hepatocellular carcinoma: A network meta-analysis of randomized controlled trials.

BACKGROUNDThe majority of clinical trials of first-line systemic treatments for hepatocellular carcinoma (HCC) used placebo or sorafenib as comparators, and there are limited data providing a cross comparison of treatments in this setting, especially for newly-approved immune checkpoint inhibitor and vascular endothelial growth factor inhibitor combination treatments.AIMTo systematically review and compare response rates, survival outcomes, and safety of first-line systemic therapies for advanced hepatocellular carcinoma.METHODSWe searched PubMed, Science Direct, the Cochrane Database, Excerpta Medica Database, and abstracts from the American Society of Clinical Oncology 2020 annual congress. Eligible studies were randomized controlled trials of systemic therapy enrolling adults with advanced/unresectable HCC. Risk of bias was assessed with the Cochrane risk of bias tool for randomized controlled trials. A network meta-analysis was used to synthesize data and perform direct and indirect comparisons between treatments. P value, a frequentist analog to the surface under the cumulative ranking curve, was used to rank treatments.RESULTSIn total, 1398 articles were screened and 27 included. Treatments compared were atezolizumab plus bevacizumab, brivanib, donafenib, dovitinib, FOLFOX4, lenvatinib, linifanib, nintedanib, nivolumab, sorafenib, sunitinib, vandetanib, 11 sorafenib combination therapies, and three other combination therapies. For overall response rate, lenvatinib ranked 1/19, followed by atezolizumab plus bevacizumab and nivolumab. For progression-free survival (PFS), atezolizumab + bevacizumab was ranked 1/15, followed by lenvatinib. With the exception of atezolizumab + bevacizumab [hazard ratios (HR)PFS = 0.90; 95% confidence interval (CI): 0.64-1.25], the estimated HRs for PFS for all included treatments vs lenvatinib were > 1; however, the associated 95%CI passed through unity for bevacizumab plus erlotinib, linifanib, and FOLFOX4. For overall survival, atezolizumab plus bevacizumab was ranked 1/25, followed by vandetanib 100 mg/d and donafinib, with lenvatinib ranked 6/25. Atezolizumab + bevacizumab was associated with a lower risk of death vs lenvatinib (HRos = 0.63; 95%CI: 0.44-0.89), while the HR for overall survival for most other treatments vs lenvatinib had associated 95%CIs that passed through unity. Vandetanib 300 mg/d and 100 mg/d were ranked 1/13 and 2/13, respectively, for the lowest incidence of treatment terminations due to adverse events, followed by sorafenib (5/13), lenvatinib (10/13), and atezolizumab + bevacizumab (13/13).CONCLUSIONThere is not one single first-line treatment for advanced HCC associated with superior outcomes across all outcome measurements. Therefore, first-line systemic treatment should be selected based on individualized treatment goals.

Camrelizumab plus apatinib combined with TACE and cryoablation in the first-line treatment of advanced hepatocellular carcinoma.

TPS4160 Background: Hepatocellular carcinoma (HCC) is a common cancer in the world, a leading cause of cancer-related death, and especially in China. Most of the HCC patients are diagnosed at an advanced stage and require a multidisciplinary approach. The IMbrave 50 trial has reported the successful efficacy of atezolizumab and bevacizumab combination therapy in advanced hepatocellular carcinoma, which indicate the potential efficacy of combination of immunotherapy and antiangiogenesis therapy in HCC patients. In some studies, the combinatorial approaches with immunotherapy and liver directed therapies such as transarterial chemoembolization (TACE), radiofrequency ablation (RFA), microwave ablation (MWA), and cryoablation are explored. Most combined interventional therapies reveal their enormous advantages as compared with any single therapeutic regimen alone, which may result from the immunologic enhancement effect of the multimodel therapy. In this study, we evaluated the efficacy and safety of combined therapy with camrelizumab plus apatinib mesylate and TACE plus cryoablation in patients with advanced HCC. Methods: This study was an open-label, single-arm, single centre, phase 2 trial in patients who were diagnosed with advanced HCC. Patients who meet the following criterias will be enrolled: (1) 18 - 75 years old; (2) Child-Pugh classification A or B(≤7);(3) Barcelona Clinic Liver Cancer stage B or C, or China liver cancer staging (CNLC) stage IIb̃IIIa; (4) Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0–1; (5) no history of previous systematic treatment; (6) expected life expectancy of more than 12 weeks; (7) adequate organs function. The key exclusion criteria were history of active autoimmune disease, or concurrent medical use of immunosuppressive medications or immunosuppressive doses of systemic corticosteroids. Eligible patients received camrelizumab 200 mg intravenously every 2 weeks and apatinib 250 mg orally once per day continuously in a treatment cycle of 4 weeks, treatment continued until 1 year or development of unacceptable toxicity or progression of disease. TACE was administrated at the first treatment cycles on day 1or 2, the chemotherapy regimens included 100-150mg oxaliplatin, 750-1000mg fluorouracil, or 30-50 mg lobaplatin, raltitrexed 2-4mg, and epirubicin 40-80 mg. Two or three weeks after the TACE, percutaneous cryoablation was performed under CT guidance. TACE and cryoablation was given as combination therapy and the periods were assessed by the investigator. The primary endpoint is objective response rate (complete or partial response according to mRECIST) and Progression-Free-Survival (Time ranges from random to the first occurrence of disease progression or death from any cause). This trial is registered with Chinese Clinical Trials Registry, ChiCTR2100043044, and is ongoing. Clinical trial information: ChiCTR2100043044.

Transjugular intrahepatic portosystemic shunt plus sequential systemic therapy for advanced hepatocellular carcinoma with tumor thrombus-related symptomatic portal hypertension: A multicenter retrospective study.

e16116 Background: Portal vein tumor thrombus (PVTT) and symptomatic portal hypertension severely affect the survival and quality of life of hepatocellular carcinoma (HCC) patients. The aim of this study was to evaluate the clinical outcomes of the transjugular intrahepatic portosystemic shunt (TIPS) plus sequential systemic therapy in advanced HCC patients with tumor thrombus-related symptomatic portal hypertension. Methods: This multi-center retrospective study explored 142 advanced HCC patients with PVTT and symptomatic portal hypertension who received either TIPS plus sequential systemic therapy (group A) or only symptomatic and supportive treatment (group B) for from April 2016 to January 2020. The Kaplan-Meier method and log-rank test were performed to determine the survival differences of variables. Univariable and multivariable Cox proportional hazards regression analyses were used to identify prognostic factors of overall survival (OS). We used independent factors for the nomogram to predict OS. Results: The median OS of group A was significantly better than that of group B (7.6 [95% CI: 4.6, 10.6] vs. 4.5 [95% CI: 2.7, 6.4], months, P &lt; 0.001). Multivariable analysis also showed that PVTT degree (I/II) (Hazard ratios [HR] = 0.679; 95% CI: 0.465, 0.994; P = 0.046), variceal bleeding (HR = 1.686; 95% CI: 1.059, 2.684; P = 0.028), Child-Pugh Class A (HR = 0.450; 95% CI: 0.272, 0.746; P = 0.002), and BCLC stage C (HR = 0.434; 95% CI: 0.222, 0.850; P = 0.015) were significant predictors of OS. These five indicators were included in the nomogram model to predict survival probabilities in 6- and 12-months OS. Conclusions: TIPS plus sequential systemic therapy is safe and feasible for the treatment of advanced HCC with tumor thrombus-related symptomatic portal hypertension.

Molecular markers of response to anti-PD1 therapy in advanced hepatocellular carcinoma.

4100 Background: Checkpoint inhibition with anti-PD1 is able to elicit objective response rates (ORR) of ̃ 20% in patients with advanced hepatocellular carcinoma (aHCC) but molecular biomarkers predicting response remain unknown. Here, we define biomarkers of response and primary resistance to anti-PD1 in aHCC by analyzing molecular features prior to systemic therapy. Methods: Through an international consortium of 13 referral centers, we gathered 111 fresh and archived tumor samples from patients with advanced HCC treated with single agent anti- PD1 therapy. Genomic analysis was performed with whole genome expression arrays, CTNNB1 exon 3 mutation assessment and histological evaluation. Results: Overall, we performed transcriptomic analysis in 83 patients, 28 of which were treated in first-line (ORR: 42.9%) while the remaining 55 patients were treated either in 2nd (41 patients, ORR 29.3%) or 3rd line (14 patients, ORR 7.1%) after prior therapy with tyrosine- kinase inhibitors (TKI) sorafenib or lenvatinib. In patients treated in frontline, response was associated with a significant upregulation in Interferon-γ signaling (IFNγ) and genesets relatedto the antigen presentation machinery (FDR &lt; 0.05). Through differential expression analysis we defined an 11-gene signature that was significantly associated with both major pathways (FDR &lt; 0.01) and was capable of predicting OR as well as progression-free- (PFS) and overall survival (OS) in patients with aHCC. The signature was validated in three independent cohorts of melanoma, lung cancer, and head and neck squamous cell cancer patients were high expression was associated with a significant increase in ORR and longer PFS. In HCC, high expression of the signature was associated with a distinct profile in the immune infiltrate, where an increase in M1 macrophages (p = 0.003), CD4 memory T cell (p &lt; 0.01) and CD4 naïve T cell-infiltration (p = 0.026) was observed. Conversely, low expression of the signature was associated with a marked upregulation of regulatory T cells (p &lt; 0.001). No association was found, however, between either the overall immune infiltrate or CTNNB1 mutations and response. In patients that were treated with TKIs in frontline before receiving subsequent anti-PD1 therapy, the signature was no longer able to predict either OR or PFS/OS, suggesting that TKIs may reshape the microenvironment in a way that renders previously inflamed tumors no longer amenable to anti-PD1. Conclusions: Here, we define an 11-gene signature of response to anti-PD1 in first line aHCC. The signature was validated in patients with other solid cancer types, where it retained its predictive ability. Of note, the signature was not able to identify responders among HCC patients that were treated with TKIs prior to anti-PD1 therapy. The molecular changes induced by different treatment lines would, thus, require fresh biopsies prior to anti-PD1to enable biomarker-driven treatment.

CaboRISE: A phase II study evaluating reduced starting dose and dose escalation of cabozantinib as second-line therapy for advanced HCC in patients with compensated liver cirrhosis.

TPS4163 Background: The multi-targeted tyrosine kinase inhibitor cabozantinib is approved for the treatment of advanced hepatocellular carcinoma (HCC) in adults, who have previously been treated with sorafenib. In the pivotal phase 3 CELESTIAL trial a significant improvement for OS and PFS was shown for cabozantinib in comparison to placebo treated patients (Abou-Alfa GK et al. N Engl J Med 2018; 379:54-63). However, in 62% of patients a dose reduction of cabozantinib was necessary and the median average daily dose was 35.8 mg. The discontinuation rate due to treatment-related adverse events (TRAEs) was 16% and grade 3-4 TRAEs occurred in 68% of patients. For HCC patients treated with sorafenib in first-line, a reduced starting dose of 200 mg BID was not inferior in terms of OS but showed a trend toward a decreased rate of sorafenib discontinuation(Reiss KA et al. J Clin Oncol 2017; 35:3575-3581). The aim of the CaboRISE trial is to study the effect of a reduced starting dose of cabozantinib on tolerability, safety, and efficacy. Methods: The CaboRISE trial is an open-label, single arm, multicenter phase II trial, including patients with advanced stage hepatocellular carcinoma (HCC) with compensated liver cirrhosis (Child-Pugh A) in second line treatment, after first line treatment with sorafenib or lenvatinib. Forty evaluable patients will be enrolled in the study to receive a reduced starting dose of 40 mg cabozantinib once-daily for 4 weeks and subsequent dose escalation to 60 mg cabozantinib once-daily to be maintained until disease progression or intolerable toxicities. The objective of the trial is to assess the tolerability of a reduced starting dose of cabozantinib, in order to reduce the treatment discontinuation rates due to treatment-related adverse events below 10%. Primary endpoint is the treatment discontinuation rate due to TRAEs. Secondary endpoints are overall survival, progression free survival at 10 weeks, objective response rate, time on treatment, treatment exposure, toxicity, and quality of life. Study start of the CaboRISE trial was in October 2020. By February 2021, 7 centers across Germany have been initiated and a total of 4 out of 40 planned patients have been enrolled. The study is currently ongoing. This study is financially supported by Ipsen. ClinicalTrials.gov: NCT04522908 EudraCT: 2020-000775-20. Clinical trial information: NCT04522908.

Safety of PD-1/PD-L1 Inhibitors Combined With Palliative Radiotherapy and Anti-Angiogenic Therapy in Advanced Hepatocellular Carcinoma.

BackgroundPrevious studies have explored cancer immunotherapy with radiotherapy or anti-angiogenic therapy, but no trials have reported a triple therapy approach. This study aimed to investigate safety and clinical outcome of PD-1/PD-L1 inhibitors combined with palliative radiotherapy and targeted angiogenesis therapy in hepatocellular carcinoma (HCC) of Barcelona Clinic Liver Cancer (BCLC) stage C.MethodsConsecutive patients (n=16) treated with PD-1/PD-L1 inhibitors combined with radiotherapy and anti-angiogenic therapy in a bi-institutional cohort between July 2017 and December 2020 were retrospectively included. Radiotherapy was conducted within 14 days of the first administration of immunotherapy. The primary endpoint was treatment-related adverse event (TRAE).ResultsThe median follow-up was 383 days. Fifteen patients (93.8%) experienced at least 1 TRAE. The most common TRAEs of any grade were rash (25%), diarrhea (25%), aspartate aminotransferase increase (18.8%), alanine transaminase increase (18.8%), decreased appetite (18.8%), and fatigue (18.8%). Grade 3/4 TRAEs occurred in 4 patients (25%) and finally led to treatment interruption. No patient death was attributed to treatment. No specific events were responsible for the addition of radiotherapy. Six patients showed partial response, 7 showed stable disease, and 2 showed progressive disease. The objective response rate and disease control rate were 40.0% (95% CI 16.3%–67.7%) and 86.7% (95% CI 59.5%–98.3%), respectively. Moreover, the median progression-free survival was 140 days. Patients had a median overall survival of 637 days, and the estimated rates of survival at 6 and 12 months were 92.3% and 75.5%, respectively.ConclusionPD-1/PD-L1 inhibitors combined with palliative radiotherapy and anti-angiogenic therapy appear to be safe, with no unexpected adverse events. Additional studies exploring the clinical benefit are warranted.

Treatment of metastatic hepatocellular carcinoma with lenvatinib. Case report and literature review

Hepatocellular carcinoma (HCC) or liver cancer is the most common primary malignant tumor of the liver, which is characterized on the first place by a poor prognosis. HCC was diagnosed in 92 patients (62.6%) in 2019 and the period from January to April 2020 in the Republic of Bashkortostan, and among them, 68.47% had stage IV cancer. International professional guidelines suggest screening for early HCC detection. Systemic drug therapy is the treatment of choice for inoperable HCC according to professional guidelines. Inhibition of the VEGF pathway is one of the current methods of therapy for advanced HCC. Lenvatinib is a tyrosine kinase inhibitor for the treatment of advanced HCC that is not subject to local interventions. This article provides a description of a clinical case of successful treatment of a 67-year-old patient with advanced hepatocellular carcinoma. He was appointed for targeted therapy with lenvatinib for HCC that was not subject to local interventions, which led to long-term stabilization. There was a positive trend in the patients condition from the first weeks of therapy. The working capacity was restored. The therapy showed a satisfactory tolerability profile.

Clinical Indicators for Long-Term Survival with Immune Checkpoint Therapy in Advanced Hepatocellular Carcinoma.

IntroductionPatients with advanced hepatocellular carcinoma have a dismal prognosis; only a subset of patients with advanced HCC will benefit from treatment with immunotherapy. We searched for clinical characteristics predicting exceptional long-term survival in HCC patients treated with immune checkpoint inhibitors.MethodsWe compared clinical characteristics of 59 patients with advanced hepatocellular carcinoma treated with immunotherapy with and without locoregional therapy between 2013–2019. We compared patients who lived less than 12 months with patients who lived more than 3 years. Traits of short-term (31 patients) and long-term (5 patients) survivors were compared. Patients who died between 12 months and 3 years of starting treatment on protocol were not included in the analysis.ResultsTwo out of five patients (40%) in the long-term survival group had a partial response (PR) or a complete response (CR) per the modified Response Evaluation Criteria in Solid Tumors (mRECIST), while, of the 31 patients in the short-term survival group, only 2 (6.5%) had a CR or PR. Two of the 5 patients with a long-term survival had immune-related adverse events grade 3 or 4 (IrAEs-3/4). None of the patients in the short-term survival group had IrAEs-3/4. The patients, who presented with IrAEs-3/4, which included colitis and adrenal insufficiency, continued to have a response off treatment. The median overall survival (OS) was 11.8 months (95% CI: 7.8–15.4 months), with a 12-month OS of 46.6% (95% CI: 33.4–58.8%) and a 3-year OS of 12.5% (95% CI: 5.0–23.7%).ConclusionWe found a possible association between immune-related adverse events grade 3 and 4 and long-term survival in patients with advanced HCC. The cases in our analysis represent extraordinary defiance of the usual predicted dismal course of advanced HCC.

Abstract No. 124 Systemic therapy in advanced hepatocellular carcinoma: where are we heading?

Hepatocellular carcinoma (HCC) is the fifth leading cause of cancer in the world and third, in cancer related mortality. Only 20% HCC are early HCCs that are eligible for therapies such as resection, liver transplantation, and local ablation due to advanced stage, tumor burden, lack of liver donors and liver dysfunction. The majority of HCCs are treated with palliative therapy, which includes Transarterial chemoembolization (TACE) and systemic therapy, while transarterial radioembolization still struggles to find a place in evidence-based treatment. In this study we explore the advances made in systemic therapy for advanced HCC, especially since the approval of sorafenib, a tyrosine kinase inhibitor, including the evolution and emerging field of immunotherapy in the last decade through relevant literature. We reviewed recently published studies in PubMed and data presented in the last decade discussing both advances and failures in the systemic treatment of HCC. After Sorafenib demonstrated improved overall survival (OS) in SHARP and Asia Pacific trials over placebo many other phase III trials have been conducted with other multi kinase inhibitors like sunitinib, brivanib and linifanib; none of which yielded significant results compared to sorafenib. Lenvatinib has been approved as first-line therapy for advanced HCC due to increased response rate, progression free similar survival outcomes like sorafenib. Tyrosine kinase inhibitors Regorafenib and Cabozantinib have shown significant improvement in survival, in RESORCE and CELESTIAL trials, respectively, as second-line treatment after sorafenib failures, radiological progression or intolerance in patients. Ramucirumab an anti VEGF monoclonal IgG antibody, studied in REACH trial demonstrated a potential survival benefit for patients with AFP ≥ 400ng/dL and Immune checkpoint inhibitors, like nivolumab and pembrolizumab although showing promising response rates and minimal adverse effects in phase II trial failed to demonstrate an improved OS in phase III trial. Despite clinical trials where combination of TACE and molecular targeted agents have failed till date, combination of TACE with sorafenib indicated success in TACTICS trial and the outcome of various ongoing combination trials with molecular targeted agents and immune checkpoint inhibitors is eagerly awaited. While a lot of progress has been made in increasing survival of patients with advanced HCC, the ongoing trials will further change the treatment paradigm significantly for HCC.

Abstract No. 37 LEAP-012 trial in progress: pembrolizumab, lenvatinib, and transarterial chemoembolization combination therapy for intermediate-stage hepatocellular carcinoma not amenable to curative treatment

Limited treatment options are available for patients with intermediate hepatocellular carcinoma (HCC). Lenvatinib, a potent multikinase inhibitor, and pembrolizumab, a programmed death receptor-1 blocking antibody, are approved first- and second-line therapies for advanced HCC, respectively. LEAP-012 (NCT04246177) is investigating lenvatinib plus pembrolizumab in combination with transarterial chemoembolization (TACE) versus placebo plus TACE in patients with intermediate HCC. LEAP-012 is a randomized double-blind phase 3 study. Adults with confirmed HCC localized to the liver without portal vein thrombosis and not amenable to curative treatment, ≥1 measurable lesion per RECIST v1.1, Eastern Cooperative Oncology Group performance status of 0 or 1, and no previous treatment with locoregional therapy or systemic chemotherapy for HCC are eligible. Patients will be randomly assigned to receive lenvatinib 8 (body weight < 60 kg) or 12 mg (body weight ≥60 kg) orally once daily plus pembrolizumab 400 mg intravenously every 6 weeks (Q6W) plus TACE or placebo orally once daily plus placebo intravenously Q6W, plus TACE. Response will be assessed by imaging every 9 weeks, and safety will be assessed throughout the study and up to 90 days after the end of treatment. Coprimary end points are overall survival and progression-free survival (PFS) per RECIST v1.1 by blinded independent central review (BICR). Secondary end points are PFS, objective response rate (ORR), disease control rate (DCR), duration of response (DOR), and time to progression (TTP) per modified RECIST by BICR; ORR, DCR, DOR, and TTP per RECIST v1.1 by BICR; and safety. Exploratory end points are PFS, ORR, DCR, DOR, TTP, and time from randomization to second/subsequent progression per RECIST v1.1 by investigator review, identification of molecular biomarkers, and health-related quality of life. Recruitment began in April 2020. The planned sample size is 950 patients. LEAP-012 will elucidate the clinical benefit of adding lenvatinib plus pembrolizumab to the current standard of care TACE for patients with intermediate-stage HCC not amenable to curative treatment.

Combining tissue and circulating tumor DNA increases the detection rate of a CTNNB1 mutation in hepatocellular carcinoma

Background and aimsStudies suggest that mutations in the CTNNB1 gene are predictive of response to immunotherapy, an emerging therapy for advanced hepatocellular carcinoma (HCC). Analysis of circulating tumor DNA (ctDNA) offers the possibility of serial non-invasive mutational profiling of tumors. Combining tumor tissue and ctDNA analysis may increase the detection rate of mutations.This study aimed to evaluate the frequency of the CTNNB1 p.T41A mutation in ctDNA and tumor samples from HCC patients and to evaluate the concordance rates between plasma and tissue. We further evaluated changes in ctDNA after various HCC treatment modalities and the impact of the CTNNB1 p.T41A mutation on the clinical course of HCC.MethodsWe used droplet digital PCR to analyze plasma from 95 patients and the corresponding tumor samples from 37 patients during 3 years follow up.ResultsIn tumor tissue samples, the mutation rate was 8.1% (3/37). In ctDNA from HCC patients, the CTNNB1 mutation rate was 9.5% (9/95) in the pre-treatment samples. Adding results from plasma analysis to the subgroup of patients with available tissue samples, the mutation detection rate increased to 13.5% (5/37). There was no difference in overall survival according to CTNNB1 mutational status. Serial testing of ctDNA suggested a possible clonal evolution of HCC or arising multicentric tumors with separate genetic profiles in individual patients.ConclusionCombining analysis of ctDNA and tumor tissue increased the detection rate of CTNNB1 mutation in HCC patients. A liquid biopsy approach may be useful in a tailored therapy of HCC.

Association of Albumin-Bilirubin Grade and Sequential Treatment with Standard Systemic Therapies for Advanced Hepatocellular Carcinoma: A Retrospective Cohort Study Using a Japanese Administrative Database.

BackgroundEvidence about the relationship between albumin-bilirubin (ALBI) grade and sequential systemic therapy for advanced hepatocellular carcinoma in real-world Japanese clinical practice is limited.ObjectiveThe objective of this study was to investigate ALBI grades and sequential treatment for advanced hepatocellular carcinoma in Japanese clinical practice.MethodsWe conducted a retrospective cohort study using a Japanese hospital-based administration database to assess treatment sequence in patients with confirmed advanced hepatocellular carcinoma and first prescription (index line) of lenvatinib (July 2014–June 2019; N = 1558) or sorafenib (July 2014–June 2016 [sorafenib-A; N = 1511] or June 2017–June 2019 [sorafenib-B; N = 1276]). Transition to subsequent line was assessed in patients who completed the index line without transarterial chemoembolization. The ALBI grade and sequential treatment relationships were analyzed in patients with baseline and/or end of index line ALBI scores.ResultsTransition to a subsequent line was low (sorafenib-A [n = 1320]: 12.6%; sorafenib-B [n = 1049]: 40.7%; lenvatinib [n = 786]: 27.2%). In patients with baseline ALBI data (combined cohorts; n = 385), overall treatment duration was shorter in those with baseline ALBI grade 2b or 3 vs grade 1 or 2a (median: 7.1, 6.7, 4.5, and 3.0 months for grades 1, 2a, 2b, and 3, respectively). In patients with baseline and end of index line ALBI data (combined cohorts; n = 222), ALBI grade worsened during index line regardless of baseline grade. Of these patients in the sorafenib-B or lenvatinib cohorts who completed the index line without transarterial chemoembolization (n = 120), transition to a subsequent line was higher with the end of index line grade 1/2a (66.7/68.4%) than with grade 2b/3 (34.0/11.1%).ConclusionsAdequate liver function, indicated by ALBI grade, at the start and end of first-line treatment is associated with successful sequential therapy in Japanese clinical practice.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40801-021-00245-8.

Combination therapy for advanced hepatocellular carcinoma: do we see the light at the end of the tunnel?

Combination therapies of anti-PD-1 and anti-angiogenesis regimens are emerging rapidly and exhibit more promising anti-tumor efficacy for advanced hepatocellular carcinoma (HCC), and consistently it is the hotspot in clinical studies. To elaborate several issues which are warranted further consideration as more regimens are being investigated in combination therapies. We searched PubMed, MEDLINE, Cochrane Library and Google Scholar by 2021 February for publications on combination therapies for HCC. Several clinical issues are worth reconsidering, such as the evaluation on appropriate primary endpoints in phase III clinical trials as for different practical problems, the translation of surrogate endpoint objective response rate (ORR) benefits into overall survival (OS) benefits, and whether conversion surgery contributes to initial expectations of long-term survival or not. New concepts in novel immunotherapy and targeted therapy in combination with loco-regional therapies may improve overall survival for HCC. Comprehensive understanding of the mechanism of immunotherapy and targeted therapy contributes to better prognosis of advanced HCC and more explorative combination therapies are needed.

An Underdiagnosed Hypothyroidism and Its Clinical Significance in Patients with Advanced Hepatocellular Carcinoma.

Many systemic therapies for advanced hepatocellular carcinoma (HCC) may cause hypothyroidism; however, in these patients, hypothyroidism prevalence before therapy and its prognostic impact remain unclear. We previously established a prospective cohort of patients who received sorafenib as first-line therapy for advanced HCC. No patients had been clinically diagnosed with hypothyroidism before or during sorafenib treatment. We retrospectively determined the levels of thyrotropin and free thyroxine before initiation of systemic therapy. Hypothyroidism was defined as thyrotropin level higher than the upper limit of the normal range. Among patients with hypothyroidism, free thyroxine level less than the lower normal range was defined as overt hypothyroidism, and free thyroxine level within the normal range was defined as subclinical hypothyroidism. In total, 79 patients were enrolled; of them, 16 (20%) had hypothyroidism (overt hypothyroidism, 10; subclinical hypothyroidism, 6). Patients with hypothyroidism, compared with those without hypothyroidism, were more likely to be older than 65 years (56% vs. 29%, p = .037), have a serum α-fetoprotein level of >400 ng/mL (81% vs. 52%, p = .037), and have a significantly poorer overall survival (OS; median, 5.5 vs. 11.6 months, p = .043). After adjusting for other potential prognostic factors, hypothyroidism remained an independent predictor for poorer OS (hazard ratio, 2.53, p = .018). Patients with overt hypothyroidism and subclinical hypothyroidism exhibited similarly poor OS (p = .768). Underdiagnosis of hypothyroidism in patients with advanced HCC was common. Hypothyroidism, whether overt or subclinical, is associated with poor prognosis of advanced HCC. The results of this study showed the underdiagnosis of hypothyroidism in patients with advanced hepatocellular carcinoma (HCC) and its influence on prognosis. These findings implied the importance of thyroid function check before initiation of systemic therapy for patients with advanced HCC.

The selective serotonin reuptake inhibitors enhance the cytotoxicity of sorafenib in hepatocellular carcinoma cells.

Sertraline and fluoxetine are the two most commonly used selective serotonin reuptake inhibitors (SSRIs) in the treatment of depression. Accumulating evidence has revealed that SSRIs can reduce the risk of hepatocellular carcinoma (HCC), but their therapeutic effects in HCC have not yet been elucidated. Previous studies have reported that sertraline and fluoxetine can suppress the growth of gastric carcinoma, melanoma and nonsmall cell lung cancers by inhibiting the mammalian target rapamycin (mTOR) activity. In this study, we found that sertraline and fluoxetine blocked the protein kinase B (AKT)/mTOR pathway and suppressed the growth of HCC cells in vitro, in xenografts and in diethylnitrosamine/carbon tetrachloride (DEN/CCL4)-induced primary liver mouse model. Sertraline and fluoxetine can synergize with sorafenib, the first approved standard therapy for advanced HCC, to inhibit the viability of HCC cells in vitro and in vivo. In addition, the combination of sorafenib and SSRIs synergistically inhibited the effects of the AKT/mTOR pathway. These results reveal novel therapeutic effects of a combination of SSRIs and sorafenib in HCC.

Comparison of Efficacy of Systemic Therapies in Advanced Hepatocellular Carcinoma: Updated Systematic Review and Frequentist Network Meta-Analysis of Randomized Controlled Trials.

BackgroundSeveral systemic agents have been approved for use in advanced hepatocellular carcinoma (aHCC). However, it is unclear which treatment is superior in either the first- or second-line settings due to the paucity of head-to-head comparative trials. Therefore, we have conducted a systematic review and network meta-analysis for the indirect comparison of the systemic agents in the first line and second line settings.MethodsRandomized clinical trials evaluating systemic agents in first and second line settings in aHCC from inception to April 2020 were identified by searching PubMed, EMBASE, and Cochrane Databases and the annual ASCO and ESMO conferences from 2017 to 2020. Studies in English reporting clinical outcomes including overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) were included. The primary outcomes of interest were pooled hazard ratios (HR) of OS and pooled odds ratios (OR) of ORR in first line studies and pooled HR of PFS and OR of ORR for second line studies. Additionally, OS for second line agents were reported in the qualitative analysis.ResultsOverall, first line studies comprised 8335 patients (13 studies) and second line studies comprised 4612 patients (11 studies). In the first line setting, atezolizumab plus bevacizumab was associated with the highest OS benefit over sorafenib (HR 0.58, 95% CI, 0.42–0.80; P-score 0.993). Additionally, lenvatinib was associated with the greatest ORR benefit (OR 3.34, 95% CI, 2.17–5.14; P-score 0.080) in the first line setting. In the second line setting, cabozantinib was associated with the highest PFS benefit over placebo (HR 0.44, 95% CI, 0.29–0.66; P-score 0.854) as well as the highest ORR benefit (OR 9.40, 95% CI, 1.25–70.83, P-score, 0.266).ConclusionAtezolizumab plus bevacizumab appears to have superior efficacy among first line agents whereas cabozantinib appears to be superior in the second line setting. Further studies are warranted to determine whether the type of prior therapy received affects the efficacy of subsequent second line therapy.

The Evolving Landscape of Checkpoint Inhibitor Combination Therapy in the Treatment of Advanced Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common cancers and a main cause of cancer-associated death worldwide. Even with the successful launch of sorafenib for the clinical treatment of HCC in 2007, the long-term survival for patients with HCC is still suboptimal, largely due to the occurrence of primary or acquired drug resistance. With an improved understanding of the molecular pathophysiology and tumor heterogeneity of HCC, therapeutic options have been evolving rapidly in recent years. While lenvatinib, cabozantinib, regorafenib, and the monoclonal antibody ramucirumab, as well as the immune checkpoint inhibitors (ICIs) atezolizumab, nivolumab, and pembrolizumab, have all shown promise in clinical trials, ICIs, especially when administered in combination with molecular-targeted drugs or cytotoxic drugs, have drawn increased attention. Recently, ample relevant clinical studies have surfaced, particularly related to the use of ICIs and exploring the therapeutic potential of ICI combination strategies. A more thorough knowledge of novel treatment strategies should help in decision making for advanced HCC therapy. The present review summarizes the mechanisms of HCC tumorigenesis, relevanttrial results for approved HCC therapies, future perspectives, and major challenges for the overall treatment of HCC.