Hepatocellular Carcinoma Clinical Trials Research Articles

Abstract PO4-23-09: Dual inhibition of FGFR4 and HER2/EGFR with Lapatinib improves targeting of Erk and Akt signaling in HER2+ breast cancer cells

Abstract In HER2-enriched (HER2E) breast cancer (BC), the dual HER2/EGFR inhibitor Lapatinib is a standard of care for advanced staged disease. Anti-HER2 therapies disrupt tumor progression through inhibition of the PI3K/AKT pathway. Some treated tumors will override inhibition by shifting to MAPK/ERK signaling to fuel cell growth, thus fostering resistance to anti-HER2 therapy. The tyrosine receptor kinase FGFR4 is included in the profile for a HER2E subtype. FGFR4 is overexpressed in ~30% of BC and can signal through PI3K/AKT and MAPK/ERK. Inhibitors for FGFR4 such as BLU554 are being investigated in phase I/II clinical trials for hepatocellular carcinoma, showing success in tumors that are positive for FGFR4’s preferred ligand FGF19. According to cBioPortal patient data, FGF19 is amplified in ~20% of BC, and has been shown to trigger an autocrine loop in triple negative BC through FGFR4. We examined BLU554 as a dual therapeutic with Lapatinib and dissected intracellular signaling stemming from the combination in HER2E BC. MDA-MB-453 BC cells (HER2+FGFR4+) were used for a dual strategy with BLU554 and Lapatinib. Cell viability assays were performed at matched doses, then as a dose response matrix, ranging from 0.1-20 µM. Findings were used for synergy analysis using synergyfinder.fimm.fi. Western blots determined protein activity in response to treatments. Ridaforolimus (mTOR inhibitor) was used in combination with either BLU554 or Lapatinib to assess MAPK/ERK and PI3K/AKT pathway crosstalk in MB-453 cells. Additionally, FGF19 was added to cells after a 2-hour pre-treatment to challenge BLU554 + Lapatinib and compare changes in signaling with FGF19 present. MB-453 cells treated with BLU554 decreased cell viability similarly to Lapatinib at 10 µM (65% [SD ± 3.3] and 63% [SD ± 2.1], respectively). Dual treatment decreased viability compared to single agents at all concentrations but the greatest difference was observed at 20 µM (38.5% in dual compared to Lapatinib [p-value = 0.00006]; 45.1% in dual compared to BLU554 [p-value = 0.00016]). Dose-response matrix of dual treatment yielded a ZIP synergy score of 16.852 ± 2.97 (>10 is synergistic), with the greatest synergy and inhibition at 10 µM and 20 µM of both drugs. BLU554 caused a therapeutic potency shift of Lapatinib, such that lower doses of Lapatinib (0.1 µM, 1 µM) are effective at higher doses of BLU554 (10 µM, 20 µM). Westerns of MB-453 with one dose of BLU554 increased phospho-ERK1/2 (pERK1/2) at 16- or 48-hr time points versus control, but when BLU554 was re-dosed then pERK1/2 was successfully inhibited. Both pAKT and pS6RP were increased by re-dosing BLU554. Cells treated for 2 hrs with Lapatinib decreased pAKT and pS6RP and did not change pERK, whereas a 2-hr treatment of BLU554 increased pAKT and decreased pERK. Dual treatment exhibited inhibition of ERK, AKT, 4EBP1, and S6RP phosphorylation all to a greater extent than single agents in combination with Ridaforolimus. Challenge by ectopic FGF19 of BLU554 + Lapatinib was unable to restore downstream signaling of AKT and ERK. BLU554 synergistically interacts with Lapatinib to decrease cell viability while increasing its therapeutic potency. Lapatinib primarily inhibits AKT signaling, whereas BLU554 targets ERK. Dual treatment simultaneously blocks MAPK/ERK and PI3K/AKT signaling and yields decreases of mTOR downstream effectors pS6RP and p4EBP1. These effects are maintained even when challenged with FGF19, suggesting that dual inhibition of FGFR4 and HER2 could prevent pathway activation from external stimuli. Citation Format: Jordan Beardsley, Joseph Goode, Deborah Altomare. Dual inhibition of FGFR4 and HER2/EGFR with Lapatinib improves targeting of Erk and Akt signaling in HER2+ breast cancer cells [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-23-09.

Surrogacy of one-year survival for overall survival in advanced hepatocellular carcinoma

BackgroundThe increasing number of sequential treatments complicates the evaluation of overall survival (OS) in clinical trials for hepatocellular carcinoma (HCC), therefore, reliable surrogate endpoints (SEs) are required. This study aimed to evaluate the surrogacy of progression-free survival (PFS) and one-year (1-yr) milestone survival for OS in HCC trials.MethodsWe systematically searched databases for randomized clinical trials that evaluated systemic treatments for advanced HCC. Individual patient data were reconstructed to calculate the 1-yr survival rate. We adopted a two-stage meta-analytic validation model to evaluate the correlation between SEs and OS, and the correlation between treatment effects on SEs and OS. The hazard ratio (HR) was calculated to assess the treatment effects on PFS and OS, and the 1-yr survival ratio was calculated to evaluate the treatment effects on the 1-yr milestone survival.ResultsThirty-two HCC trials involving 13,808 patients were included. A weak correlation was detected between the median PFS and median OS (R2 = 0.32), whereas the correlation improved between PFS HR and OS HR (R2 = 0.58). We identified strong correlations between the 1-yr survival rate and median OS and between the 1-yr survival ratio and OS HR (R2 = 0.74 and 0.65, respectively). In subgroup analyses, PFS HR strongly correlated with OS HR in trials relevant to immune checkpoint inhibitors (ICIs). Although the correlation remained weak between PFS and OS even in trials with PFS HR ≤ 0.6, the 1-yr survival rate and 1-yr survival ratio were strong surrogates for median OS and OS HR, respectively (R2 = 0.77 and 0.75).ConclusionsOne-year milestone survival outperformed PFS as a SE for OS in HCC, indicating the application of 1-yr survival as a secondary endpoint. In particular, PFS HR was a potential SE for OS HR in the ICI trials.

Intratumoral injection of norcantharidin liposome emulsion hybrid delivery system amplifies the cancer-fighting effects of oral sorafenib against hepatocellular carcinoma

Interventional therapies are increasingly used in clinical trials for hepatocellular carcinoma (HCC). Sorafenib is the front-line remedy for HCC, however, chemoresistance occurs immutably and affects the effectiveness of treatment. In a previous study, a norcantharidin liposome emulsion hybrid (NLEH) delivery system for HCC was developed. This study aims to examine the therapeutic effects of the combination of intratumoral injection of NLEH and sorafenib in treating HCC. Sorafenib combined with NLEH activated the apoptosis pathway by synergistically upregulating caspase-9, promoting cytotoxicity, apoptosis (64.57%), and G2/M cell cycle arrest (48.96%). Norcantharidin could alleviate sorafenib resistance by counteracting sorafenib-induced phosphorylation of Akt. Additionally, intratumoral injection of NLEH exhibited a sustained accumulation in the tumor within 24 h and didn't distribute to other major organs. Intratumoral injection of NLEH in combination with oral sorafenib displayed the most potent tumor growth inhibitory effect (77.91%) in vivo. H&E staining results and the indicators of the renal and liver function tests demonstrated the safety of this combination therapy. Overall, these results showed that intratumoral injection of NLEH in combination with oral sorafenib treatment represented a rational potential therapeutic option for HCC.

Obesity, non-alcoholic fatty liver disease and hepatocellular carcinoma: current status and therapeutic targets.

Obesity is a global epidemic and overwhelming evidence indicates that it is a risk factor for numerous cancers, including hepatocellular carcinoma (HCC), the third leading cause of cancer-related deaths worldwide. Obesity-associated hepatic tumorigenesis develops from nonalcoholic fatty liver disease (NAFLD), progressing to nonalcoholic steatohepatitis (NASH), cirrhosis and ultimately to HCC. The rising incidence of obesity is resulting in an increased prevalence of NAFLD and NASH, and subsequently HCC. Obesity represents an increasingly important underlying etiology of HCC, in particular as the other leading causes of HCC such as hepatitis infection, are declining due to effective treatments and vaccines. In this review, we provide a comprehensive overview of the molecular mechanisms and cellular signaling pathways involved in the pathogenesis of obesity-associated HCC. We summarize the preclinical experimental animal models available to study the features of NAFLD/NASH/HCC, and the non-invasive methods to diagnose NAFLD, NASH and early-stage HCC. Finally, since HCC is an aggressive tumor with a 5-year survival of less than 20%, we will also discuss novel therapeutic targets for obesity-associated HCC and ongoing clinical trials.

Abstract 5667: CYT-303 FLEX-NKTM engager dose response efficacy mechanisms in HCC tumor model and safety in cynomolgus monkey toxicology studies support clinical evaluation in hepato-cellular carcinoma

Abstract BACKGROUND: CYT-303 is a multifunctional bispecific NK engager (NKE) targeting NK cell activating receptor NKp46 and tumor antigen Glypican-3 (GPC3) expressed in HCC (hepatocellular carcinoma). Cytovia’s proprietary FLEX-NKTM platform utilizes a novel FLEX-linker and human IgG1 back bone to allow for simultaneous binding to targeted cancer cells and NK cells. We evaluated CYT-303 dose response pharmacology efficacy mechanisms in HCC tumor models and conducted safety assessment studies in cynomolgus monkeys to support first in human clinical studies in HCC patients. METHODS: CYT-303 dose response pharmacology mechanistic studies were conducted in NSG-hIL-15 mice bearing Hep3B tumors and flow cytometry was used to assess bold and tumor NK cells. A 4-week CYT-303 repeat dose GLP toxicology study in cynomolgus monkeys at 6, 20 and 60 mg/kg dose was conducted following weekly intravenous infusions followed by a 6-week recovery period. CYT-303 toxicokinetic and anti-drug antibody (ADA) assessments were conducted using validated immunoassays. RESULTS: CYT-303 dose response in HCC tumor models showed increased tumor growth inhibition at the lower 2-3 mg/kg doses compared to higher 5-10 mg/kg doses consistent with the dose response previously reported in NK cell redirected cytotoxicity assays against HCC tumors. The increased anti- tumor efficacy observed at the lower doses were associated increased infiltration of PBNK’s to the tumor and corresponding reductions in PBNK’s in blood suggesting CYT-303 facilitates PBNK entry and retention in HCC tumors expressing GPC3 tumor antigen. CYT-303 safety assessment in the 4-week toxicology study in cynomolgous monkeys showed no treatment related toxicities or cytokine release and the NOAEL was determined to 60 mg/kg/week the highest dose administered in the study. No treatment related clinical signs, clinical pathology (hematology and clinical chemistry) and anatomic pathology (macroscopic, microscopic and organ weights) changes were observed. CYT-303 toxicokinetic analysis showed dose dependent increases in Cmax and AUC’s and no evidence for CYT-303 accumulation. CYT-303 anti-drug antibodies in monkeys were minimal and only observed in one low dose animal (1 out of 22) which also showed reduced CYT-303 exposures. Based on these pharmacology and toxicology results a pharmacologically active dose (PAD) based approach together with pharmacokinetic modeling would be utilized to estimate first in human dosing in HCC patients. CONCLUSIONS: CYT-303 efficacious doses identified in the HCC model together with safety in cynomolgus monkeys and planned human pharmacokinetic modeling studies support clinical evaluation of CYT-303 in first in human HCC clinical trials. Citation Format: Vishal Khairnar, Christine Waters, Solgalim Diaz, David De Franco, Jean Kadouche, Daniel Teper, Wei Li, Antonio Arulanandam. CYT-303 FLEX-NKTM engager dose response efficacy mechanisms in HCC tumor model and safety in cynomolgus monkey toxicology studies support clinical evaluation in hepato-cellular carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5667.

Serum IGF-1 Scores and Clinical Outcomes in the Phase III IMbrave150 Study of Atezolizumab Plus Bevacizumab versus Sorafenib in Patients with Unresectable Hepatocellular Carcinoma.

PurposeChild-Turcotte-Pugh class A (CTP-A) in unresectable hepatocellular carcinoma (HCC) is the standard criterion for active therapy and clinical trial enrollment. We hypothesized that insulin-like growth factor-1 (IGF-1) derived scores may provide improved survival prediction over CTP classification. This study aimed to evaluate the potential prognostic and predictive effects of IGF-1 derived scores in the phase III IMbrave150 study.Patients and MethodsBaseline and on-treatment serum IGF-1 levels from 371 patients were subjected to central analysis. Patients’ IGF-1 score (1/2/3) and IGF-CTP score (A/B/C) were determined based on pre-specified cutoffs. Outcomes were analyzed by baseline and by on-treatment changes of the IGF-1 and IGF-CTP scores within and between the two treatment arms. The interaction between these scores and outcomes was assessed using univariate and multivariate analyses.ResultsBaseline IGF-CTP score (A vs B/C) showed prognostic significance for OS in both the atezolizumab-bevacizumab (hazard ratio [HR], 0.33; 95% confidence interval [CI], 0.20–0.56; P<0.001) and sorafenib (HR, 0.32; 95% CI, 0.16–0.65; P=0.002) arms. Baseline IGF-1 score (1 vs 2/3) also showed prognostic significance for OS in both the atezolizumab-bevacizumab (HR, 0.33; 95% CI, 0.20–0.55; P<0.001) and sorafenib (HR, 0.48; 95% CI, 0.26–0.89; P=0.02) arms. HRs for PFS were consistent with those for OS. No significant predictive effects were observed for either score between the two arms. Kinetic analysis revealed that patients with increased IGF-1 score (1-> 2/3) at 3 weeks post treatment had shorter OS than patients with stable IGF-1 score of 1 in both the atezolizumab-bevacizumab (HR, 3.70; 95% CI, 1.56–8.77; P=0.003) and sorafenib (HR, 5.83; 95% CI, 1.88–18.12; P=0.0023) arms.ConclusionBaseline and kinetic change of IGF-CTP and IGF-1 scores are independent prognostic factors for patients with unresectable HCC treated with atezolizumab-bevacizumab or sorafenib. These novel scores may provide improved patient stratification in future HCC clinical trials. IMbrave150 ClincialTrials.gov number, NCT03434379.

FGFR redundancy limits the efficacy of FGFR4-selective inhibitors in hepatocellular carcinoma

Aberrant fibroblast growth factor 19 (FGF19) signaling mediated by its receptor, FGF receptor 4 (FGFR4), and coreceptor, klotho β (KLB), is a driver of hepatocellular carcinoma (HCC). Several potent FGFR4-selective inhibitors have been developed but have exhibited limited efficacy in HCC clinical trials. Here, by using HCC cell line models from the Cancer Cell Line Encyclopedia (CCLE) and the Liver Cancer Model Repository (LIMORE), we show that selective FGFR4 inactivation was not sufficient to inhibit cancer cell proliferation and tumor growth in FGF19-positive HCC. Moreover, genetic inactivation of KLB in these HCC cells resulted in a fitness defect more severe than that resulting from inactivation of FGFR4. By a combination of biochemical and genetic approaches, we found that KLB associated with FGFR3 and FGFR4 to mediate the prosurvival functions of FGF19. KLB mutants defective in interacting with FGFR3 or FGFR4 could not support the growth or survival of HCC cells. Genome-wide CRISPR loss-of-function screening revealed that FGFR3 restricted the activity of FGFR4-selective inhibitors in inducing cell death; the pan-FGFR inhibitor erdafitinib displayed superior potency than FGFR4-selective inhibitors in suppressing the growth and survival of FGF19-positive HCC cells. Among FGF19-positive HCC cases from The Cancer Genome Atlas (TCGA), FGFR3 is prevalently coexpressed with FGFR4 and KLB, suggesting that FGFR redundancy may be a common mechanism underlying the de novo resistance to FGFR4 inhibitors. Our study provides a rationale for clinical testing of pan-FGFR inhibitors as a treatment strategy for FGF19-positive HCC.

Tumor-associated macrophages in liver cancer: From mechanisms to therapy.

Multidimensional analyses have demonstrated the presence of a unique tumor microenvironment (TME) in liver cancer. Tumor-associated macrophages (TAMs) are among the most abundant immune cells infiltrating the TME and are present at all stages of liver cancer progression, and targeting TAMs has become one of the most favored immunotherapy strategies. In addition, macrophages and liver cancer cells have distinct origins. At the early stage of liver cancer, macrophages can provide a niche for the maintenance of liver cancer stem cells. In contrast, cancer stem cells (CSCs) or poorly differentiated tumor cells are key factors modulating macrophage activation. In the present review, we first propose the origin connection between precursor macrophages and liver cancer cells. Macrophages undergo dynamic phenotypic transition during carcinogenesis. In this course of such transition, it is critical to determine the appropriate timing for therapy and block specific markers to suppress pro-tumoral TAMs. The present review provides a more detailed discussion of transition trends of such surface markers than previous reviews. Complex crosstalk occurs between TAMs and liver cancer cells. TAMs play indispensable roles in tumor progression, angiogenesis, and autophagy due to their heterogeneity and robust plasticity. In addition, macrophages in the TME interact with other immune cells by directing cell-to-cell contact or secreting various effector molecules. Similarly, tumor cells combined with other immune cells can drive macrophage recruitment and polarization. Despite the latest achievements and the advancements in treatment strategies following TAMs studies, comprehensive discussions on the communication between macrophages and cancer cells or immune cells in liver cancer are currently lacking. In this review, we discussed the interactions between TAMs and liver cancer cells (from cell origin to maturation), the latest therapeutic strategies (including chimeric antigen receptor macrophages), and critical clinical trials for hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA) to provide a rationale for further clinical investigation of TAMs as a potential target for treating patients with liver cancer.

P-290 Real-world evidence of anlotinib in patients with advanced hepatocellular carcinoma and clinical role of α-fetoprotein

Anlotinib, a novel multi-targeting tyrosine kinase inhibitor (TKI), has been investigated in a variety of malignant tumors and has shown efficacy in clinical trials for hepatocellular carcinoma (HCC). This study was designed to compare the efficacy of anlotinib versus some other protein kinase inhibitors (PKIs) as a first- or second-line therapy for advanced or metastatic HCC, and to identify the early predictive biomarkers for treatment response. 158 patients with a diagnosis of locally advanced or metastatic HCC receiving PKIs agents were retrospectively enrolled in this study. Patients treated with anlotinib were assigned to anlotinib group, while those receiving other common targeted drugs (sorafenib, lenvatinib, regorafenib, apatinib) were assigned to other PKIs group. All patients in anlotinib group received treatment at a dose of 12 mg on day 1 through 14 of a 21-day cycle. Patients were regularly followed-up by the investigators. Radiological imaging was done for all patients every 6 weeks after the first intervention dose. Laboratory test results were collected from the time of drug assignment to 30 days following treatment discontinuation. The efficacy of the treatment was assessed by the tumor response and survival. The primary end point was overall survival (OS). Between August 6, 2013 and October 18, 2021, 158 eligible patients were enrolled after PSM analysis. 54 were assigned to anlotinib and 104 were assigned to other PKIs. Median OS for anlotinib group was 14.8 months (95% CI: 13.6-16.2 months) versus 11.7 months (95% CI: 10.1-13.4 months) for other PKIs group (p=0.005). The median PFS was 5.7 versus 5.1 months (P=0.100). Subgroup analyses demonstrated a trend of superior OS benefit with anlotinib over other PKIs was consistently observed across most predefined subgroups. 24 or 30 patients were treated with anlotinib as first- or second-line therapy in anlotinib group. The number of patients treated with other PKIs as first- or second-line therapy was 51 or 53. In first-line therapy, anlotinib was not associated with a significantly longer PFS or OS than other PKIs. Anlotinib only exhibited superior OS versus other PKIs in second-line therapy. Hepatic biochemical markers were used to investigate early predictors for disease control. A multivariate analysis identified AFP response (a reduction in AFP of ≥40% from baseline) as an independent predictor of disease control in patients undergoing anlotinib treatment (P=0.001). We performed in-depth analyses to determine whether anlotinib could show superior clinical outcomes over other PKIs in both first- and second-line therapy. For first-line therapy, mPFS was 5.0 months with anlotinib and 4.0 months with other PKIs (P=0.144), and mOS was 20.0 vs. 15.0 months (P=0.077). For second-line therapy, PFS was not improved either. Only mOS (13.0 vs. 10.0 months, p=0.001) were improved with anlotinib versus other PKIs. We separated patients with anlotinib into AFP response (a reduction in AFP of ≥40% from baseline) group and non-response group. Two groups show different DCR (P=0.001).

Antiviral Treatments Eliminate the Adverse Impacts of High Baseline HBV Loads on the Survival of HBV-Related HCC Patients.

BackgroundIn consideration of no standard exclusion criteria for hepatitis B virus (HBV) loads in hepatocellular carcinoma (HCC)-related clinical trials, this study aimed to investigate the prevalence of HBV-related exclusion criteria among current clinical trials and evaluate whether antiviral treatments could eliminate the adverse effects from high HBV loads for HCC patients.MethodsThis is a retrospective study including 772 HCC clinical trials on ClinicalTrials.gov and 1784 HCC patients receiving antiviral treatment. The Kaplan–Meier (K-M) method was used to compare the progression-free survival (PFS) and overall survival (OS) between different groups, and Cox regression analyses were performed to validate possible risk factors on PFS and overall survival OS.ResultsAmong 772 clinical trials, 58.3% did not adopt baseline HBV loads as exclusion criteria, 18.0% was 2000 IU/mL, and 10.5% was receiving antiviral therapy. We observed baseline HBV loads had no significant impact on PFS (p = 0.491, 0.155, 0.119, 0.788, 0.280, 0.683 respectively) and OS (p = 0.478, 0.741, 0.263, 0.039, 0.999, 0.581 respectively) in all patients or each treatment group including hepatectomy, radiofrequency ablation, interventional therapy, targeted drugs and anti-programmed cell death immunotherapy, except for the OS of interventional therapy group, where patients with high HBV loads had higher BCLC stage, serum AFP level and ALBI grade (p = 0.009, 0.015 and 0.003, respectively).ConclusionAntiviral treatments could eliminate the adverse impacts of high HBV loads on the survival of HCC patients. Simplified eligibility criteria can be adopted for HCC patients with HBV infection where regular antiviral therapy should be enough.

Inactivators of Ornithine Aminotransferase for the Treatment of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the second or third leading cause of cancer mortality worldwide (depending on which statistics are used), yet there is no effective treatment. Currently, there are nine FDA-approved drugs for HCC, five monoclonal antibodies and four tyrosine kinase inhibitors. Ornithine aminotransferase (OAT) has been validated as a target in preclinical studies, which demonstrates that it is a potential target to treat HCC. Currently, there are no OAT inactivators in clinical trials for HCC. This Innovation describes evidence to support inhibition of OAT as a novel approach for HCC tumor growth inhibition. After the mechanism of OAT is discussed, the origins of our involvement in OAT inactivation, based on our previous work on mechanism-based inactivation of GABA-AT, are described. Once it was demonstrated that OAT inactivation does lead to HCC tumor growth inhibition, new selective OAT inactivators were designed and their inactivation mechanisms were elucidated. A summary of these mechanistic studies is presented. Inactivators of OAT provide the potential for treatment of HCC, targeting the Wnt/β-catenin pathway.

Selective Inhibitor of the c-Met Receptor Tyrosine Kinase in Advanced Hepatocellular Carcinoma: No Beneficial Effect With the Use of Tivantinib?

Advanced hepatocellular carcinoma (HCC) remains a formidable health challenge worldwide, with a 5-year survival rate of 2.4% in patients with distant metastases. The hepatocyte growth factor/cellular-mesenchymal-epithelial transition (HGF/c-Met) signaling pathway represents an encouraging therapeutic target for progressive HCC. Tivantinib, a non-adenosine triphosphate-competitive c-Met inhibitor, showed an attractive therapeutic effect on advanced HCC patients with high MET-expression in phase 2 study but failed to meet its primary endpoint of prolonging the overall survival (OS) in two phase 3 HCC clinical trials. Seven clinical trials have been registered in the “ClinicalTrials.gov” for investigating the safety and efficacy of tivantinib in treating advanced or unresectable HCC. Eight relevant studies have been published with results. The sample size ranged from 20 to 340 patients. The methods of tivantinib administration and dosage were orally 120/240/360 mg twice daily. MET overexpression was recorded at 34.6% to 100%. Two large sample phase 3 studies (the METIV-HCC study of Australia and European population and the JET-HCC study of the Japanese population) revealed that tivantinib failed to show survival benefits in advanced HCC. Common adverse events with tivantinib treatment include neutropenia, ascites, rash, and anemia, etc. Several factors may contribute to the inconsistency between the phase 2 and phase 3 studies of tivantinib, including the sample size, drug dosing, study design, and the rate of MET-High. In the future, high selective MET inhibitors combined with a biomarker-driven patient selection may provide a potentially viable therapeutic strategy for patients with advanced HCC.

Current Landscape and Future Directions of Biomarkers for Immunotherapy in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the most common liver cancer and one of the leading causes of cancer-related deaths in the world. Multiple immunotherapeutic approaches have been investigated to date, and immunotherapy has become the new standard of care therapy in HCC. However, the current role of immunotherapy in HCC remains non-curative. Given this context, a high priority for oncology is understanding the biomarkers that predict clinical response to immunotherapy, have the potential to improve patient selection to maximize the clinical benefit, and spare unnecessary toxicity. In this review, we summarize the key predictive and prognostic biomarkers investigated in immunotherapy clinical trials in HCC and the emerging biomarkers to serve as a roadmap for future clinical trials. Biomarkers from tumoral tissues including PDL-1 expression, tissue infiltrating lymphocytes, tumor mutational burden (TMB) and specific immune signatures, and from peripheral blood including neutrophil-to-lymphocytes ratio, platelet-to-lymphocytes ratio, circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and specific cytokines, along with gut microbiota are among the studied biomarkers to date in the HCC era. More integrative approaches, including mathematical biomarkers to predict immunotherapy outcomes, are yet to be studied in HCC.

Understanding the patient experience in hepatocellular carcinoma: a qualitative patient interview study

PurposeThis study aimed to elucidate the patient experience of hepatocellular carcinoma (HCC) to guide patient-centered outcome measurement in drug development.MethodsPatients with HCC participated in qualitative interviews to elicit disease-related signs/symptoms and impacts, using discussion guides developed from literature searches and discussions with oncologists. Interview participants rated the disturbance of their experiences (0–10 scale). A conceptual model was developed and mapped against patient-reported outcome (PRO) instruments identified from database reviews.ResultsInterviews were conducted with 25 individuals with HCC (68% were men; median age: 63 years; 12% Barcelona clinic liver cancer (BCLC) stage A; 32% stage B; and 56% stage C) in the USA. Fifty-one HCC-related concepts were identified from the interviews and were grouped into eight sign/symptom categories (eating behavior/weight changes; extremities [arms, legs]; fatigue and strength; gastrointestinal; pain; sensory; skin; other) and four impact categories (emotional; physical; cognitive function; other) for the conceptual model. The most prevalent and disturbing experiences across the disease stages were fatigue/lack of energy and emotional impacts such as frustration, fear, and depression. Abdominal pain and skin-related issues were particularly common and disturbing in individuals with HCC stage C. The EORTC QLQ-C30 and HCC18 were identified as commonly used PRO instruments in HCC studies and captured the relevant signs/symptoms associated with the patient experience.ConclusionPatients with HCC reported a range of signs/symptoms and impacts that negatively affect daily functioning and quality of life. Including PRO measures in HCC clinical trials can provide meaningful patient perspectives during drug development.

Effect of prior cancer on survival of hepatocellular carcinoma: implications for clinical trial eligibility criteria

BackgroundPatients with cancer history are usually excluded from hepatocellular carcinoma (HCC) clinical trials. However, whether previous malignancy affects the oncological outcomes of HCC patients has not been fully assessed. This study aimed to evaluate whether prior cancer compromised the survival of HCC patients.MethodsPatients with HCC were extracted from the Surveillance, Epidemiology, and End Results database between 2004 and 2015, and then they were classified into groups with and without prior cancer. The Kaplan-Meier and multivariate Cox regression analysis were adopted to evaluate whether prior cancer impacted clinical outcomes after propensity score matching (PSM) adjusting baseline differences. Validation was performed in the cohort from our institution.ResultsWe identified 2642 HCC patients with prior cancer. After PSM, the median overall survival (OS) time were 14.5 and 12.0 months respectively for groups with and without prior cancer. Prior cancer did not compromise prognosis in patients with HCC (p = 0.49). The same tendency was found in subgroups stratified by tumor stages and cancer interval period: OS was similar between groups with and without prior cancer (both p values> 0.1). In the multivariate Cox regression model, prior cancer did not adversely impact patients’ survival (HR: 1.024; 95% CI: 0.961–1.092). In the validation cohort from our institution, prior cancer had no significant association with worse outcomes (p = 0.48).ConclusionFor HCC patients, prior cancer did not compromise their survival, regardless of tumor stage and cancer interval period. Exclusion criteria for HCC clinical trials could be reconsidered.

Trends of clinical outcomes with sorafenib in randomized controlled trials for patients with treatment-naïve advanced hepatocellular carcinoma.

327 Background: Sorafenib was first approved by the US FDA to treat patients with advanced hepatocellular carcinoma (HCC) after two landmark trials (SHARP and Asia-Pacific) showed improved overall survival (OS). Since those two landmark trials, median OS has increased in the sorafenib arms in several recent phase III trials in HCC. We analyzed trends in OS, progression-free survival (PFS), and objective response rates (ORR) in published randomized clinical trials of sorafenib in HCC to better understand factors underlying the improvements. Methods: We searched PubMed for all published trials of sorafenib in advanced HCC. Trials were included if the patients were naïve to systemic therapy and had a comparison arm that was active systemic therapy or placebo. We extracted demographic and trial-level outcome data to correlate outcomes such as OS, PFS, ORR, and duration of therapy. T-tests were used to compare outcomes and linear regression was used to identify temporal trends with significance set at p£0.05. Results: The PubMed search returned 100 studies. A total of 15 studies met inclusion criteria with a total of 3755 patients treated with sorafenib (9 phase III and 6 phase II). Included trials enrolled patients from 2005-2019. The median OS in all trials was 10.0 mos (range: 6.5-14.8 mos). OS has significantly improved since the first trial began accruing (p = 0.04). A total of 12 studies provided data on PFS using RECIST 1.1, with a median PFS of 4.0 months (range: 2.7-6.6 mos). PFS has not changed over time (p = 0.99). However, ORR assessed by RECIST 1.1 have trended toward improvement over time (p = 0.08). Median duration of therapy with sorafenib has decreased by 53% since the enrollment of the first clinical trial in 2005, from 23.1 weeks to 12.2 weeks (p = 0.02). Despite this, no significant correlations were observed with the interaction of duration of therapy and OS (p = 0.92). Further, there was no significant change in the age of patients included, proportion of patients with Childs-Pugh A, Barcelona Clinic Liver Cancer (BCLC) B, BCLC C, ECOG performance status 0, HBV or HCV, proportion of patients with extrahepatic spread or vascular invasion at time of enrollment, or proportion of patients who have undergone prior locoregional therapies to explain the OS findings. Conclusions: The OS of patients with advanced HCC on the sorafenib arm in published trials has been increasing, however the reasons for this increase are not apparent from data available in the published literature. At the same time, the median duration of treatment with sorafenib has been decreasing over time and PFS is unchanged, suggesting improvements in sorafenib delivery may not be the primary factor. It is possible these trends represent heretofore unquantified changes in patient selection for systemic therapy, improvements in supportive care, or post-progression treatment for patients on HCC clinical trials.

An update on atezolizumab for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a worldwide problem, with a high prevalence in nonindustrialized countries and a rising incidence in industrialized countries. Its close association with chronic liver diseases and liver cirrhosis represents a significant challenge in its treatment. Sorafenib, the first front-line systemic treatment for unresectable HCC cases, was approved only in 2007. The role of sorafenib remained largely unchallenged until very recently, with the sole exception of a trial demonstrating the noninferiority of lenvatinib, another tyrosine kinase inhibitor. The therapeutic scenario changed dramatically in 2020, when the combination of atezolizumab and bevacizumab proved to be significantly superior to sorafenib and, thus, establishing a new standard of care. In this monograph we provide an update about the safety and efficacy of atezolizumab reported in the clinical trials of HCC, as monotherapy or in combination with other agents.

Molecular and immunological paradigms of hepatocellular carcinoma: Special reference to therapeutic approaches

The development of hepatocellular carcinoma (HCC) is a multistep process with a complex interaction of various genetic backgrounds and the tumor microenvironment. In addition to the development of rational approaches to epidemiologic research, early detection, and diagnosis, considerable progress has been made in systemic treatment with molecular-targeted agents for patients with advanced HCC. Moreover, encouraging reports of recent clinical trials of combination therapy with immune-checkpoint inhibitors (ICIs) has raised high hopes. Each HCC is the result of a unique combination of somatic alterations, including genetic, epigenetic, transcriptomic, and metabolic events, leading to conclusive tumoral heterogeneity. Recent advances in comprehensive genetic analysis have accelerated molecular classification and defined subtypes with specific characteristics, including immune-associated molecular profiles reflecting the immune reactivity in the tumor. In considering the development of therapeutic strategies in combination with immunotherapy, proper interpretation of molecular pathological characterization could lead to effective therapeutic deployment and enable individualization of the management of HCC. Here, we review distinctive molecular alterations in the subtype classification of HCC, current therapies, and representative clinical trials with alternative immune-combination approaches from a molecular pathological point.

Telomere length is key to hepatocellular carcinoma diversity and telomerase addiction is an actionable therapeutic target

Telomerase activation is the earliest event in hepatocellular carcinoma (HCC) development. Thus, we aimed to elucidate the role of telomere length maintenance during liver carcinogenesis. Telomere length was measured in the tumor and non-tumor liver tissues of 1,502 patients (978 with HCC) and integrated with TERT alterations and expression, as well as clinical and molecular (analyzed by genome, exome, targeted and/or RNA-sequencing) features of HCC. The preclinical efficacy of anti-TERT antisense oligonucleotides (ASO) was assessed in vitro in 26 cell lines and in vivo in a xenograft mouse model. Aging, liver fibrosis, male sex and excessive alcohol consumption were independent determinants of liver telomere attrition. HCC that developed in livers with long telomeres frequently had wild-type TERT with progenitor features and BAP1 mutations. In contrast, HCC that developed on livers with short telomeres were enriched in the non-proliferative HCC class and frequently had somatic TERT promoter mutations. In HCCs, telomere length is stabilized in a narrow biological range around 5.7 kb, similar to non-tumor livers, by various mechanisms that activate TERT expression. Long telomeres are characteristic of very aggressive HCCs, associated with the G3 transcriptomic subclass, TP53 alterations and poor prognosis. In HCC cell lines, TERT silencing with ASO was efficient in highly proliferative and poorly differentiated cells. Treatment for 3 to 16 weeks induced cell proliferation arrest in 12 cell lines through telomere shortening, DNA damage and activation of apoptosis. The therapeutic effect was also obtained in a xenograft mouse model. Telomere maintenance in HCC carcinogenesis is diverse, and is associated with tumor progression and aggressiveness. The efficacy of anti-TERT ASO treatment in cell lines revealed the oncogenic addiction to TERT in HCC, providing a preclinical rationale for anti-TERT ASO treatment in HCC clinical trials. Telomeres are repeated DNA sequences that protect chromosomes and naturally shorten in most adult cells because of the inactivation of the TERT gene, coding for the telomerase enzyme. Here we show that telomere attrition in the liver, modulated by aging, sex, fibrosis and alcohol, associates with specific clinical and molecular features of hepatocellular carcinoma, the most frequent primary liver cancer. We also show that liver cancer is dependent on TERT reactivation and telomere maintenance, which could be targeted through a novel therapeutic approach called antisense oligonucleotides.

Assessment of Current Gene Therapy Practices in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer and the fifth most common cancer worldwide. HCC is recognized as the fourth most common cause of cancer related deaths worldwide due to the lack of effective early diagnostic tools, which often leads to individuals going undiagnosed until the cancer has reached late stage development. The current FDA approved treatments for late stage HCC provide a minimal increase in patient survival and lack tumor specificity, resulting in toxic systemic side effects. Gene therapy techniques, such as chimeric antigen receptor (CAR)-T Cells, viral vectors, and nanoparticles, are being explored as novel treatment options in various genetic diseases. Pre-clinical studies using gene therapy to treat in vitro and in vivo models of HCC have demonstrated potential efficacy for use in human patients. This review highlights genetic targets, techniques, and current clinical trials in HCC utilizing gene therapy.