Therapy For Advanced Hepatocellular Carcinoma Research Articles

Systemic targeted and immunotherapy for advanced hepatocellular carcinoma.

The activity of targeted agents and immunotherapy in the management of advanced hepatocellular carcinoma (HCC) is reviewed. The first drug approved by the Food and Drug Administration for advanced HCC, sorafenib, was approved in 2007. Regorafenib, the second drug, was approved 10 years later. Six additional drugs have been approved since. Targeted agents and checkpoint inhibitors are the only agents approved for systemic therapy of advanced HCC. Sorafenib and lenvatinib are approved as first-line agents, with regorafenib, cabozantinib, ramucirumab, nivolumab (used alone or with ipilimumab), and pembrolizumab approved for patients who have received prior sorafenib therapy. Most patients in phase 3 studies had Child-Pugh class A cirrhosis, and data on the use of these agents in patients with more advanced hepatic dysfunction are limited. All of the targeted agents improve survival in patients with advanced disease. Median overall survival durations of up to 12.3 and 13.6 months were reported with use of sorafenib and lenvatinib, respectively, in phase 3 trials. Overall survival durations of 10.6, 10.2, and 9.2 months have been achieved with use of regorafenib, cabozantinib, and ramucirumab as second-line therapy after sorafenib. A median overall survival of 13.2 months was reported in 1 cohort of a dose-expansion study of nivolumab in which all patients received prior sorafenib therapy. Median survival durations of 12.9 months and 13.9 months were reported with use of pembrolizumab in patients with a history of sorafenib therapy. The most common adverse effects associated with targeted agents are dermatological effects, diarrhea, fatigue, and hypertension. Immune-mediated adverse effects are associated with checkpoint inhibitors. Targeted agents and checkpoint inhibitors are the standard of therapy for patients who need systemic therapy for advanced HCC.

Personalised versus standard dosimetry approach of selective internal radiation therapy in patients with locally advanced hepatocellular carcinoma (DOSISPHERE-01): a randomised, multicentre, open-label phase 2 trial

All randomised phase 3 studies of selective internal radiation therapy for advanced hepatocellular carcinoma published to date have reported negative results. However, these studies did not use personalised dosimetry. We aimed to compare the efficacy of a personalised versus standard dosimetry approach of selective internal radiation therapy with yttrium-90-loaded glass microspheres in patients with hepatocellular carcinoma. DOSISPHERE-01 was a randomised, multicentre, open-label phase 2 trial done at four health-care centres in France. Patients were eligible if they were aged 18 years or older and had unresectable locally advanced hepatocellular carcinoma, at least one measurable lesion 7 cm or more in size, a hepatic reserve of at least 30% after selective internal radiation therapy, no extrahepatic spread (other than to the lymph nodes of the hilum, with a lesion <2 cm in size), and no contraindications to selective internal radiation therapy, as assessed by use of a technetium-99m macro-aggregated albumin scan. Patients were randomly assigned (1:1) by use of a permutated block method, with block sizes of four and without stratification, to receive either standard dosimetry (120 ± 20 Gy) targeted to the perfused lobe; standard dosimetry group) or personalised dosimetry (≥205 Gy targeted to the index lesion; personalised dosimetry group). Investigators, patients, and study staff were not masked to treatment. The primary endpoint was the investigator-assessed objective response rate in the index lesion, according to European Association for the Study of the Liver criteria, at 3 months after selective internal radiation therapy in the modified intention-to-treat population. Safety was assessed in all patients who received at least one selective internal radiation therapy injection, and analysed on the basis of the treatment actually received (defined by central dosimetry assessment). The trial is registered with ClinicalTrials.gov, NCT02582034, and has been completed. Between Dec 5, 2015, and Jan 4, 2018, 93 patients were assessed for eligibility. Of these patients, 60 were randomly assigned: 31 to the personalised dosimetry group and 29 to the standard dosimetry group (intention-to-treat population). 56 (93%) patients (28 in each group) were treated (modified intention-to-treat population). In the modified intention-to-treat population, 20 (71% [95% CI 51-87]) of 28 patients in the personalised dosimetry group and ten (36% [19-56]) of 28 patients in the standard dosimetry group had an objective response (p=0·0074). In the safety analysis population, a least one serious adverse event was reported in seven (20%) of the 35 patients who received personalised dosimetry, and in seven (33%) of the 21 patients who received standard dosimetry. The most frequent (ie, occurring in >5% of patients) grade 3 or higher adverse events were ascites (one [3%] patient who received personalised dosimetry vs two [10%] patients who received standard dosimetry), hepatic failure (two [6%] vs none), lymphopenia (12 [34%] vs nine [43%]), increased aspartate aminotransferase concentrations (three [9%] vs two [10%]), increased alanine aminotransferase concentrations (three [9%] vs none), anaemia (two [6%] vs one [5%]), gastrointestinal haemorrhage (none vs two [10%]), and icterus (none vs two [10%]). One treatment-related death occurred in each group. Compared with standard dosimetry, personalised dosimetry significantly improved the objective response rate in patients with locally advanced hepatocellular carcinoma. The results of this study suggest that personalised dosimetry is likely to improve outcomes in clinical practice and should be used in future trials of selective internal radiation therapy. Biocompatibles UK, a Boston Scientific Group company.

Role of immunotherapy in the management of hepatocellular carcinoma: current standards and future directions.

The multikinase inhibitor sorafenib was the only approved systemic therapy in advanced hepatocellular carcinoma (hcc) for about a decade. In recent years, the number of approved agents has increased significantly as a result of a number of positive phase iii clinical trials. Lenvatinib as a first-line treatment, and regorafenib, cabozantinib, and ramucirumab in the second-line setting are now approved by the U.S. Food and Drug Administration (fda) and the European Medicines Agency. In phase ii studies, immunotherapy with nivolumab and monotherapy using pembrolizumab yielded impressive results for overall survival in therapy-naïve and pretreated patients, leading to the accelerated approval by the fda of nivolumab and pembrolizumab for second-line treatment. However, phase iii trials of nivolumab in the first line and pembrolizumab in the second line as single agents failed to reach statistical significance, although clinical benefit for a subset of patients with long durations of response could be demonstrated. Despite that setback, immunotherapy for hcc is a promising therapeutic approach, and the combination of immunotherapy with other treatment modalities such as monoclonal antibodies, tyrosine kinase inhibitors, or local therapies has the potential to increase the overall response rate and survival. Recently, the results of a phase iii trial of combination atezolizumab-bevacizumab compared with sorafenib showed a highly significant survival benefit and median overall survival that was not reached in the immunotherapy arm, making the combination the preferred standard of care in first-line therapy. Despite the impressive results and generally good toxicity profile of immunotherapy, patients who respond to therapy constitute only a subset of the overall population, and response rates are still limited. This review focuses on the currently reported results and ongoing clinical trials of checkpoint inhibitor-based immunotherapy in hcc.

Apatinib as an alternative therapy for advanced hepatocellular carcinoma.

Angiogenesis plays an important role in the occurrence and development of tumors. Registered tyrosine kinase inhibitors targeting vascular endothelial growth factor reduce angiogenesis. Apatinib, a tyrosine kinase inhibitor, can specifically inhibit vascular endothelial growth factor receptor 2, showing encouraging anti-tumor effects in a variety of tumors including advanced hepatocellular carcinoma (HCC). This article intends to review the clinical research and application prospects of apatinib in the field of HCC.

Mutations in circulating tumor DNA predict primary resistance to systemic therapies in advanced hepatocellular carcinoma.

Little is known about the mutational landscape of advanced hepatocellular carcinoma (HCC), and predictive biomarkers of response to systemic therapies are lacking. We aimed to describe the mutational landscape of advanced HCC and to identify predictors of primary resistance to systemic therapies using circulating tumor DNA (ctDNA). We prospectively enrolled 121 patients between October 2015 and January 2019. We performed targeted ultra-deep sequencing of 25 genes and Digital Droplet PCR of TERT promoter, including sequential samples throughout treatment. Primary endpoint was progression-free survival (PFS) stratified by mutation profiles in ctDNA. Secondary endpoints were overall survival and objective response rate. The most frequent mutations in ctDNA of advanced HCC were TERT promoter (51%), TP53 (32%), CTNNB1 (17%), PTEN (8%), AXIN1, ARID2, KMT2D, and TSC2 (each 6%). TP53 and CTNNB1 mutations were mutually exclusive. Patients with mutations in the PI3K/MTOR pathway had significantly shorter PFS than those without these mutations after tyrosine kinase inhibitors (2.1 vs 3.7 months, p < 0.001), but not after immune checkpoint inhibition (CPI). WNT pathway mutations were not associated with PFS, overall survival, or objective response after CPI. Serial profiling of ctDNA in a subset correlated with treatment response. Mutation profiling of ctDNA in advanced HCC shows similar mutation frequencies for known HCC drivers compared to early stages and identifies predictive biomarkers of response to systemic therapies.

Efficacy and Safety of the Radiotherapy for Liver Cancer: Assessment of Local Controllability and Its Role in Multidisciplinary Therapy

Simple SummaryWe have shown the efficacy and safety of radiotherapy for the hepatocellular carcinoma as a curative therapy and a part of multidisciplinary therapy which could safely be combined with various therapies. The assessment of local controllability and survival showed the anti-tumor efficacy of the procedure, and the analyses of the serum biochemical factors and hepatic function, including the Child–Pugh score and albumin–bilirubin (ALBI)-grade, demonstrated its safety. While the assessment of a larger number of cases and well-designed randomized trials are essential, the results provided here will contribute to understanding the efficacy of radiotherapy as an additional therapy for the treatment of hepatocellular carcinoma and help physicians make therapeutic decisions.This study investigated the efficacy and safety of radiotherapy as part of multidisciplinary therapy for advanced hepatocellular carcinoma (HCC). Clinical data of 49 HCC patients treated with radiotherapy were assessed retrospectively. The efficacy of radiotherapy was assessed by progression-free survival, disease control rate, and overall survival. Safety was assessed by symptoms and hematological assay, and changes in hepatic reserve function were determined by Child–Pugh score and albumin–bilirubin (ALBI) score. Forty patients underwent curative radiotherapy, and nine patients with portal vein tumor thrombus (PVTT) underwent palliative radiotherapy as part of multidisciplinary therapy. Local disease control for curative therapy was 80.0% and stereotactic body radiotherapy was 86.7% which was greater than that of conventional radiotherapy (60.0%). Patients with PVTT had a median observation period of 651 days and 75% three-year survival when treated with multitherapy, including radiotherapy for palliative intent, transcatheter arterial chemoembolization, and administration of molecular targeted agents. No adverse events higher than grade 3 and no changes in the Child–Pugh score and ALBI score were seen. Radiotherapy is safe and effective for HCC treatment and can be a part of multidisciplinary therapy.

Ablation Reboots the Response in Advanced Hepatocellular Carcinoma With Stable or Atypical Response During PD-1 Therapy: A Proof-of-Concept Study

Background: The anti-programmed cell death protein-1 (PD-1) inhibitor is one of the second-line therapies for advanced hepatocellular carcinoma (HCC) after sorafenib failure. The goal of this study is to evaluate the feasibility and safety of ablation on the tumor in patients with advanced HCC who had stable disease or atypical response during single anti-PD-1 therapy after sorafenib failure. Atypical response defined as mixed responses in different lesions of the same individual (e.g., active or stable lesions mixed with progressive lesions).Patients and Methods: This proof-of-concept clinical trial enrolled 50 patients treated with an anti-PD-1 inhibitor of nivolumab or pembrolizumab monotherapy between July 2015 and Nov 2017. Thirty-three cases with stable disease or atypical response to anti-PD-1 inhibitor received subtotal thermal ablation. The safety and the response of ablation during anti-PD-1 therapy were evaluated. The survival was estimated by the Kaplan-Meier curve.Results: Of all 50 patients treated with anti-PD-1 therapy, the rate of response, stable disease, atypical and typical progression were 10% (n = 5), 42% (n = 21) 32% (n = 16), and 12% (n = 6), respectively. Additional ablation improved efficacy with tolerable toxicity, and the response rate was increased from 10 to 24% (12/50). The median time to progression, progression-free survival, and overall survival was 6.1 months (95%CI, 2.6–11.2), 5 months (95%CI, 2.9–7.1), and 16.9 months (95%CI, 7.7–26.1), respectively.Conclusions: This proof-of-concept trial suggested that additional ablation may increase the objective response rate with tolerated toxicity and achieved a relatively better median survival, in advanced HCC patients who had stable or atypical progressive diseases during anti-PD-1 therapy, which may provide a potentially promising strategy to treat advanced HCC.Trial registration number: ClinicalTrials.gov identifier: NCT03939975.

Integrating Genomics Into Clinical Practice in Hepatocellular Carcinoma: The Challenges Ahead.

The incidence and mortality related to hepatocellular carcinoma (HCC) continue to increase in the United States, with most patients presenting at advanced stages where curative therapy and long-term survival is unlikely. Fortunately, significant progress has been made in identifying the landscape of HCC mutations due to advances in whole genome expression profiling. Drug development has also evolved in recent years with multiple first- and second-line systemic chemotherapy agents approved for HCC for the first time in over a decade. However, despite advances in molecular profiling, mutations that were identified at the highest frequency were not amenable to drug development, and curative therapy for advanced HCC remains elusive. This review focuses on the current understanding of HCC genomics and the limitations of translating the current HCC molecular profiling into clinical practice and examines the effectiveness and benefits of approved systemic therapies for advanced HCC.

Hepatocellular carcinoma: considerations for managed care professionals.

Liver cancer is the most rapidly increasing cancer in the United States and is associated with a high cancer-related mortality. Seventy-five percent of liver cancers are hepatocellular carcinoma (HCC) resulting from cirrhosis. Patients are typically diagnosed late in the disease, with a relatively small percentage eligible for curative treatments. Despite the addition of several new therapies for advanced HCC, the 5-year survival rate is just 18%. The direct and indirect costs of HCC are substantial, and are expected to increase with the rise in disease incidence as well as a growing number of high-cost therapies entering the market. There are opportunities to improve the quality of care for patients with HCC through implementation of value-based reimbursement principles and pharmacist involvement in care.

A concise review of the changing landscape of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the fastest rising cause of cancer-related deaths in the United States, increasing by 2% to 3% annually, with a dismal 5-year survival rate of 18%. The Barcelona Clinic Liver Cancer criteria used to guide treatment considers performance status and assessment of liver function by Child-Pugh score in addition to tumor size and location. Curative therapies for HCC include surgical resection, liver transplantation, and tumor ablation. Patients with unresectable or inoperable lesions should be considered for arterially directed embolic therapy, systemic therapy, or radiation. Options for first-line systemic therapy of advanced HCC include sorafenib, lenvatinib, and atezolizumab plus bevacizumab. Nivolumab may be an option in patients with advanced HCC who are ineligible for tyrosine kinase inhibitors or other anti-angiogenic agents. Options for subsequent therapy following disease progression include regorafenib, cabozantinib, ramucirumab, lenvatinib, nivolumab, nivolumab plus ipilimumab, sorafenib, or pembrolizumab. Patients with advanced HCC are at a high risk of adverse effects because of baseline hepatic dysfunction, comorbidities associated with chronic liver disease, and potential drug-drug interactions. Improved tolerance of therapies for advanced HCC may lead to reduction in treatment discontinuation and contribute to better patient outcomes. Managed care pharmacists should understand the recent efficacy and safety data, guideline recommendations, and treatment algorithms for management of HCC.

Effect of sarcopenia on systemic targeted therapy response in patients with advanced hepatocellular carcinoma.

Sarcopenia is an independent prognostic indicator for hepatocellular carcinoma (HCC). Our objective was to determine the effect of sarcopenia on response to systemic targeted therapy in patients with advanced HCC. This was a retrospective, Institutional Review Board approved study of 36 patients on systemic targeted therapy with immune checkpoint blockade (n = 25) or tyrosine kinase inhibitor (n = 11) for biopsy-proven advanced HCC. Skeletal muscle index (SMI) was calculated from erector spinae muscle area (SMA) at the level of T12 on pretreatment CT: [SMI = SMA (cm2)/height (m2)]. SMI was compared to treatment response defined as overall survival ≥ 1year (nonsurgical patients) or > 50% HCC necrosis (surgical patients). Receiver operating characteristic curve and area under the curve was used for analysis with p < 0.05 for statistical significance. Median age of men and women was 66.5years (range 32-83) and 70years (range 54-78), respectively. Liver disease etiology was nonalcoholic steatohepatitis (n = 9), hepatitis C (n = 10), hepatitis B (n = 5), alcohol (n = 3) and unknown (n = 9). Mean (± SD) height and SMI for men were 1.7m (± 0.1) and 11.4 (± 3.6); values for women were 1.7m (± 0.1) and 8.2 (± 1.9). Treatment was withdrawn in five patients due to treatment intolerance. Response occurred in 10/31 (32.3%) patients (23 men, 8 women). T12SMI correlated with treatment response using a threshold of 7.21-8.23 for women (AUC = 1; p = 0.037), and 11.47 for men (AUC = 0.83; p = 0.015); correlation was increased for men ≥ 60years, (AUC = 0.87; p = 0.023). Sarcopenia was associated with reduced survival and HCC necrosis in patients treated with systemic targeted therapy. Sarcopenia may help in predicting outcomes to targeted therapy in advanced HCC.

The combination therapy of transarterial chemoembolisation and sorafenib is the preferred palliative treatment for advanced hepatocellular carcinoma patients: a meta-analysis

BackgroundTo compare the efficacy of three types of palliative therapy for advanced hepatocellular carcinoma (HCC), including transarterial chemoembolisation (TACE) monotherapy, sorafenib alone and their combination.MethodsThe databases of PubMed, Embase and Cochrane Library were retrieved. The odds ratio (OR) with its 95% confidence interval (CI) was used to investigate the binary variables, and the standardised mean difference (SMD) with its 95% CI was employed to evaluate the continuous variables. All statistical tests were performed by using Stata/SE, version 12.0.ResultsThirty-one clinical studies, containing 5125 unique cases of patients with advanced HCC, were included. There were significant improvements in overall survival (OS) (pooled SMD = 2.54; 95% CI 1.74–3.34) and time to progression (TTP) (pooled SMD = 2.49; 95% CI 0.87–4.12) of the patients after receiving the combination therapy of TACE and sorafenib, compared to TACE monotherapy, and the OS in the combined treatment cohort was also longer than that in the sorafenib-alone cohort (pooled SMD = 2.92; 95% CI 1.72–4.13). The combination therapy group in comparison to the TACE group benefited a significantly increased overall response rate (ORR) (pooled OR = 2.61; 95% CI 1.43–4.77), 1-year (pooled OR = 2.96; 95% CI 1.71–5.14) and 2-year (pooled OR = 1.64; 95% CI 1.18–2.28) survival rates and reduced disease progression rate (DPR) (pooled OR = 0.47; 95% CI 0.33–0.68); in parallel, the ORR in the group was also significantly higher than that in the sorafenib-alone group (pooled OR = 3.62; 95% CI 1.28–10.22), although without a difference in the DPR (pooled OR = 0.28; 95% CI 0.05–1.48). In addition, we discovered that the 1-year (pooled OR = 1.39; 95% CI 0.84–2.29) and 2-year (pooled OR = 1.70; 95% CI 0.69–4.18) survival rates in the TACE monotherapy cohort were not significantly different to those in the sorafenib-alone cohort.ConclusionThe combination therapy is more effective than monotherapy in improving the prognostic outcomes of patients with advanced HCC. Therefore, we recommend it as the preferred treatment intervention for those patients.

Optimizing Survival and the Changing Landscape of Targeted Therapy for Intermediate and Advanced Hepatocellular Carcinoma: A Systematic Review.

Systemic therapy for hepatocellular carcinoma (HCC) consisting of the tyrosine kinase inhibitor sorafenib has remained unchanged for over a decade, although results from phase III targeted therapy trials have recently emerged. This review considers available phase III evidence on the use and sequencing of targeted therapy for intermediate and advanced non-locoregional therapy (LRT) eligible HCC and discusses implications for clinical practice. Published and presented literature on phase III data reporting on targeted therapy for advanced HCC that was not eligible for loco-regional therapies was identified using the key search terms "hepatocellular cancer" AND "advanced" AND "targeted therapy" AND "phase III" OR respective aliases (PRISMA). Ten phase III trials assessed targeted therapy first-line and eight following sorafenib. In the first-line, atezolizumab plus bevacizumab statistically significantly improved overall survival (OS) and patient-reported outcomes (PROs) compared with sorafenib, while lenvatinib demonstrated non-inferior OS. Following progression on sorafenib, statistically significant OS improvements over placebo were seen for cabozantinib and regorafenib in unselected patients and for ramucirumab in those with baseline α-fetoprotein≥400 ng/mL. Based on improved OS and PROs, atezolizumab plus bevacizumab appears to be a preferred first-line treatment option for intermediate or advanced non-LRT eligible HCC. Phase III data informing sequencing of later lines of treatment is lacking. Therefore, sequencing principles are proposed that can be used to guide treatment selection. Ongoing trials will continue to inform optimal therapy. Multiple targeted therapies have improved OS in intermediate or advanced non-LRT eligible HCC, although optimal sequencing is an area of ongoing investigation.

982P Comparison of donafenib and sorafenib as advanced hepatocellular carcinoma first-line treatments: Subgroup analysis of an open-label, randomized, parallel-controlled, multicentre phase II/III trial

Donafenib, a deuterated sorafenib derivative, has demonstrated efficacy and safety in phase Ia/Ib studies in advanced hepatocellular carcinoma (HCC). This phase II/III trial assessed efficacy of donafenib to determine noninferiority/superiority vs sorafenib as a first-line therapy for advanced HCC.

Eligibility for Second-line Therapy in Patients With Advanced Hepatocellular Carcinoma: A Population-based Study.

With an increasing number of systemic therapy options for hepatocellular carcinoma (HCC), optimal sequencing is an important consideration. There remains limited real-world data about the eligibility of patients for second-line therapies in advanced HCC. We characterized real-world eligibility and use of second-line therapies post sorafenib. We identified all patients with advanced HCC who received ≥1 cycle of first-line sorafenib between January 1, 2014 and December 31, 2017 in British Columbia, Canada. All patients were Child-Pugh class A for initiation of sorafenib. Baseline characteristics and clinical outcomes were reviewed. Eligibility for second-line therapy was determined using the RESORCE and CELESTIAL study entry criteria. Of 144 patients with advanced HCC who received ≥1 cycle of first-line sorafenib, median age was 65.3 years (range, 32.2 to 83.4 y) and 85% were male. Median duration of sorafenib was 2.6 months. Twelve patients (8%) received second-line treatment but 37 patients (26%) were eligible for second-line therapies based on inclusion criteria from recent registration trials. Primary reasons for ineligibility included ECOG ≥2 (58%), and deterioration to Child-Pugh status B (28%). On Cox regression, improved survival was associated with better ECOG and recurrent disease after initial locoregional therapy. Eligibility for second-line treatment was associated with improved median overall survival from end of first-line treatment (8.5 vs. 5.1 mo; P<0.01). Only a minority of real-world patients with advanced HCC were eligible for second-line therapies based on trial criteria. Given the high rate of attrition, improved first-line treatment options are urgently needed.

Seven immune-related genes prognostic power and correlation with tumor-infiltrating immune cells in hepatocellular carcinoma.

BackgroundGiven poor prognosis and the lack of efficient therapy for advanced hepatocellular carcinoma, immunotherapy has emerged as an increasingly important role. However, there were few reports on the correlation between immune‐related genes and HCC. The purpose of this study is to construct a novel immune‐related gene‐based prognostic signature for HCC and to explore the potential mechanisms.MethodsWe organized expression data of 374 HCC samples and 50 nontumor samples from TCGA database. A robust signature was constructed by Cox regression analysis based on the immune‐related genes, which were filtered by differential genes analysis and Cox regression analysis. Then, the correlation analysis between the signature and clinical characteristics was conducted. And the signature was validated in ICGC database. Furthermore, the relationships between immune cell infiltration and the signature were explored by bioinformatics analysis.ResultsSeven genes‐based model (Risk score = BIRC5 * 0.0238 + FOS * 0.0055 + DKK1 * 0.0085 + FGF13 * 0.3432 + IL11 * 0.0135 + IL17D * 0.0878 + SPP1 * 0.0003) was constructed eventually and it was proved to be an independent prognostic factor for HCC patients. The signature‐calculated risk scores were shown to be positively correlated with the infiltration of these five immune cells, including macrophages, neutrophils, CD8+T, dendritic, and B cells. And the results suggested that high amplication of BIRC5, FGF13, IL11, IL17D, and SPP1 were more likely correlated with immune cell infiltration. Finally, PPI network, TFs‐based regulatory network and gene enrichment plots were performed to show potential molecular mechanisms.ConclusionWe construct a robust immune‐related gene‐based prognostic signature with seven genes and explore potential mechanisms about it, which may contribute to the immunotherapy research for HCC.

A Case of Hepatocellular Carcinoma with a Complete Response to Second-Line Chemotherapy with Ramucirumab

Introduction: Ramucirumab has become the standard of care in second-line systemic therapy for advanced Hepatocellular Carcinoma (HCC) (AFP ≥400 ng/ml). A Complete Response (CR) to systemic therapy is generally very rare. We encountered a patient who achieved CR to secondline therapy with ramucirumab. Case presentation: We herein report a case of a 62-year-old male diagnosed with HCC and lung metastases 6 months after liver surgery. AFP and PIVKA-II were elevated and his liver function was Child-Pugh A. Sorafenib at 800 mg as the first-line therapy was administered for 6 weeks, and after the progression of the first-line therapy ramucirumab was administered as second-line systemic therapy. The tumor decreased in size and this was judged to be a partial response. Due to the absence of recurrence for approximately 5 years after the cessation of treatment, the present case was considered to have achieved CR. Conclusion: We encountered a case of HCC with CR to second-line systemic therapy with ramucirumab after sorafenib. The high affinity of ramucirumab to vascular endothelial growth factor receptor 2 (VEGFR2) may have exerted additional anti-tumor effects in cases refractory to systemic therapy having anti-VEGF effects.

High FLT3 Levels May Predict Sorafenib Benefit in Hepatocellular Carcinoma.

To identify a predictive biomarker of sorafenib for hepatocellular carcinoma personalized therapy. The patients treated with or without sorafenib after hepatocellular carcinoma recurrence from multicenters were matched with propensity score matching analysis. The expression levels of Fms-like tyrosine kinase 3 (FLT3) in hepatocellular carcinoma specimens of the matched patients (n = 276) were analyzed by IHC. The optimal cut-off point of FLT3 levels for overall survival (OS) was defined via Cutoff Finder. Subgroup analysis of OS was employed to investigate the association between FLT3 levels and sorafenib benefit. The predictive value was assessed via Cox regression models with an interaction term. Hepatocellular carcinoma and paratumoral normal tissues were used to investigate the expression and copy-number variation of FLT3. Patient-derived xenograft (PDX) models were used to confirm the association between FLT3 levels and sorafenib response. Patients with FLT3-high hepatocellular carcinoma exhibited a superior OS upon sorafenib treatment. High FLT3 levels were predictive of sorafenib benefit in terms of OS (P interaction = 0.00006). Copy-number losses and decreased expression of FLT3 in hepatocellular carcinoma were detected in about 64% of patients. Moreover, the PDXs derived from tumors with high FLT3 levels also displayed a better response to sorafenib. Sorafenib may be able to delay tumor progression in patients with FLT3-high hepatocellular carcinoma. This potential biomarker needs to be further validated in independent cohorts prior to helping stratify patients for precision therapy in advanced hepatocellular carcinoma.

PI16 attenuates response to sorafenib and represents a predictive biomarker in hepatocellular carcinoma.

Sorafenib has become the only FDA‐approved first‐line therapy for advanced hepatocellular carcinoma (HCC) for more than 10 years, but there is still no validated predictive or prognostic marker. Peptidase inhibitor 16 (PI16) is a functionally unknown gene in cancer research. This study aimed to determine the exact function of PI16 in HCC and whether it can represent as a biomarker for sorafenib response. We found that PI16 was over expressed in HCC tissues vs paired normal tissues. PI16 knockdown sensitize HCC cells to sorafenib treatment both in vitro and in vivo, whereas ectopic PI16 expression produced the opposite effect. Mechanistically, PI16 could suppress p38 MAPK/caspase‐dependent apoptosis in this process, and p38 MAPK inhibitor reversed the sorafenib sensitive phenotype caused by PI16 inhibition. Clinically, immunohistochemistry was used to detect PI16 levels in resected patients with HCC prior to sorafenib treatment. We showed that high PI16 levels represented an independent risk factor for disease progression in patients treated with sorafenib. Patients with low PI16 showed significantly better progression free survival and overall survival after sorafenib therapy. In conclusion, PI16 attenuates response to sorafenib treatment in HCC, and may be a helpful prognostic biomarker of sorafenib treatment.

Chimeric Antigen Receptor-Glypican-3 T-Cell Therapy for Advanced Hepatocellular Carcinoma: Results of Phase I Trials.

Our preclinical studies demonstrated the potential of chimeric antigen receptor (CAR)-glypican-3 (GPC3) T-cell therapy for hepatocellular carcinoma (HCC). We report herein the first published results of CAR-GPC3 T-cell therapy for HCC. In two prospective phase I studies, adult patients with advanced GPC3+ HCC (Child-Pugh A) received autologous CAR-GPC3 T-cell therapy following cyclophosphamide- and fludarabine-induced lymphodepletion. The primary objective was to assess the treatment's safety. Adverse events were graded using the Common Terminology Criteria for Adverse Events (version 4.03). Tumor responses were evaluated using the RECIST (version 1.1). A total of 13 patients received a median of 19.9 × 108 CAR-GPC3 T cells by a data cutoff date of July 24, 2019. We observed pyrexia, decreased lymphocyte count, and cytokine release syndrome (CRS) in 13, 12, and nine patients, respectively. CRS (grade 1/2) was reversible in eight patients. One patient experienced grade 5 CRS. No patients had grade 3/4 neurotoxicity. The overall survival rates at 3 years, 1 year, and 6 months were 10.5%, 42.0%, and 50.3%, respectively, according to the Kaplan-Meier method. We confirmed two partial responses. One patient with sustained stable disease was alive after 44.2 months. CAR T-cell expansion tended to be positively associated with tumor response. This report demonstrated the initial safety profile of CAR-GPC3 T-cell therapy. We observed early signs of antitumor activity of CAR-GPC3 T cells in patients with advanced HCC.