Treatment Of Unresectable Hepatocellular Carcinoma Research Articles

Comparative study between sorafenib and lenvatinib as the first-line therapy in the sequential treatment of unresectable hepatocellular carcinoma in a real-world setting.

AimsThere is a paucity of comparative data on the use of sorafenib and lenvatinib for unresectable hepatocellular carcinoma. We assessed the real‐world treatment outcomes between using sorafenib and lenvatinib for unresectable hepatocellular carcinoma in the multiple molecular‐targeted therapy era.Methods and ResultsWe enrolled 386 patients treated with sorafenib or lenvatinib as the first‐line therapy for unresectable hepatocellular carcinoma at multiple centers. Propensity score matching was performed to adjust for differences in baseline and tumor characteristics between the two groups. Propensity score matching identified 110 patients in each treatment group. The median overall survival was similar between lenvatinib and sorafenib (14.8 and 13.0 months, respectively; P = 0.352). The median progression‐free survival was longer with lenvatinib than with sorafenib (7.6 and 3.9 months, respectively; P < 0.001). The overall response rate (P < 0.001) and disease control rate (P = 0.015), as defined by the modified Response Evaluation Criteria in Solid Tumors, were significantly better with lenvatinib than with sorafenib. The median overall survival was longer in patients who received subsequent treatment than in those who did not in the sorafenib group (23.1 and 5.7 months, respectively; P < 0.001), whereas the median overall survival with or without subsequent treatment did not differ significantly in the lenvatinib group (17.8 and 14.7 months, respectively; P = 0.439).ConclusionOverall survival with sorafenib and lenvatinib was not significantly different. However, patients who received subsequent treatments had longer overall survival than those who received only first‐line treatment with sorafenib, whereas lenvatinib did not show this effect.

Early experience of atezolizumab plus bevacizumab treatment for unresectable hepatocellular carcinoma BCLC-B stage patients classified as beyond up to seven criteria - Multicenter analysis.

Although systemic therapy is recommended for patients with multiple intermediate stage unresectable hepatocellular carcinoma (u-HCC) classified as beyond the up-to-7 criteria (UT-7 out/multiple) as a transcatheter arterial chemoembolization (TACE) unsuitable condition, few reports have examined the therapeutic efficacy of atezolizumab plus bevacizumab combination therapy (Atez/Bev) in such cases. This study aimed to elucidate the therapeutic response of Atez/Bev in u-HCC patients classified as UT-7 out/multiple. From September 2020 to September 2021, 95 u-HCC Japanese patients classified as UT-7 out/multiple/Child-Pugh A were enrolled from 21 institutions (median age 76years, males 73, Child-Pugh 5:6=68:27, TNM stage II:III=17:78). Therapeutic response was retrospectively evaluated using Response Evaluation Criteria in Solid Tumors (RECIST), ver. 1.1 and modified RECIST (mRECIST). Atez/Bev was given as first-line treatment to 52 (54.7%). Objective response rate (ORR)/disease control rate (DCR) at six weeks of RECIST and mRECIST were 17.7%/84.7% and 42.5%/86.2%, respectively. Median PFS was 8.0months (median observation period: 6.0months). Child-Pugh A/modified Albumin-bilirubin grade (mALBI) 1 and 2a at baseline, 3, 6, and 9weeks, were 100%/69.4%, 89.8%/57.3%, 94.8%/65.3%, and 91.4%/60.0%, respectively. Among adverse events (any-grade, >10%) during the present observation period, general fatigue was most frequent (23.2%), followed by urine protein (21.1%), appetite loss (20.0%), and hypertension (13.7%). Atez/Bev treatment showed favorable therapeutic response with less influence on hepatic function, suggesting it as a useful therapeutic option for patients with such condition.

A combined miR-34a and arsenic trioxide nanodrug delivery system for synergistic inhibition of HCC progression after microwave ablation

BackgroundMicrowave ablation (MWA) has become an alternative treatment for unresectable hepatocellular carcinoma (HCC), but it does not eliminate the risk of recurrence and metastasis after treatment. Recent studies have demonstrated that miR-34a presents decreased gene expression in residual tumours after ablation therapy and can increase the therapeutic effect of arsenic trioxide against HCC, which brings new opportunities for HCC treatment.MethodsA pH-sensitive charge inversion material was used to construct a nanotargeted delivery system based on the synergistic effects of miR-34a and As2O3. We established in vitro and in vivo models of HCC microwave ablation and performed in-depth research on the dual-drug system to inhibit the rapid progression and induce pyroptosis in HCC cells after microwave ablation.ResultsThe antitumour effects were enhanced with the dual-drug nanoparticles relative to the single-drug formulations, and the therapeutic efficacy of the nanoparticles was more significant in a weakly acidic environment. The dual-drug nanoparticles increased the N-terminal portion of GSDME and decreased the expression of Cyt-c and c-met.ConclusionsDual-drug nanoparticles may improve the therapeutic efficacy of HCC treatment after insufficient ablation through Cyt-c and GSDME-N and decrease the expression levels of c-met. These nanoparticles are expected to provide new treatment methods for residual HCC after MWA, prolong the survival of patients and improve their quality of life.

TwinLiverNet: Predicting TACE Treatment Outcome from CT scans for Hepatocellular Carcinoma using Deep Capsule Networks.

Predicting response to treatment plays a key role to assist radiologists in hepato-cellular carcinoma (HCC) therapy planning. The most widely used treatment for unresectable HCC is the trans-arterial chemoembolization (TACE). A complete radiological response after the first TACE is a reliable predictor of treatment favourable outcome. However, visual inspection of contrast-enhanced CT scans is time-consuming, error prone and too operator-dependent. Thus, in this paper we propose TwinLiverNet: a deep neural network that is able to predict TACE treatment outcome through learning visual cue from CT scans. TwinLiverNet, specifically, integrates 3D convolutions and capsule networks and is designed to process simultaneously late arterial and delayed phases from contrast-enhanced CTs. Experimental results carried out on a dataset consisting of 126 HCC lesions show that TwinLiverNet reaches an average accuracy of 82% in predicting complete response to TACE treatment. Furthermore, combining multiple CT phases (specifically, late arterial and delayed ones) yields a performance increase of over 12 percent points. Finally, the introduction of capsule layers into the model avoids the model to overfit, while enhancing accuracy.Clinical relevance- TwinLiverNet supports radiologists in visual inspection of CT scans to assess TACE treatment outcome, while reducing inter-operator variability.

Drug-eluting bead transarterial chemoembolization with medium-sized versus small-sized CalliSpheres microspheres in unresectable primary liver cancer.

PurposeThe optimal microparticle size for drug‐eluting beads transarterial chemoembolization (DEB‐TACE) remains unknown. This retrospective cohort study analyzed the efficacy and safety of CalliSpheres microsphere embolization in the treatment of unresectable hepatocellular carcinoma (HCC) to determine the influence of particle size on the results.Patients and methodsForty‐two patients with unresectable HCC were enrolled in this retrospective study from January 2018 to January 2020. Patients received DEB‐TACE with CalliSpheres of 100–300 μm (small‐size, n = 15) or 300–500 μm (medium‐size, n = 27). The tumor response was evaluated via enhanced CT or MRI at 1 month, 3 months, and 6 months after treatment, based on the Modified Response Evaluation Criteria in Solid Tumors. Adverse events after DEB‐TACE were recorded.ResultsComplete response, partial response, stable disease, and progressive disease were recorded in 20%, 20%, 33.3%, 26.7%, respectively, of patients in the small‐size group and 3.7%, 25.9%, 44.4%, 25.9% of patients in the medium‐size group, respectively. No significant difference was found between the two groups (p = 0.516). Major adverse events, including grade three liver toxicity (n = 4) and liver abscess (n = 3), occurred significantly more in the small‐size group, while none were reported in the medium size group (p < 0.05).ConclusionDEB‐TACE with medium‐size (300–500 μm) CalliSpheres microspheres had similar efficacy and a better safety profile than DEB‐TACE with small‐size (100–300 μm) CalliSpheres, indicating that medium‐size microspheres may be a better choice for unresectable primary liver cancer.

Survival Outcomes of Patients With Unresectable Hepatocellular Carcinoma Secondary to Viral vs. Non-Viral Etiologies Treated with Definitive Radiotherapy

Radiation therapy (RT) is a critical modality for the treatment of unresectable hepatocellular carcinoma (HCC). Little is known about how the etiology of HCC impacts overall and progression free survival (OS and PFS) in patients treated with definitive RT. We hypothesize that patients treated with definitive RT for HCC secondary to hepatitis B and hepatitis C viruses (viral group) would have favorable OS and PFS when compared to patients with HCC secondary to other etiologies (non-viral group).Medical records were retrospectively reviewed at a single institution for patients diagnosed with unresectable HCC and treated with definitive RT between 1/2011 and 12/2020. Patients treated with prior surgery or radiofrequency ablation were excluded. Progress notes were reviewed to determine date of last follow-up, progression, and death. Notes were also assessed to determine the etiology of HCC, age at diagnosis, Child-Pugh classification (CPC), AJCC 8th edition T stage, RT strategy, and planning target volume (PTV). Descriptive statistics were quantified for baseline characteristics. Survival curves were estimated via Kaplan-Meier method; statistical difference was determined using the log-rank test. Multivariate (MVA) Cox proportional hazards analysis was conducted to estimate hazard ratios (HR) when controlling for confounding factors.Forty-six patients were included in the analysis. 30 (65%) patients were in the viral group, while 16 (35%) patients were in the non-viral group. Median ages at diagnosis for the viral and non-viral groups were 64 (interquartile range (IQR): 60 to 69) and 71 years (IQR: 66.5 to 76.5), respectively (P = 0.014). Treatment with hypofractionated RT (P = 0.559), proton therapy (P = 0.686), performance status (P = 0.222), CPC (P = 0.270), T stage (P = 0.639), and PTV (P = 0.472) were not different between groups. There was a trend toward improved Median OS for the viral group compared to the non-viral group: 17.9 months (95% confidence interval (CI): 9.7 to not-reached (NR)) vs. 8.8 months (95% CI: 6.1 to NR) (P = 0.072). Similarly, PFS was not different between viral and non-viral groups: 9.3 (95% CI: 7.4 to 19.0) vs. 8.0 (95% CI: 4.0 to 10.3), P = 0.314. However, after controlling for confounding factors with MVA Cox proportional hazards models, the viral group had superior OS (HR = 4.20, 95% CI: 1.47 to 12.02, P = 0.008); the viral group also had superior PFS (HR = 2.48, 95% CI: 1.06 to 5.81, P = 0.037).Our retrospective review of patients with unresectable HCC treated with definitive RT provides evidence that viral etiologies of HCC may fare better in OS and PFS when compared to non-viral etiologies. The etiology of HCC development for virally vs non-virally mediated tumors may have implications for treatment and response in the setting of radiation therapy.

Pretreatment Neutrophil-to-Lymphocyte Ratio as a Predictive Marker of Response to Atezolizumab Plus Bevacizumab for Hepatocellular Carcinoma.

Background: Combination therapy with anti-programmed death-ligand 1 monoclonal antibody atezolizumab plus anti-vascular endothelial growth factor agent bevacizumab (Atezo/Bev) was approved in 2020 as a first-line treatment for unresectable hepatocellular carcinoma (HCC). Atezo/Bev therapy is relatively well tolerated; however, factors that can predict its response have not yet been reported. Thus, we aimed to investigate whether the pretreatment neutrophil-to-lymphocyte ratio (NLR) could predict the therapeutic response in patients with HCC treated with Atezo/Bev therapy. Methods: We analyzed the course of 40 patients with HCC who received Atezo/Bev therapy at our hospital and attempted to identify pretreatment factors that could predict response by comparing those who achieved disease control with those who did not. Results: The pretreatment NLR value in patients who achieved disease control was significantly lower than that in patients with disease progression (2.47 vs. 4.48, p = 0.013). Using the optimal NLR cut-off value for predicting response (3.21) determined by receiver operating characteristic curve analysis, patients with NLR ≤ 3.21 had significantly better progression-free survival than those with NLR > 3.21 (p < 0.0001), although there were no significant differences in liver function or tumor-related background factors between the two groups. Conclusions: The pretreatment NLR value may be a useful predictor of response to Atezo/Bev therapy for HCC.

Hepatotoxicity of systemic therapies for unresectable hepatocellular carcinoma

AbstractThe number of effective systemic therapies for the treatment of unresectable hepatocellular carcinoma (uHCC) is rapidly increasing and the advent of immunotherapy changed the treatment paradigm for these patients, leading to a significant improvement in survival outcomes. While sorafenib, a tyrosine‐kinase inhibitor monotherapy, remained the only effective treatment for almost a decade, the combination of atezolizumab, an immune checkpoint inhibitor (ICI) targeting programmed death‐ligand 1, plus bevacizumab, an antiangiogenic agent targeting vascular endothelial growth factor, now represents the new standard of care for patients with uHCC. Moreover, several further clinical trials are ongoing to evaluate novel combinations between ICIs with other drugs, belonging to the same class or to other classes. As HCC occurs in most cases in the setting of cirrhosis, the evaluation of the risk/benefit ratio of systemic treatments represents a critical point. The underlying liver disease significantly influences the safety and the effectiveness of current and future systemic treatments for uHCC. For this reason, the hepatotoxicity profile and impact on liver function of these molecules should be carefully assessed in both clinical trials and in the real‐world setting. Here, we review hepatotoxicity data on systemic treatments for uHCC and offer suggestions on monitoring and managing liver‐related adverse events occurring during the treatment.

A Broad Range High-Throughput Assay for Lenvatinib Using Ultra-High Performance Liquid Chromatography Coupled to Tandem Mass Spectrometry With Clinical Application in Patients With Hepatocellular Carcinoma.

Lenvatinib is increasingly being selected as the first-line treatment for unresectable hepatocellular carcinoma (HCC) based on the results of the REFLECT trial. However, early discontinuation of lenvatinib because of adverse effects is a frequent occurrence. Hence, lenvatinib is a difficult drug for use in the clinical setting. One of the causes is that the dose of lenvatinib is mainly determined by body weight alone, despite high interindividual variability. To overcome this problem, a dosing regimen of lenvatinib based on a population pharmacokinetic (PPK) model for HCC patients is proposed. The aim of this study was to develop a high-throughput quantification method for lenvatinib using ultra-high performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS) that can be applied to a PPK analysis of HCC patients in the future. After a simple solid-phase extraction step using a 96-well plate, lenvatinib was analyzed by UHPLC-MS/MS in a positive electrospray ionization mode. The novel method fulfilled the requirements of the US Food and Drug Administration guidance on bioanalytical method validation. The calibration curve was linear over the 0.2-1000 ng/mL concentration range. The average recovery rate was 98.63 ± 4.55% (mean ± SD). The precision was below 6.05%, and the accuracy was within 12.96% for all quality control levels. The matrix effect varied between 103.33% and 134.61%. This assay was successfully applied to the measurement of plasma concentrations in 6 HCC patients receiving lenvatinib. A novel high-throughput UHPLC-MS/MS assay for quantification of lenvatinib in human plasma was successfully developed. This method can be applied to PPK analysis for patients receiving lenvatinib in the clinical setting.

A case of sorafenib-induced severe thrombocytopenia during treatment of unresectable hepatocellular carcinoma

Abstract An 81-year-old male with unresectable hepatocellular carcinoma underwent transarterial chemoembolization (TACE) combined with sorafenib. Platelet count was normal before and after TACE treatment, after which oral administration of sorafenib (400 mg po bid) was initiated. During this period, the patient experienced significant diarrhea, so the dosage was reduced to 200 mg po bid. Later, the patient showed obvious gingival bleeding with progressive exacerbation, and his blood routine examination showed a platelet count of 2 × 109 cells/L. The patient was clinically diagnosed with extreme severe thrombocytopenia. The patient was advised to stop taking sorafenib and was immediately treated with hemostasis, platelet transfusion, and suspended red blood cells. After the above treatment, the patient’s symptoms improved, and he was discharged. Up to the date of follow-up, there was no further bleeding.

Sequential therapy including regorafenib for unresectable hepatocellular carcinoma: Effect of early relative changes in hepatic functional reserve after regorafenib administration on prognosis.

Regorafenib is a second-line treatment for unresectable hepatocellular carcinoma after sorafenib-refractory treatment. This study examined the effects of regorafenib administration on hepatic functional reserve and the treatment course after regorafenib discontinuation. This retrospective, multicenter study involved 51 patients treated with regorafenib after sorafenib-refractory treatment for u-HCC at seven institutions before March 2021. Fourteen, 13, and 24 patients were classified based on modified albumin-bilirubin (mALBI) grade 1, 2a, and 2b, respectively. The median survival time and progression-free survival were 16.7 and 3.3months, respectively. Only mALBI grade 2b or 3 was significantly associated with survival rate (hazard ratio, 2.13; 95% confidence interval, 1.01-4.49; p=0.047). A comparison of median ALBI scores at the initiation of regorafenib (-2.35) with those at 4weeks (-1.93) revealed a significant relative change (p=0.0001). After 4weeks, grade 1 or 2a persisted in 15 patients (Group 1); grade 1 or 2a deteriorated to 2b in 12 patients (Group 2); grade 2b or 3 before regorafenib administration was present in 22 patients (Group 3); and MST was 33.3, 12.8, and 11.3months in the three groups, respectively (p=0.05). Patients treated with lenvatinib (LEN) (n=27, MST=23.4months) after regorafenib had a significantly longer survival time from regorafenib initiation than those not treated with LEN (n=24, 11.8months; p=0.043). Hepatic functional reserve significantly declined after regorafenib administration. During regorafenib treatment, favorable hepatic functional reserve before administration and maintenance of favorable hepatic reserve after administration lead to prolonged prognosis.

OATP1B1 Plays an Important Role in the Transport and Treatment Efficacy of Sorafenib in Hepatocellular Carcinoma.

Background Sorafenib is an anticancer drug used in the treatment of unresectable hepatocellular carcinoma and advanced renal cell carcinoma. It is a substrate for the human OATP1B1. This study is aimed at assessing the role of OATP1B1 in transportation and uptake of sorafenib in hepatocellular carcinoma and how OATP1B1 affects the pharmacodynamics of sorafenib in vitro and in vivo. Methods Sorafenib transport was measured in HepG2, HepG2-OATP1B1∗1a, HepG2-OATP1B1∗1b, HepG2-OATP1B1∗15, LO2, LO2-OATP1B1∗1a, LO2-OATP1B1∗1b, and LO2-OATP1B1∗15 cells, as well as in HepG2 cells transfected with miR-148a mimics. The viability and apoptosis rate of cells treated with sorafenib were evaluated. A liver cancer rat model was established to explore the pharmacokinetics and pharmacodynamics of sorafenib after overexpression of Oatp2. Results Changes in expression and genetic mutations of OATP1B1 significantly affected the uptake of sorafenib in HepG2 and LO2 transgenic cells, and the uptake of sorafenib was higher in HepG2 than LO2. Genetic mutations of OATP1B1 significantly affected the cell viability and apoptosis rate of HepG2 cells after sorafenib treatment. Compared to control group, the uptake of sorafenib in miR-148a mimic-transfected HepG2 cells was decreased, and the cell viability was increased. PCN significantly increased the expression of Oatp2 and affected the pharmacokinetics of sorafenib. Vascular endothelial growth factor levels and microvascular density in tumor-adjacent tissues decreased significantly, suggesting that increased Oatp2 expression improves the treatment effect of sorafenib in a rat model of liver cancer. Conclusions OATP1B1 plays an important role in the pharmacokinetics and pharmacodynamics of sorafenib in hepatocellular carcinoma.

Changes in the Mean Intrahepatic Target Computed Tomography Attenuation Value During Treatment May Be a Useful New Predictor of the Post-progression Survival Associated with Lenvatinib Treatment.

Objective The relationship between the prognosis and magnitude of a decrease in tumor blood flow according to estimated tumor differentiation remains unclear. This study investigated the relationship between reductions in the rate of mean computed tomography (CT) attenuation values and the clinical prognosis. Methods We evaluated 63 consecutive patients who received lenvatinib treatment for unresectable hepatocellular carcinoma (HCC). The oncological aggressiveness of the tumors was estimated using classification by dynamic CT enhancement patterns. The utility of changes in mean CT attenuation values of intra-hepatic targets during treatment to estimate the prognosis was investigated by calculating the progression-free survival (PFS) and post-progression survival (PPS). A multivariate analysis was used to identify potential confounders for the survival after progression during lenvatinib therapy. Results The rate of decrease in the mean CT attenuation value gradually increased according to the degree of deterioration in estimated tumor differentiation, and the rate of a decrease in attenuation ≥40% showed a tendency to increase (p=0.064). This trend was reflected by a better objective response in oncological aggressiveness heterogeneous enhancement patterns (Type-3 and Type-4) than a homogeneous enhancement pattern (Type-2) (83% vs. 56% of modified Response Evaluation Criteria in Solid Tumors). This resulted in a similar PFS between the groups (p=0.773), whereas the PPS was significantly worse when the rate of decrease in the attenuation value was ≥40% (p=0.012). A multivariate analysis confirmed that a rate of decease in attenuation value ≥40% was a poor prognostic factor for the PPS (hazard ratio, 2.993; 95% confidence interval, 1.196-7.490; p=0.019). Conclusion A rate of decrease in attenuation ≥40% may reflect a good response of a highly malignant tumor to lenvatinib. Therefore, this value may have utility as a surrogate marker for estimating the oncological aggressiveness of tumors and their associated prognosis.

Atezolizumab plus bevacizumab for unresectable or metastatic hepatocellular carcinoma

Introduction The treatment of unresectable hepatocellular carcinoma (HCC) has radically changed after the approval of the combination of atezolizumab plus bevacizumab as first-line treatment. A strong preclinical rationale exists to support the combination of bevacizumab, an anti-vascular endothelial growth factor monoclonal antibody (mAb), and atezolizumab, an anti-programmed death ligand 1 mAb. The efficacy of the combination was first assessed in the phase Ib GO30140 study, and the combination was then proven superior to the prior standard of care, sorafenib, in the phase III IMbrave150 trial. Areas covered This article focuses on the mechanism of action of atezolizumab and bevacizumab, their synergistic action and the two clinical trials leading to approval. We also collected the body of post-hoc analyses and meta-analyses to help guide the decision-making process in terms of patient selection and subsequent treatments. Expert opinion Atezolizumab plus bevacizumab is the current standard of care for first-line treatment of unresectable or metastatic HCC and treatment-naïve patient should be treated with the combination, unless contraindications to the drugs. Since all the available agents for further lines of treatment have been approved for sorafenib-pretreated patients, prospective trials, post-hoc analyses, and real-world data assessing valid treatment sequencing are strongly needed.

Charge-assisted bond and molecular self-assembly drive the gelation of lenvatinib mesylate

Lenvatinib mesylate (LM) is a first-line anticancer agent for the treatment of unresectable hepatocellular carcinoma, while it formed viscoelastic hydrogel when contacting with aqueous medium, which would significantly hinder its in vitro dissolution. The aim of this study was to systematicly explore the gelation mechanism and gel properties via thermal analysis, rheology, morphology and spectroscopy studies. The formed hydrogel was found to be composed of a new polymorph of crystalline LM, and its mechanical strength depended on the cross-linking degree of the fibrillar network structure. Spectroscopy analyses revealed that the intermolecular hydrogen bonds (the bifurcated hydrogen bond between the adjacent urea groups and the NH⋯OC hydrogen bond between the primary amide groups) as well as π-π stacking interactions (between the benzene ring and the quinoline ring) were suggested to be the driving forces for the self-assembly of LM during gelation process. Additionally, no gelation phenomenon was observed when suspending the base form lenvatinib in water, while it could form gel in various acidic solutions (e.g. hydrochloric acid, phosphoric acid and methanesulfonic acid) because the regenerated N+-H group increased the solubility of lenvatinib and promoted the balance between the dissolution or aggregation of LX (X: acid radical ion) molecules in solutions. In conclusion, the charge-assisted bond N+-H in LM molecule and intermolecular non-covalent interactions drived the hydrogel formation of LM in aqueous media. This study elucidates the gelation mechanism and gel properties of LM hydrogel, which would be helpful to figure out strategy to eliminate its gelation fundamentally and pave the way for its further formulation development in future.

LncRNA H19 modulated by miR-146b-3p/miR-1539-mediated allelic regulation in transarterial chemoembolization of hepatocellular carcinoma.

Transarterial chemoembolization (TACE) is an effective treatment for unresectable hepatocellular carcinoma (HCC) patients. Although overall survival (OS) of TACE-treated patients has been evidently prolonged, not all unresectable HCC patients can benefit from TACE. Genome-wide association studies identified multiple HCC susceptibility single nucleotide polymorphisms (SNPs). However, it is still unclear how lncRNAs and their functional SNPs impact therapeutic responses of TACE. In the study, we hypothesized that the functional lncRNA H19 SNP(s) might impact H19 expression and, thus, prognosis of TACE-treated HCC patients. We found that the H19 rs3741219 SNP was significantly associated with OS of HCC patients received TACE. Cox proportional hazards model demonstrated that the rs3741219 CC genotype was associated with longer OS and a 37% decreased death risk compared with the TT carriers after TACE therapy (P = 0.001). Interestingly, the rs3741219 T-to-C change led to allelic down-regulation of lncRNA H19 expression via creating the binding sites of miR-146b-3p and miR-1539. Luciferase reporter gene assays indicated that miR-146b-3p and miR-1539 could markedly silence the rs3741219 C-allelic H19 expression but not lncRNA H19 with the T allele. Consistently, there was significantly reduced expression of lncRNA H19 in HCC and normal tissues of the C allele carriers compared with the H19 levels in patients with the T allele. Knock-down of lncRNA H19 significantly promoted the anti-viability efficiency of oxaliplatin (the main chemotherapy drug used in TACE) to HCC cells. In view of these results, we assume that lncRNA H19 might be a potential therapeutic target for unresectable HCC patients.

Abstract CT009: IMbrave150: Updated efficacy and safety by risk status in patients (pts) receiving atezolizumab (atezo) + bevacizumab (bev) vs sorafenib (sor) as first-line treatment for unresectable hepatocellular carcinoma (HCC)

Abstract Background: Based on the Ph III IMbrave150 trial, atezo + bev has been approved globally and is the standard of care for pts with unresectable HCC who have not received prior systemic therapy. With an additional 12 mo of follow-up from the primary analysis (median, 15.6 mo), atezo + bev showed consistent clinically meaningful treatment benefit and safety (Finn ASCO GI 2021). Here, we report results of updated analyses considering high-risk factors. Methods: Pts were randomized 2:1 to receive atezo 1200 mg IV q3w + bev 15 mg/kg IV q3w or sor 400 mg PO BID until loss of clinical benefit or unacceptable toxicity. High-risk pts were defined as those who had tumor invasion of the main trunk of the portal vein and/or the portal vein branch contralateral to the primarily involved lobe (Vp4), and/or bile duct invasion and/or tumor occupancy of ≥ 50% of liver. Results: In the ITT population, 64 (19%) pts randomized to atezo + bev and 37 (22%) pts randomized to sor were defined as high risk. 10 pts had bile duct invasion, 73 had Vp4 portal vein invasion and 31 had liver tumor occupancy of ≥ 50%. 9 pts in the atezo + bev arm and 4 pts in the sor arm had 2 high-risk factors. OS, PFS and ORR all favored atezo + bev over sor, in both non-high-risk and high-risk patients. See table for efficacy results. In safety-evaluable pts, Grade 3/4 treatment-related AEs (TRAEs) occurred in 122 (45%) of 269 non-high-risk and 21 (35%) of 60 high-risk atezo + bev pts. Grade 5 TRAEs occurred in 5 (2%) non-high-risk and 1 (2%) high-risk atezo + bev pt. Conclusions: Efficacy benefit was seen with atezo + bev vs sor regardless of the presence of high-risk features. HRs remained similar despite the numerical differences in median OS between non-high-risk and high-risk pts. Further, the overall safety data in the atezo + bev arm were comparable between non-high-risk and high-risk pts and in line with the known safety profile of each drug. Non-High RiskHigh RiskITTAtezo + BevSorAtezo + BevSorAtezo + BevSorEvaluable for OS/PFS, n2721286437336165Median OS (95% CI), mo22.8 (19.1, 24.9)15.7 (13.2, 19.0)7.6 (6.6, 12.8)5.5 (4.1, 6.7)19.2 (17.0, 23.7)13.4 (11.4, 16.9)HR (95% CI)0.68 (0.51, 0.91)0.62 (0.39, 1.00)0.66 (0.52, 0.85)Median PFS (95% CI), moa7.2 (6.5, 9.6)4.4 (4.0, 5.8)5.4 (4.0, 6.9)2.8 (2.5, 5.3)6.9 (5.7, 8.6)4.3 (4.0, 5.6)HR (95% CI)0.61 (0.48, 0.78)0.74 (0.47, 1.17)0.65 (0.53, 0.81)Evaluable for ORR, n2631246335326159Confirmed ORR, n (%)a,b81 (31)13 (10)16 (25)5 (14)97 (30)18 (11)Complete response, n (%)a20 (8)05 (8)1 (3)25 (8)1 (1)Median DOR (95% CI), moa,c19.0 (14.6, NE)12.6 (4.9, 17.0)16.3 (13.5, NE)16.5 (3.9, NE)18.1 (14.6, NE)14.9 (4.9, 17.0)NCT03434379.Clinical cutoff date: Aug 31, 2020.DOR, duration of response; HR, hazard ratio; IRF, independent review facility; NE, not estimable; ORR, objective response rate; OS, overall survival; PFS, progression-free survival.aAssessed by an IRF per RECIST 1.1.bORR IRF RECIST 1.1-evaluable population was based on patients who presented with measurable disease at baseline.cDOR analysis was based on all confirmed responders. Citation Format: Richard S. Finn, Shukui Qin, Masafumi Ikeda, Peter R. Galle, Michel Ducreux, Tae-You Kim, Masatoshi Kudo, Ho Yeong Lim, Valeriy Breder, Philippe Merle, Ahmed Kaseb, Daneng Li, Yin-Hsun Feng, Wendy Verret, Alan Nicholas, Lindong Li, Ning Ma, Andrew X. Zhu, Ann-Lii Cheng. IMbrave150: Updated efficacy and safety by risk status in patients (pts) receiving atezolizumab (atezo) + bevacizumab (bev) vs sorafenib (sor) as first-line treatment for unresectable hepatocellular carcinoma (HCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT009.

Efficacy of Drug-Eluting Beads Transarterial Chemoembolization Plus Apatinib Compared with Conventional Transarterial Chemoembolization Plus Apatinib in the Treatment of Unresectable Hepatocellular Carcinoma.

ObjectiveThe aim of the study was to compare the efficacy and safety of drug-eluting beads TACE plus apatinib (D-TACE-A) with those of conventional TACE plus apatinib (C-TACE-A) for the treatment of unresectable HCC.MethodsWe retrospectively reviewed 187 consecutive patients who received TACE plus apatinib in our institution from January 1, 2017, to July 1, 2019. Among them, 91 patients received C-TACE-A, and 96 patients received D-TACE-A. The primary endpoint was overall survival (OS), and the secondary endpoints were progression-free survival (PFS) and disease control rate (DCR). Propensity score matching (PSM) was used to reduce selection bias.ResultsBefore PSM, the median OS was 15 months (95% CI: 12.5–17.5) and 13 months (95% CI: 11.1–14.9; P=0.480) in the C-TACE-A and D-TACE-A groups, respectively. The median PFS was 7 months (95% CI: 5.9–8.1) in the C-TACE-A group and 7 months (95% CI: 5.6–8.4; p=0.677) in the D-TACE-A group. The DCR was 81.3% in the C-TACE-A group and 72.9% in the D-TACE-A group. Cox regression analysis showed that D-TACE-A did not increase mortality risk or tumor recurrence risk. After PSM, there was no statistically significant difference in median OS or PFS between the two groups. In the subgroup analysis, after adjusting for relative factors, D-TACE-A increased the mortality risk more than C-TACE-A in patients with BCLC stage C (HR: 1.678, 95% CI: 1.129–2.495; P=0.011), but D-TACE-A lowered the tumor recurrence risk compared with C-TACE-A in patients with Child–Pugh B (HR: 0.210, 95% CI: 0.082–0.538; P=0.001) and cirrhosis (HR: 0.481, 95% CI: 0.293–0.791; P=0.004). Grade III and IV adverse events in patients with D-TACE-A were similar to those in patients treated with C-TACE-A (P>0.05).ConclusionPatients with unresectable HCC treated with D-TACE-A might not show increased survival compared with patients treated with C-TACE-A. Advanced HCC patients without cirrhosis may receive greater survival benefits from C-TACE-A than D-TACE-A.

P-72 A patient preference study on risk thresholds to switch between daily tablets and biweekly infusions in second-line treatment for advanced hepatocellular carcinoma

There are various available second-line (2L) systemic treatments for unresectable hepatocellular carcinoma (HCC) utilizing different route of administration (eg, tablets and intravenous [IV] infusions) and having different safety profiles. Therefore, patient preferences should be considered in treatment decisions. However, there are insufficient data regarding patient preferences in the real-world setting in the US. The objectives of this study were to determine patients’ preferences for mode of administration and risk of adverse events (AEs) for regorafenib (4 tablets once daily [QD]) and ramucirumab (once in 2 weeks [Q2W] IV for 30/60 minutes) with similar efficacy profile but different AE profiles, and to determine the proportion of patients who preferred ramucirumab over regorafenib.

Chinese clinical practice guidelines for transarterial chemoembolization of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a malignancy originating from liver cells. Hepatitis B virus (HBV) is the major etiological factor contributed to the development of HCC in China. Pathologically, HCC is usually characterized of hypervascularity. The rationale of transarterial chemoembolization (TACE) is that the intraarterial infusion of cytotoxic agents followed by embolization of the tumor-feeding blood vessels causes a strong tumor killing effect. TACE is the most widely used primary treatment for unresectable HCC. In 2018, Chinese clinical practice guidelines for transarterial chemoembolization of hepatocellular carcinoma were published by Chinese College of Interventionalists. After several clinical and scientific advances are achieved, a new version of practice guidelines is updated in 2021.