Advanced Unresectable Hepatocellular Carcinoma Research Articles

Multimodal treatment involving molecular targeted agents and on-demand transcatheter arterial chemoembolization for advanced hepatocellular carcinoma: A case report and review of the literature.

Formulating sequential therapeutic strategies based on the pathological conditions of patients and by using molecular targeted agents (MTAs) and transcatheter arterial chemoembolization (TACE) is crucial for the treatment of unresectable advanced hepatocellular carcinoma (HCC). The current report presents the case of a patient with HCC involving a large intrahepatic primary tumor and lung metastases, and discusses treatment strategies for advanced HCC based on the current literature. Sequential therapy with MTAs was effective after TACE. Lenvatinib was effective for treating the metastases in the lungs and spleen. Only the progressing intrahepatic tumor was additionally treated with TACE. The patient has been alive for 3 years and continued lenvatinib treatment without HCC progression or decline in liver function. In conclusion, although multiple MTAs introduced into the clinic have been gradually replacing TACE, on-demand TACE in the multidisciplinary treatment of advanced HCC may be effective for intrahepatic hypervascular tumors resistant to MTAs, including lenvatinib. It may be possible to re-initiate lenvatinib treatment with good efficacy against distant metastatic lesions, thereby contributing to long-term survival.

Cost-effectiveness of atezolizumab and bevacizumab in advanced hepatocellular carcinoma.

e18829 Background: The IMbrave150 trial found that atezolizumab and bevacizumab significantly prolonged progression-free survival (PFS) and overall survival (OS) in patients with locally advanced metastatic or unresectable hepatocellular carcinoma (HCC), compared to sorafenib. However, atezolizumab and bevacizumab are costly treatments and are administered indefinitely until disease progression. Therefore, it is unclear whether atezolizumab-bevacizumab is cost-effective in this clinical setting. Methods: We constructed a partitioned survival model to compare the costs and effectiveness of atezolizumab-bevacizumab to sorafenib in advanced HCC. PFS and OS curves for each treatment strategy were derived from the IMbrave150 trial using parametric survival modeling. The utility of each health state and the costs of treatment, adverse events, and terminal care were derived from literature and Medicare fee schedules. We calculated the incremental cost-effectiveness ratio (ICER) of atezolizumab-bevacizumab from a US healthcare perspective, using a lifetime horizon, an annual discount rate of 3%, and a willingness-to-pay threshold of $150,000/quality-adjusted life year (QALY). One-way and probabilistic sensitivity analyses were performed to evaluate the robustness of model conclusions. Results: Atezolizumab-bevacizumab was associated with an incremental cost of $102,648 and an incremental effectiveness of 0.42 QALYs compared to sorafenib, leading to an ICER of $244,213/QALY (Table). The price of atezolizumab would need to be reduced by 40% (from ̃$9,400 to ̃$5,700 per dose) or the price of bevacizumab would need to be reduced by 47% (from ̃$8,400 to ̃$4,400 per dose) for atezolizumab-bevacizumab to be cost-effective compared to sorafenib. Alternatively, the price of both atezolizumab and bevacizumab would need to be simultaneously decreased by ̃21% for the combination therapy to be cost-effective. Our model was most sensitive to the hazard ratios (HR) of OS and PFS; varying the HRs across the 95% confidence interval reported in IMbrave150 (0.42-0.79) corresponded to ICERs of $137,435/QALY and $621,365/QALY, respectively. During probabilistic sensitivity analyses, >99%, 99%, and 90% of iterations produced ICERs greater than willingness-to-pay thresholds of $50,000/QALY, $100,000/QALY, and $150,000/QALY, respectively. Conclusions: Use of atezolizumab-bevacizumab for advanced HCC is unlikely to be cost-effective under current pricing. Significant price reduction of atezolizumab and/or bevacizumab would be required to reduce the ICER to a more widely acceptable value.[Table: see text]

PD-1 inhibitor combined with lenvatinib for unresectable liver cancer as the conversion therapy: An open-label, non-randomized, phase IV study.

e16173 Background: The combination of lenvatinib and PD-1 inhibitor has shown to be a promising regimen for advanced hepatocellular carcinoma (HCC). We aimed to assess the feasibility of conversion therapy by lenvatinib combined with PD-1 inhibitor in unresectable HCC in a non-randomized phase IV study (ChiCTR1900023914). Methods: Eligible patients had histologically or cytologically confirmed unresectable HCC (AASLD); BCLC B or C; an ECOG status of 0 or 1 and Child-Pugh A-B. Patients received lenvatinib (8-12mg, oral QD) and PD-1 inhibitor (IV Q3W) until disease progression, unacceptable toxicity or satisfied for curative surgery. Surgical patients received maintenance therapy based on the pathological evaluation (pCR: PD-1 inhibitor 6-12m, pPR: combination therapy 6-12m, pPD: personalized). The primary endpoint was conversion rate for surgery based on radiological assessment. The secondary endpoints were objective response rate (ORR), disease control rate (DCR), relapse-free survival (RFS) and overall survival (OS) by modified RECIST. Tumor tissue samples were collected at diagnosis and surgery. Immune cell subsets (CD8+ T cell, macrophage, NK cell) in tumor and stromal were measured by multiplex fluorescent immunohistochemistry. Whole exosome sequencing was performed with tumor samples and matched white blood cells. Results: and received the combination therapy. 49 patients were evaluated for the efficacy, 51.0% patients (5 CR, 17 PR and 3 SD) were conversed successfully based on their radiological evaluation after 3-7 cycles of combination therapy, among whom 15 patients (30.6%) actually received curative surgery upon comprehensive evaluation and patient preference. The median duration of follow-up was 271 days. The ORR was 53.1% (26/49, 5 CR and 21 PR) and the DCR was 69.4% (34/49). The median RFS and median OS of the 15 surgical patients were unreached. The 12-month OS was 74.1% and the 12-month RFS was 61.1%. Treatment-related adverse events occurred in 46.9% (23/49) of patients (grade ≥ 3, 6.1%). In both pre- and post-therapy tumor tissues, more CD8+ T cells (pre: p = 0.083, post: p = 0.007) and M1 macrophages (pre: p = 0.127, post: p = 0.120) were present in responders compared with non-responders. The conversion therapy could promote macrophage differentiating into M1 type in treatment-sensitive patients, as post-therapy tumoral M1/M2 ratio were higher in responders than non-responders (p = 0.073). Higher frequency of KMT2C mutation (missense and splicing, p = 0.040) were observed in response group. Conclusions: Combination of PD-1 inhibitor with lenvatinib as conversion therapy could benefit unresectable advanced HCC patients to achieve curative surgery. Tumor microenvironment and genomic characteristics may explain the potential mechanism of the clinical response. Clinical trial information: ChiCTR1900023914.

Triple combination therapy comprising angiogenesis inhibitors, anti-PD-1 antibodies, and hepatic arterial infusion chemotherapy in patients with advanced hepatocellular carcinoma.

e16124 Background: The effects of single-drug therapy for the systemic treatment of advanced unresectable hepatocellular carcinoma (HCC) remain unsatisfactory, promoting the emergence of multi-drug and combination therapies. Here we assess the safety and efficacy of a triple combination therapy for treating advanced HCC. Methods: This single-center retrospective study included patients with unresectable HCC treated with triple combination therapy comprising angiogenesis inhibitors (oral apatinib 250 mg/day, lenvatinib 8 mg/day, or sorafenib 400 mg BID), anti-programmed cell death 1 antibodies (iv camrelizumab or sintilimab, 200 mg every 3 weeks), and hepatic arterial infusion chemotherapy (FOLFOX every 4–8 weeks). Eligible patients had completed at least one cycle of therapy and had an imaging assessment. Treatment-related adverse events (TRAEs) were assessed according to the Common Terminology Criteria for Adverse Events. Efficacy data were summarized according to modified RECIST (mRECIST) and RECIST v1.1. Results: Of 34 patients who received triple combination therapy, 25 (19 men and 6 women; median age: 59 years [range: 49–78]) had an imaging assessment. TRAEs were manageable; 28.0% of patients experienced grade 3–4 TRAEs. Efficacy outcomes are summarized in the Table. The objective response rate was 96.0% (mRECIST), the median time to response was 50.5 days (95% CI: 31.02–64.00) and the surgical conversion rate was 56%, indicating a robust therapeutic effect. Overall, 12 patients (48.0%) achieved a complete response (CR), 12 (48.0%) achieved a partial response, and one (4.0%) had stable disease (mRECIST). Fourteen patients (56.0%) underwent surgical resection, after which seven (28.0%) achieved a pathologic CR. After a median follow-up of 9.67 months, no cases of post-operative recurrence or metastasis emerged. Conclusions: Triple combination therapy had a robust therapeutic effect with a high surgical conversion rate in patients with advanced HCC. TRAEs were acceptable, and long-term efficacy is reasonably expected. Summary of efficacy outcomes (n = 25).[Table: see text]

Drug-Drug Interaction between Metformin and Sorafenib Alters Antitumor Effect in Hepatocellular Carcinoma Cells

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is one of the leading causes of cancer-related deaths worldwide. The multitarget inhibitor sorafenib is a first-line treatment of patients with advanced unresectable HCC. Recent clinical studies have evidenced that patients treated with sorafenib together with the antidiabetic drug metformin have a survival disadvantage compared with patients receiving sorafenib only. Here, we examined whether a clinically relevant dose of metformin (50 mg/kg per day) could influence the antitumoral effects of sorafenib (15 mg/kg per day) in a subcutaneous xenograft model of human HCC growth using two different sequences of administration, i.e., concomitant versus sequential dosing regimens. We observed that the administration of metformin 6 hours prior to sorafenib was significantly less effective in inhibiting tumor growth (15.4% tumor growth inhibition) than concomitant administration of the two drugs (59.5% tumor growth inhibition). In vitro experiments confirmed that pretreatment of different human HCC cell lines with metformin reduced the effects of sorafenib on cell viability, proliferation, and signaling. Transcriptomic analysis confirmed significant differences between xenografted tumors obtained under the concomitant and the sequential dosing regimens. Taken together, these observations call into question the benefit of parallel use of metformin and sorafenib in patients with advanced HCC and diabetes, as the interaction between the two drugs could ultimately compromise patient survival. SIGNIFICANCE STATEMENT: When drugs are administered sequentially, metformin alters the antitumor effect of sorafenib, the reference treatment for advanced hepatocellular carcinoma, in a preclinical murine xenograft model of liver cancer progression as well as in hepatic cancer cell lines. Defective activation of the AMP-activated protein kinase pathway as well as major transcriptomic changes are associated with the loss of the antitumor effect. These results echo recent clinical work reporting a poorer prognosis for patients with liver cancer who were cotreated with metformin and sorafenib.

Combined Inhibition of TGF-β1-Induced EMT and PD-L1 Silencing Re-Sensitizes Hepatocellular Carcinoma to Sorafenib Treatment.

Hepatocellular carcinoma (HCC) is the most common type of primary hepatic malignancy. HCC is one of the leading causes of cancer deaths worldwide. The oral multi-tyrosine kinase inhibitor Sorafenib is the standard first-line therapy in patients with advanced unresectable HCC. Despite the significant survival benefit in HCC patients post treatment with Sorafenib, many patients had progressive disease as a result of acquiring drug resistance. Circumventing resistance to Sorafenib by exploring and targeting possible molecular mechanisms and pathways is an area of active investigation worldwide. Epithelial-to-mesenchymal transition (EMT) is a cellular process allowing epithelial cells to assume mesenchymal traits. HCC tumour cells undergo EMT to become immune evasive and develop resistance to Sorafenib treatment. Immune checkpoint molecules control immune escape in many tumours, including HCC. The aim of this study is to investigate whether combined inhibition of EMT and immune checkpoints can re-sensitise HCC to Sorafenib treatment. Post treatment with Sorafenib, HCC cells PLC/PRF/5 and Hep3B were monitored for induction of EMT and immune checkpoint molecules using quantitative reverse transcriptase (qRT)- PCR, western blot, immunofluorescence, and motility assays. The effect of combination treatment with SB431542, a specific inhibitor of the transforming growth factor (TGF)-β receptor kinase, and siRNA mediated knockdown of programmed cell death protein ligand-1 (PD-L1) on Sorafenib resistance was examined using a cell viability assay. We found that three days of Sorafenib treatment activated EMT with overexpression of TGF-β1 in both HCC cell lines. Following Sorafenib exposure, increase in the expression of PD-L1 and other immune checkpoints was observed. SB431542 blocked the TGF-β1-mediated EMT in HCC cells and also repressed PD-L1 expression. Likewise, knockdown of PD-L1 inhibited EMT. Moreover, the sensitivity of HCC cells to Sorafenib was enhanced by combining a blockade of EMT with SB431542 and knockdown of PD-L1 expression. Sorafenib-induced motility was attenuated with the combined treatment of SB431542 and PD-L1 knockdown. Our findings indicate that treatment with Sorafenib induces EMT and expression of immune checkpoint molecules, which contributes to Sorafenib resistance in HCC cells. Thus, the combination treatment strategy of inhibiting EMT and immune checkpoint molecules can re-sensitise HCC cells to Sorafenib.

Cost-effectiveness of Atezolizumab Plus Bevacizumab vs Sorafenib for Patients With Unresectable or Metastatic Hepatocellular Carcinoma

Atezolizumab plus bevacizumab as a first-line therapy for patients with unresectable or metastatic hepatocellular carcinoma has been shown to improve overall and progression-free survival compared with standard sorafenib treatment. However, because of the high cost of atezolizumab plus bevacizumab, assessment of its value by considering both efficacy and cost is needed. To evaluate the cost-effectiveness of atezolizumab plus bevacizumab vs sorafenib for patients with unresectable or metastatic hepatocellular carcinoma from a US payer perspective. This economic evaluation was performed from June through September 2020, with a 6-year investment time period. Hypothetical patients were male and female adults 18 years or older who had a diagnosis of locally advanced metastatic or unresectable hepatocellular carcinoma confirmed by histologic or clinical features. Health care costs (adjusted to 2020 US dollars), life-years, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER) of atezolizumab plus bevacizumab vs sorafenib were examined using a partitioned survival model. One-way deterministic and probabilistic sensitivity analyses were used to examine model uncertainty. The model was also used to estimate price reductions of atezolizumab plus bevacizumab that would achieve more favorable cost-effectiveness. In the base case analysis of a hypothetical sample of 424 patients, atezolizumab plus bevacizumab was associated with an increase of 0.623 life-years (1.840 vs 1.218 life-years) and 0.484 QALYs (1.412 vs 0.928 QALYs) and with an incremental cost of $156 210 per patient compared with sorafenib. The ICER was $322 500 per QALY (5th to 95th percentile, $149 364-$683 744 per QALY), with 0.6% and 5.1% chance of being cost-effective at willingness-to-pay thresholds of $100 000 and $150 000 per QALY, respectively. The ICER never decreased below $150 000 per QALY in the 1-way sensitivity analyses. To achieve more favorable cost-effectiveness under the thresholds of $150 000 to $100 000 per QALY, the prices of atezolizumab and bevacizumab would need to be reduced by 37% to 47%. In this economic evaluation, atezolizumab plus bevacizumab was associated with clinical benefit but was not cost-effective compared with sorafenib for first-line treatment of unresectable or metastatic hepatocellular carcinoma from a US payer perspective. A substantial reduction in price for atezolizumab plus bevacizumab would be needed to achieve favorable cost-effectiveness for this new therapy.

A combination of sorafenib and radiotherapy reduces NF‑κB activity and growth of hepatocellular carcinoma in an orthotopic mouse model

Hepatocellular carcinoma (HCC) is difficult to diagnose at an early stage, and its prognosis is generally poor. Sorafenib is the primary treatment for unresectable advanced HCC and targets multiple receptor tyrosine kinases. However, sorafenib only extends the average survival time by 3 months. This observation indicates that sorafenib may need to be combined with other treatments to further improve outcomes. We previously showed that combination of sorafenib with radiotherapy (RT) enhances tumor inhibition in subcutaneous HCC mouse models compared with monotherapy. The present study demonstrated that combining sorafenib and RT could suppress tumor growth in an orthotopic HCC model by regulating apoptosis and NF-κB-related pathways. Moreover, decreased numbers of visible liver tumors and a smaller percentage of spleen metastases were found in the combination group. A transient drop in body weight was initially observed after RT, but progressive recovery of body weight occurred. The current study showed that the combination of sorafenib and RT could be a safe strategy for HCC treatment.

Transcriptomic characterization reveals prognostic molecular signatures of sorafenib resistance in hepatocellular carcinoma.

Sorafenib is the first-line treatment for patients with advanced unresectable hepatocellular carcinoma (HCC); however, only a small number of patients benefit from sorafenib, and many develop sorafenib resistance (SR) and severe side effects. To identify biomarkers for SR, we systematically analyzed the molecular alterations in both sorafenib-resistant HCC specimens and cultured cells. By combining bioinformatics tools and experimental validation, four genes (C2orf27A, insulin-like growth factor 2 receptor, complement factor B, and paraoxonase 1) were identified as key genes related to SR in HCC and as independent prognostic factors significantly associated with clinical cancer stages and pathological tumor grades of liver cancer. These genes can affect the cytotoxicity of sorafenib to regulate the proliferation and invasion of Huh7 cells in vitro. Additionally, immune-cell infiltration according to tumor immune dysfunction and exclusion, a biomarker integrating the mechanisms of dysfunction and exclusion of T cells showed good predictive power for SR, with an AUC of 0.869. These findings suggest that immunotherapy may be a potential strategy for treating sorafenib-resistant HCC. Furthermore, the results enhance the understanding of the underlying molecular mechanisms of SR in HCC and will facilitate the development of precision therapy for patients with liver cancer.

Contemporary real-world treatment patterns and outcomes of patients with advanced/metastatic hepatocellular carcinoma receiving second-line systemic therapy in the United States.

279 Background: Several therapies have recently gained regulatory approval in the United States (US) as second-line (2L) treatment options for patients with advanced unresectable or metastatic hepatocellular carcinoma (HCC). Treatment patterns and associated outcomes in a real-world population, especially in the contemporary era, remain understudied. Methods: This retrospective study utilized electronic health record data collected during routine patient care in outpatient oncology practices in the US. Adult patients diagnosed with advanced/ metastatic HCC between April 2017 and January 2020 were identified from the Concerto HealthAI database. Patients who survived at least one month from the end of first-line (1L) systemic therapy but did not initiate 2L therapy were classified as having received supportive care alone (SCA). Demographics, patient and disease characteristics, treatment patterns, and outcomes were described descriptively. Median overall survival (OS) from initiation of 2L therapy or end of 1L therapy for patients receiving SCA until death was estimated by the Kaplan-Meier method. Results: A total of 586 patients with advanced/ metastatic HCC were identified in the database. 330 patients received 1L therapy, and of those patients 63% (N= 207) received systemic 2L therapy (n= 105) or SCA (n= 102). At first diagnosis of advanced/ metastatic HCC, the median age was 64 years, and 86% were male. Of patients with ECOG status available at diagnosis (67%), 45% had ECOG status 0-1. The most common 1L agents prescribed were sorafenib (n= 126, 61%), lenvatinib (n= 28,14%) and sorafenib + nivolumab (n= 13, 6%) The most frequent agents prescribed in 2L were nivolumab (n= 44, 42%), sorafenib (n=18,17%), and lenvatinib (n=9, 9%). The median OS of patients receiving any systemic 2L therapy was 7.7 months (95% confidence interval 5.7-11.1) from time of receiving 2L therapy, whereas the median OS of patients receiving SCA was 5.0 months (95% confidence interval 3.3-7.1) from time of end of 1L therapy. Conclusions: In this contemporary national real-world cohort of patients with advanced/ metastatic HCC, a third of patients who received 1L therapy subsequently received 2L therapy. Next steps include investigating factors associated with non-receipt of 2L therapy, sequencing of therapies when multiple lines of therapies are received, and evaluating outcomes by type of agent received in 2L and beyond.

Comparative Efficacy of Atezolizumab plus Bevacizumab and Other Treatment Options for Patients with Unresectable Hepatocellular Carcinoma: A Network Meta-Analysis

Background: Most phase 3 clinical trials of systemic therapy for first-line unresectable hepatocellular carcinoma (HCC) have failed, with the exception of SHARP, REFLECT, and IMbrave150. We conducted indirect comparisons of therapies evaluated for first-line HCC treatment. Summary: We conducted a systematic review and meta-analysis of treatments for adults with locally advanced or metastatic unresectable HCC and no prior systemic treatment, including atezolizu­mab plus bevacizumab, sorafenib, lenvatinib, nivolumab, selective internal radiotherapy (SIRT), transarterial chemoembolization, and placebo or best supportive care. Randomized controlled trials published from January 1, 2007, to March 12, 2020, were retrieved from MEDLINE and Embase. Qualitative assessment of heterogeneity evaluated study designs, populations, and outcomes. Indirect comparisons used generalized linear models with random effects within a Bayesian framework and informative priors. We calculated relative efficacy estimates with 95% credible intervals (CrIs) and Bayesian posterior probability estimates of atezolizumab-bevacizumab being superior to other treatments. Nine clinical studies with a total of 3,897 participants were identified from 8,783 records and used to build the all-trials evidence network. Indirect comparisons suggested an improved overall survival (OS) with atezolizumab-bevacizumab versus lenvatinib (odds ratio, 0.63 [95% CrI 0.39–1.04]; with 97% Bayesian posterior probability of being superior), nivolumab (0.68 [95% CrI 0.41–1.14]; 94%), sorafenib (0.59 [95% CrI 0.39–0.87]; 99%), SIRT (0.51 [95% CrI 0.32–0.82]; 100%), or placebo/best supportive care (0.40 [95% CrI 0.25–0.64]; 100%). Key Messages: Within the context of indirect comparisons, analyses of OS favored atezolizumab-bevacizumab versus other treatment options for patients with locally advanced or metastatic unresectable HCC.

Efficacy and toxicity of SBRT in advanced hepatocellular carcinoma with portal vein tumor thrombosis - a retrospective study.

The purpose of this study was to evaluate the outcome of stereotactic body radiation therapy (SBRT) in patients of unresectable hepatocellular carcinoma (HCC ) complicated with portal vein tumor thrombosis (PVTT) who are also unsuitable for other locoregional therapies. Between May 2018 and January 2020, twenty-nine patients with advanced unresectable HCC s, treated with SBRT, were enrolled in this retrospective audit. Patients of Child status A5-B7 and with healthy liver volume, ≥ 700 ccs were treated. Local control (LC), overall survival (OS), progression-free survival (PFS), PVTT opening rate, and effect of prognostic factors were analyzed. The median tumor diameter was 8.6 cm (5-14), and the median tumor volume was 275 cc (151-1196). The median SBRT dose prescription was 48 Gy in 6 fractions (32-50 Gy in 5-6 fractions). The median follow up was eight months (1-20), 1-year local control, progression-free survival, and overall survival were 95%, 53.4%, and 60%, respectively. Overall rate of grade III toxicity was less than 5%, and the most common toxicity was lymphocytopenia. Tumors of more than 350cc had worse OS and PFS when compared to tumors < 350 cc (median OS and PFS of tumors > 350 cc was 4 months and two months, p = .01 and .003, respectively). A total of fifteen patients progressed with the disease and the median time to progression was two months [1-4]. SBRT is safe and provides excellent local control in advanced HCC complicated with PVTT. The out of field failure pattern and time to failure in these patients highlights the need for adjuvant systemic therapy after completion of local treatment. Our data warrant the need for multimodality trials in this patient cohort.

MT4 The Cost-Effectiveness of Selective Internal Radiation Therapy (SIRT) for Treating Advanced Unresectable Hepatocellular Carcinoma in the United Kingdom

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. Approximately 50% of European patients are diagnosed with advanced stage disease (BCLC stage C), which in the UK is currently treated using systemic agents such as sorafenib and lenvatinib. Selective internal radiation therapies (SIRT) offer an alternative approach to treatment, delivering radiation directly to liver tumours via microspheres injected into the hepatic artery. The National Institute for Health and Clinical Excellence (NICE) sought to assess the clinical- and cost-effectiveness of three SIRT technologies: TheraSphere®, SIR-Spheres®, and QuiremSpheres® for use in the UK. The project aimed to assess the clinical and cost-effectiveness of SIRT technologies for treating patients with advanced unresectable HCC on behalf of NICE. Systematic searches were undertaken to identify relevant clinical effectiveness literature. Estimates of the relative effectiveness of the different treatments were generated using network meta-analysis (NMA). An economic model was built to evaluate the cost-effectiveness of SIRT. The outcome of the work-up procedure was captured using a decision tree which fed into a three-state partitioned survival model. The NMA showed no meaningful differences in overall survival between any of the treatments. In the base-case economic analysis, SIRT generated fewer QALYs than sorafenib or lenvatinib, but was associated with higher costs. In the fully incremental analysis considered by the NICE Technology Appraisal Committee, including confidential discounts, lenvatinib was the most cost-effective and dominated SIRT. Sorafenib also dominated each SIRT in pairwise comparisons. Scenario analyses showed that SIRT was more likely to be cost-effective in a subgroup of patients with low tumour burden and good liver function, and when downstaging to transplant was possible. In advanced HCC, SIRT has similar effectiveness to sorafenib and is not cost-effective. Some subgroups may offer the potential for cost-effective treatment, but certainty in available evidence was insufficient for decision making.

FDA Approval Summary: Atezolizumab Plus Bevacizumab for the Treatment of Patients with Advanced Unresectable or Metastatic Hepatocellular Carcinoma.

On May 29, 2020, the FDA approved atezolizumab for use in combination with bevacizumab, for the treatment of adult patients with unresectable locally advanced or metastatic hepatocellular carcinoma (HCC) with no prior systemic treatment. The approval was based on data from Study IMbrave150, which randomly allocated (2:1) patients to receive either atezolizumab plus bevacizumab (atezolizumab-bevacizumab) or sorafenib. Overall survival (OS) and independently assessed progression-free survival (PFS) in the intent-to-treat population were the primary endpoints. At the time of the primary analysis, the estimated median OS could not be estimated in the atezolizumab-bevacizumab arm and was 13.2 months in the sorafenib arm [HR, 0.58; 95% confidence interval (CI), 0.42-0.79]. The estimated median PFS was 6.8 months (95% CI, 5.8-8.3) and 4.3 months (95% CI, 4.0-5.6) in the atezolizumab-bevacizumab and sorafenib arms, respectively. Adverse reactions occurring in >20% of patients receiving atezolizumab-bevacizumab were hypertension, fatigue/asthenia, and proteinuria. Adverse reactions occurring in >20% of patients receiving sorafenib were palmar-plantar erythrodysesthesia, diarrhea, hypertension, and decreased appetite. Hemorrhage was reported more frequently in patients receiving atezolizumab-bevacizumab (25%) than in patients receiving sorafenib (17%). An evaluation for the presence of varices is recommended within 6 months of initiation of atezolizumab-bevacizumab in patients with HCC. Approval of atezolizumab-bevacizumab is likely to change the treatment paradigm for HCC, given that treatment with atezolizumab-bevacizumab resulted in improved OS and PFS compared with sorafenib, an accepted standard of care for first-line treatment of patients with unresectable HCC.See related commentary by Castet et al., p. 1827.

Combination of TACE and FOLFOX4 in the treatment of unresectable advanced hepatocellular carcinoma: a prospective cohort study*

Abstract Objective The aim of the study was to assess the effectiveness and safety of a combined therapy with transcatheter arterial chemoembolization (TACE) and FOLFOX4, in patients with unresectable advanced hepatocellular carcinoma (HCC). Methods In this study, patients with advanced HCC, that received treatment between November 2015 and October 2017, were recruited. Among these, 30 patients were treated with TACE only (TACE group); whereas 33 patients were treated with a combination of FOLFOX4 chemotherapy and TACE (combination group). Survival analyses, including overall survival (OS) and progression free survival (PFS) analysis, were performed for both groups. Following this, the responses of patients to treatment were evaluated every 3 months, and the toxic and adverse events were observed. Results The median follow-up time was 9.2 months (3-36 months). In the combination group, at 3 months, a disease control rate (DCR) of 60.6%, and a median OS of 9.1 months was obtained [95% confidence interval (CI) 6.5-11.7]. In the TACE group, the DCR and OS were 33.3% and 5.5 months (95% CI 4.3-6.7), respectively. On the other hand, the PFS in the combination and TACE groups were observed as 5.6 months (95% CI 3.6-7.6) and 2.6 months (95% CI 2.0-3.2), respectively. Both these findings indicate a statistically significant difference (P = 0.01) between both the groups. Similar TACE associated adverse events were observed in both groups. In the combination group, frequently observed FOLFOX4 related adverse effects included nausea (90.9%), leukopenia (75.8%), thrombocytopenia (69.7%), and vomiting (69.7%). Most adverse reactions were between grades I-III and were alleviated after symptomatic treatments. Conclusion The combination of TACE with FOLFOX4 therapy has better effectivity and safety than TACE alone.

Reduction in Tumor Stain at 2 Weeks after Treatment Initiation Is a Predictor of the Efficacy of Lenvatinib in Patients with Unresectable Hepatocellular Carcinoma

Background and Aims: Lenvatinib is an oral anticancer drug for patients with unresectable advanced hepatocellular carcinoma (HCC). We evaluated whether a reduction in tumor stain at 2 weeks after lenvatinib treatment in patients with unresectable HCC is a predictor of early treatment efficacy at 12 weeks. Patients and Methods: Of the 23 patients who initiated lenvatinib treatment between April 2018 and January 2019, treatment efficacy was measured in 15 patients for more than 12 weeks after treatment. Changes in tumor stain, tumor size on contrast-enhanced computed tomography (CT), and serum levels of tumor markers were evaluated 2 weeks after lenvatinib treatment. Therapeutic efficacy was assessed by tumor stain and tumor size by contrast-enhanced CT within the first 12 weeks, according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST) guidelines. Results: At 12 weeks, efficacy evaluation of 15 patients revealed that 11 of them experienced partial responses, for a response rate of 73.3%. In the first 2 weeks, 13 patients (86.7%) experienced a decreased tumor stain, including 10 responders (90.9%) and 3 non-responders (75.0%). All patients in the non-responder group had required a lenvatinib dose reduction due to adverse events within 12 weeks. On contrast-enhanced CT, the change rate of tumor stain to HCC at 2 weeks after treatment was <0.8 among 10 responders (90.9%) and 1 non-responder (25.0%; p = 0.033). No significant differences between responders and non-responders were observed with regard to most characteristics at baseline and at 2 weeks after treatment initiation. However, significant differences were observed between groups in the presence or absence of a dose suspension period, the presence or absence of lenvatinib dose reduction from the maximum value during the first 2 weeks, and decreased tumor stain at 2 weeks after treatment initiation. Conclusion: Reduction in tumor stain at 2 weeks after lenvatinib treatment may be an early biomarker of efficacy at 12 weeks in patients with unresectable HCC.

1001P PD1midKLRG1+Tbethigh effector memory T in the peripheral blood correlates with tumor response to combined therapy with lenvatinib and anti-PD-1 antibodies in unresectable hepatocellular carcinoma

Combination therapy of anti-angiogenic therapy and anti-PD-1antibody had shown promising anti-tumor effects for advanced hepatocellular carcinoma (HCC) in clinical trials. Despite the remarkable effect of combined therapy with lenvatinib and anti-PD-1 antibodies in HCC, most patients do not respond to the combination therapy, or develop resistance. Predicting tumor responses to the combination therapy is an important unmet need. Patients with advanced unresectable HCC received Lenvatinib 8 mg/d regardless of patient body weight and anti-PD-1 antibody either q2wk (nivolumab or camrelizumab) or q3wk (pembrolizumab, sintilimab or toripalimab). Patients who completed at least one efficacy and safety assessment were eligible for this study. High-dimensional single-cell mass cytometry (CyTOF) and a bioinformatics pipeline for the in-depth characterization of the immune cell subsets was used to identify T cell subsets in the peripheral blood of patients before the treatment. From May 2019 to Dec. 2019, we recruited 15 patients. All the patients are assessable for efficacy. Two patients achieved complete response (CR), 7 patients achieved partial response (PR), and 6 patients achieved progressing disease (PD) per mRECIST. CyTOF identified 36 meta-clusters contained all of the major immune cell populations such as T cells, B cells, NK cells, DC cells and momocytes with a panel of 42 antibodies. Moreover, we delineated an PD1midKLRG1+Tbethigh effector memory T cell phenotype that was significantly more abundant in responders (CR or PR, n=9) to combined therapy compared with non-responders (n=6) (PD, P < 0.05). PD1midKLRG1+Tbethigh effector memory T cell in the peripheral blood may be a useful biomarker for predicting tumor response to the combination therapy in HCC.

Additional Treatment Using Transcatheter Arterial Infusion with Drug-Eluting Beads Transarterial Chemoembolization Contributes to Prolonged Survival of Patients with BCLC Stage C Hepatocellular Carcinoma after Discontinuing Lenvatinib: Preliminary Study

Objective: Lenvatinib is considered the first-line treatment for unresectable advanced hepatocellular carcinoma (HCC); however, in some clinical cases, discontinuation of lenvatinib is unavoidable. It is important to elucidate if transcatheter arterial infusion (TAI) with drug-eluting beads transarterial chemoembolization (DEB-TACE) is a feasible second-line treatment after discontinuing lenvatinib. In this study, we aimed to evaluate the efficacy, hepatic function and nutritional status associated with TAI with DEB-TACE for patients who previously discontinued lenvatinib. Materials and Methods: We included 35 patients who were prescribed lenvatinib for unresectable HCC between July 2018 and December 2019, of whom 12 discontinued lenvatinib during the study. The changes in the albumin-bilirubin (ALBI) score and the controlling nutritional status (CONUT) score before and after discontinuing lenvatinib were examined. Furthermore, the tolerability and survival of patients treated using TAI with DEB-TACE as a second-line treatment were analysed. Results: The ALBI and CONUT scores were significantly worse when lenvatinib was started and stopped (p&lt;0.05). The CONUT score was significantly worse in the second-line group than in the follow-up group when beginning and discontinuing lenvatinib; however, this score tended to improve after DEB-TACE. The group that underwent TAI with DEB-TACE as a second-line treatment had significantly better survival than the follow-up group (log‑rank test, p=0.029; generalized Wilcoxon test, p=0.042). Conclusion: In patients who could undergo TAI with DEB-TACE as a second-line treatment after discontinuing lenvatinib, the CONUT score improved, while the ALBI score was maintained and welltolerated; these scores may have contributed to improved survival compared with follow-up patients. Future studies with larger sample sizes are necessary to confirm our findings.

Combining cellular immunotherapy was an optional choice for unresectable advanced HCC: A systematic review and meta-analysis

The efficacy of cellular immunotherapy in advanced hepatocellular carcinoma (HCC) was controversial. This study was conducted to compare the effectiveness of combining cellular immunotherapy with that of incurable treatment alone. The Ovid Medline, Embase, Cochrane Library and Pubmed were systematically searched due to January 8th 2020. The keywords include "immunotherapy", "HCC" and study type. Treatment response was evaluated and progression-free survival (PFS) and overall survival (OS) were calculated using hazard ratio (HR) and 95% confidence interval (CI). A total of 19 studies with 1275 patients were included in the meta-analysis. The median complete response rate (CR) was 19% in combining cellular immunotherapy comparing to 9% in the control group (RR=0.55, P=0.003). No significant difference was found in partial response and stable disease (RR=1.06 and 0.78, P>0.05, respectively). The progression disease rate was higher in the non-cellular immunotherapy group (31%) compared to the cellular immunotherapy group (RR=2.20, P=0.002). Patients treating with cellular immunotherapy had a better OS and PFS compared to those without cellular immunotherapy (HR=0.52 and 0.63, P<0.001). In the subgroup analysis, the only CIK infusion therapy and combined DC with CIK perfusion therapy patients had a better OS (HR=0.52 and 0.49, P<0.001 and P=0.002, respectively). Our results suggested that combining use of cellular immunotherapy in advanced HCC could increase the complete response rate, and thereafter extend the progression-free and overall survival rate. Subgroup analysis suggested that combining use of CIK and DC or using CIK alone could provide the benefit in survival outcome.

Synergistic anti-tumor activity of miriplatin and radiation through PUMA-mediated apoptosis in hepatocellular carcinoma.

The prognosis for patients with unresectable advanced hepatocellular carcinoma (HCC) is poor. Miriplatin is a hydrophobic platinum compound that has a long retention time in lesions after transarterial chemoembolization (TACE). We investigated anti-tumor activity of miriplatin combined with irradiation on HCC cells, and its underlying mechanism of apoptosis. We also analyzed the effectiveness of miriplatin-TACE and radiotherapy for locally advanced HCC. Human HCC cell lines HepG2 and HuH-7 were treated with DPC (active form of miriplatin) and radiation, and synergy was evaluated using a combination index (CI). Apoptosis-related proteins and cell cycles were analyzed by western blotting and flowcytometry. We retrospectively analyzed treatment outcomes in 10 unresectable HCC patients with vascular/bile duct invasion treated with miriplatin-TACE and radiotherapy. DPC or X-ray irradiation decreased cell viability dose-dependently. DPC plus irradiation decreased cell viability synergistically in both cell lines (CI < 1, respectively). Cleaved PARP expression was induced much more strongly by DPC plus irradiation than by each treatment alone. Expression of p53 up-regulated modulator of apoptosis (PUMA) was significantly induced by the combination, and knockdown of PUMA with siRNA significantly decreased apoptosis in both cell lines. DPC plus irradiation caused sub-G1, G2/M, and S phase cell arrest in those cells. The combination of miriplatin-TACE and radiotherapy showed a high response rate for patients with locally advanced HCC despite small number of patients. Miriplatin plus irradiation had synergistic anti-tumor activity on HCC cells through PUMA-mediated apoptosis and cell cycle arrest. This combination may possibly be effective in treating locally advanced HCC.