Therapy For Advanced Hepatocellular Carcinoma Research Articles

Risk versus Benefit of Tyrosine Kinase Inhibitors for Hepatocellular Carcinoma: ASystematic Review and Meta-Analysis of Randomized Controlled Trials.

Although the treatment landscape has rapidly evolved over the last years, hepatocellular carcinoma (HCC) is one of the most lethal cancers. With recent advances, both immunotherapy and tyrosine kinase inhibitors (TKIs)-based chemotherapy constitute the standard treatment for advanced HCC. A systematic search of randomized clinical trials employing TKIs was performed in 17 databases, obtaining 25 studies evaluating the prognosis, tumor response, and presence of adverse events (AEs) related to TKIs in HCC. Overall effect sizes were estimated for the hazard ratios (HR) and odds ratios (OR) with 95% confidence interval (CI), either extracted or calculated with the Parmar method, employing STATA 16. Heterogeneity was assessed by Chi-square-based Q-test and inconsistency (I2) statistic; source of heterogeneity by meta-regression and subgroup analysis; and publication bias by funnel plot asymmetry and Egger's test. The research protocol was registered in PROSPERO (CRD42023397263). Meta-analysis revealed a correlation between survival and tumor response parameters and TKI treatment vs. placebo, despite detecting high heterogeneity. Combined TKI treatment showed a significantly better objective response rate (ORR) with no heterogeneity, whereas publication bias was only detected with time to progression (TTP). Few gastrointestinal and neurological disorders were associated with TKI treatment vs. placebo or with combined treatment. However, a higher number of serious AEs were related to TKI treatment vs. sorafenib alone. Results show positive clinical benefits from TKI treatment, supporting the approval and maintenance of TKI-based therapy for advanced HCC, while establishing appropriate strategies to maximize efficacy and minimize toxicity.

Assessment of Macrovascular Invasion in Advanced Hepatocellular Carcinoma: Clinical Implications and Treatment Outcomes with Systemic Therapy

Introduction: Macrovascular invasion (MVI) is a strong prognostic factor for advanced hepatocellular carcinoma (HCC). The current criteria for radiological assessment are unclear in evaluating the impact of MVI on systemic therapy. In this study, we standardized the assessment of MVI and validated its clinical relevance. Methods: Clinical data were collected from patients with advanced HCC and MVI who received first-line systemic therapy at four medical centers in Japan. First, we used macrovascular invasion progression disease (MVI-PD) to track MVI progression, and Response Evaluation Criteria in Solid Tumours version 1.1 progression disease (RECIST v1.1-PD) to evaluate tumor enlargement other than MVI and the appearance of new lesions. Next, we assessed the prognostic value of MVI-PD and RECIST v1.1-PD. Results: Of the 207 advanced HCC patients with MVI, 189 received appropriate imaging evaluation. 40 (21.2%) patients had MVI-PD and RECIST v1.1-PD, 51 (27.0%) had prior MVI-PD, and 61 (32.3%) had prior RECIST v1.1-PD. In a landmark analysis, the prognosis of 163 patients who survived more than three months was analyzed based on the assessment of imaging response during the first three months. The median overall survival (OS) was 5.4 months in those who had MVI-PD and RECIST v1.1-PD, 7.4 months in those who had RECIST v1.1-PD only, 7.2 months in those who had MVI-PD only, and 19.7 months in patients who had neither (p<0.001). The correlation coefficients between progression-free survival and OS in patients with appropriate imaging assessments were similar for MVI-PD (0.515) and RECIST v1.1-PD (0.498). Conclusion: Our findings demonstrate the link between MVI progression and poor OS in systemic therapy for advanced HCC, emphasizing the importance of an accurate method for assessing MVI progression.

Dynamics of the neutrophil‑to‑lymphocyte ratio during lenvatinib treatment for unresectable hepatocellular carcinoma.

Lenvatinib is an approved therapy for advanced hepatocellular carcinoma (HCC). Recently, immune checkpoint inhibitors have been approved as frontline chemotherapies for HCC, and the tumor immune microenvironment (TIME) has been demonstrated to significantly affect HCC treatment. The neutrophil-to-lymphocyte ratio (NLR) is associated with the TIME, and the dynamics of the NLR are associated with prognosis or treatment efficacy in various cancer types. The present study investigated the dynamics of the TIME using the NLR in 101 patients with HCC treated with lenvatinib. Immunostaining for CD8+ tumor-infiltrating lymphocytes (TILs) was also performed in 9 patients who underwent liver tumor biopsy prior to subsequent chemotherapy for progression or discontinuation due to adverse events on lenvatinib treatment. The NLR values measured at the start of treatment (SOT), after 1 month of treatment and after 3 months of treatment were 2.78±2.20, 2.61±1.86 and 2.66±2.36, respectively (P=0.733). Among the patients with no reduction in the initial dose, there was no significant difference between the NLR after 1 month (2.34±0.25) and that at the SOT (2.86±2.33) (P=0.613). In patients who achieved a complete or partial response, the NLR at the time of the best tumor response was 1.65±0.56, which was significantly lower than that at the SOT (2.05±0.78) (P=0.023). In patients who did not respond to lenvatinib, the NLR at the time of disease progression was 3.68±3.19, which was significantly higher than that at the SOT (2.78±1.79) (P=0.043). Overall, 5 out of the 6 patients who did not respond to lenvatinib had low CD8+ TIL counts at disease progression. Although the present study included a limited number of patients, the NLR was associated with the therapeutic effects of lenvatinib. These findings suggest the potential of lenvatinib as an immunomodulator.

Conversion therapy for advanced hepatocellular carcinoma in the era of precision medicine: Current status, challenges and opportunities.

Hepatocellular carcinoma (HCC), the most prevalent malignancy of the digestive tract, is characterized by a high mortality rate and poor prognosis, primarily due to its initial diagnosis at an advanced stage that precludes any surgical intervention. Recent advancements in systemic therapies have significantly improved oncological outcomes for intermediate and advanced-stage HCC, and the combination of locoregional and systemic therapies further facilitates tumor downstaging and increases the likelihood of surgical resectability for initially unresectable cases following conversion therapies. This shift toward high conversion rates with novel, multimodal treatment approaches has become a principal pathway for prolonged survival in patients with advanced HCC. However, the field of conversion therapy for HCC is marked by controversies, including the selection of potential surgical candidates, formulation of conversion therapy regimens, determination of optimal surgical timing, and application of adjuvant therapy post-surgery. Addressing these challenges and refining clinical protocols and research in HCC conversion therapy is essential for setting the groundwork for future advancements in treatment strategies and clinical research. This narrative review comprehensively summarizes the current strategies and clinical experiences in conversion therapy for advanced-stage HCC, emphasizing the unresolved issues and the path forward in the context of precision medicine. This work not only provides a comprehensive overview of the evolving landscape of treatment modalities for conversion therapy but also paves the way for future studies and innovations in this field.

Regorafenib with immunotherapy versus regorafenib alone as second-line treatment for hepatocellular carcinoma: A multicenter real-world study.

Regorafenib remains the standard and widely used second-line strategy for advanced hepatocellular carcinoma (HCC). There is still a lack of large-scale multicenter real-world evidence concerning the concurrent use of regorafenib with immune checkpoint inhibitors (ICI). This study aims to evaluate whether combining regorafenib with ICI provides greater clinical benefit than regorafenib monotherapy as second-line therapy for advanced HCC under real-world circumstances. The study included 208 patients from five medical facilities. One hundred forty-three patients received regorafenib plus ICI combination therapy, while 65 patients received regorafenib monotherapy. Propensity score matching (PSM) analysis was employed. The regorafenib plus ICI group demonstrated significantly higher objective response rate (24.3% vs. 10.3%, after PSM, p = 0.030) and disease control rate (79.4% vs. 50.0%, after PSM, p < 0.001) compared to the regorafenib monotherapy group based on mRECIST criteria. Median progression-free survival (7.9 vs. 3.2 months, after PSM, p < 0.001) and overall survival (25.6 vs. 16.4 months, p = 0.010, after PSM) were also considerably longer in the regorafenib plus ICI group. The incidence of Grades 3-4 treatment-related adverse events (TRAEs) was marginally greater in the regorafenib plus ICI group than in the regorafenib group (23.8% vs. 20.0%, p = 0.546). Notably, there were no instances of treatment-related mortality or emergence of new TRAEs in any treatment group. The combination of regorafenib and ICI shows potential as a viable second-line treatment for advanced HCC, exhibiting favorable efficacy while maintaining a tolerable safety profile in contrast to regorafenib monotherapy.

Systemic Therapies for Hepatocellular Carcinoma in India

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality in India. This review explores the epidemiological trends and the landscape of systemic therapy for HCC in the Indian context, acknowledging the recent shift in etiology from viral hepatitis to lifestyle-associated factors. A comprehensive review of the literature was conducted, including data from the Global Cancer Observatory and the Indian Council of Medical Research, along with a critical analysis of various clinical trials. The article investigates systemic therapies in-depth, discussing their mechanisms, efficacy, and adaptation to Indian healthcare framework. Progression-free survival with a hazard ratio (HR) ≤0.6 compared to sorafenib, overall survival of ∼16-19 months, and objective response rate of 20-30% are the defining thresholds for systemic therapy clinical trials. Systemic therapy for advanced HCC in India primarily involves the use of tyrosine kinase inhibitors (TKIs) such as sorafenib, lenvatinib, regorafenib, and cabozantinib, with sorafenib being the most commonly used drug for a long time. Monoclonal antibodies like ramucirumab and bevacizumab and immune checkpoint inhibitors such as atezolizumab, nivolumab and pembrolizumab, are expanding treatment horizons. Lenvatinib has emerged as a cost-effective alternative, and the combination of atezolizumab and bevacizumab has demonstrated superior outcomes in terms of overall survival and progression-free survival. Despite these advances, late-stage diagnosis and limited healthcare accessibility pose significant challenges, often relegating patients to palliative care.Addressing HCC in India demands an integrative approach that not only encompasses advancements in systemic therapy but also targets early detection and comprehensive care models. Future strategies should focus on enhancing awareness, screening for high-risk populations, and overcoming infrastructural disparities. Ensuring the judicious use of systemic therapies within the constraints of the Indian healthcare economy is crucial. Ultimately, a nuanced understanding of systemic therapeutic options and their optimal utilization will be pivotal in elevating the standard of HCC care in India.

Current Roles of Ramucirumab in the Sequential Treatment of Unresectable Hepatocellular Carcinoma.

The treatment algorithm for systemic therapies for advanced hepatocellular carcinoma (HCC) has changed dramatically; however, the therapeutic landscape for sequential second-line or later-line treatments, including ramucirumab, remains controversial. This study aimed to investigate the role of ramucirumab for treating HCC. We retrospectively analyzed data from 17 patients with advanced HCC who received ramucirumab, and 8 of them who received lenvatinib re-administration after ramucirumab treatment failure. The median overall survival of 17 patients treated with ramucirumab was 11.5 months. The median ratios of the 1-month post-treatment α-fetoprotein (AFP) levels and albumin-bilirubin (ALBI) scores to the pre-treatment AFP levels and ALBI scores following ramucirumab treatment were 0.880 and 0.965, respectively. The median ratios of the 1-month post-treatment AFP and ALBI levels to the pre-treatment levels were 1.587 and 0.970 for mALBI grade 1/2a, and 1.313 and 0.936 for mALBI grade 2b/3, respectively. Six of the eight patients who received lenvatinib rechallenge treatment exhibited a decrease in AFP levels one month post-lenvatinib treatment. Deterioration of liver function 3 months post-lenvatinib treatment was noted in five of the eight patients who received lenvatinib rechallenge treatment after ramucirumab. Ramucirumab may be equally useful in patients with unresectable HCC who have poor liver function or whose liver function is aggravated by other therapies. Rechallenge treatment with lenvatinib after ramucirumab may be a valid treatment option for HCC.

Systemic Therapy for Advanced Hepatocellular Carcinoma: ASCO Guideline Update Clinical Insights.

Systemic Therapy for Advanced Hepatocellular Carcinoma: ASCO Guideline Update Clinical Insights.

Effect of HBV DNA load on the safety and prognosis of systematic therapy in advanced hepatocellular carcinoma

Objective: To study the effect of hepatitis B virus (HBV) infection on the occurrence of liver damage, HBV reactivation (HBVr) and the influence of HBVr on the prognosis of patients with advanced hepatocellular carcinoma (HCC) receiving systemic therapy. Methods: The clinical data of 403 patients with HBV-related HCC at the Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-Sen University et al, from July 2018 to December 2020 were collected. The incidence of liver damage and HBVr during systematic therapy, and the influence of HBVr on survival prognosis were analyzed. Results: Of the 403 patients, 89.1% were male (n=359), with a median age of 51 years (51.5±12.1). Before propensity score matching (PSM), the proportion of patients with cirrhosis, TNM and advanced BCLC stage was higher in high HBV-DNA (baseline HBV-DNA>1000 U/ml, n=147) group comparing with the low HBV-DNA (baseline HBV DNA≤1000 u/ml, n=256) group (P<0.05). There was no significant difference in baseline indexes between the two groups after PSM. In 290 patients after PSM, there was no significant difference in the incidence of liver damage and HBVr between high HBV-DNA group and low HBV-DNA group (P>0.05). Survival analysis was performed on 169 patients with survival data, the median overall survival (OS) was found to be 11.49 months (95%CI: 7.77-12.89) and 16.65 months (95%CI: 10.54-21.99, P=0.008) in the high and low HBV-DNA groups, respectively. And median progression-free survival (PFS) was 7.41 months (95%CI: 5.06-8.67) and 10.55 months (95%CI: 6.72-13.54, P=0.038), respectively, with a statistically significant difference. There were no differences in overall survival (OS) and progression-free survival (PFS) between patients with and without HBVr and those with or without liver damage (P>0.05). Conclusions: HBV-DNA levels above 1 000 U/ml before systemic therapy do not increase the risk of liver damage or HBVr during systemic therapy in patients with HBV-related hepatocellular carcinoma, and such patients can safely receive systemic therapy.

Abstract 4572: Ginsenoside Rh3 increases the susceptibility of regorafenib-mediated cancer cell death by inhibiting the JAK/STAT3 signaling pathway in hepatocellular carcinoma

Abstract Ginsenosides, bioactive compounds derived from Panax ginseng, exhibit diverse pharmacological effects, including anti-cancer properties. Regorafenib, a potent multi-kinase inhibitor, is employed as a second-line therapy for advanced hepatocellular carcinoma (HCC). However, the modest survival benefits observed in treated patients may be attributed to drug resistance. In this study, we screened a panel of 40 ginsenosides for their activity in combination with regorafenib in HCC cell lines and investigated their underlying cellular mechanisms. Synergistic effects were evaluated using the WST-8 assay, and optimal drug concentrations were determined through synergy scoring. A phospho-kinase assay was conducted to elucidate the mechanism of action, and in vivo experiments validated our findings. Ginsenoside Rh3 emerged as a promising candidate, enhancing the sensitivity of HCC cells to regorafenib-induced anticancer effects by promoting apoptosis. The phospho-kinase array revealed that the combined treatment's apoptotic effect was associated with the inhibition of signal transducer and activator of transcription 3 (STAT3) activation through the Janus kinase pathway. In vivo results demonstrated the combination treatment's inhibitory effects on tumor growth. Our study proposes a novel treatment strategy, highlighting the potential efficacy of combining regorafenib and ginsenoside Rh3 for HCC treatment. Citation Format: Youngsic Jeon, Hyukjoon Kwon, Young Nyun Park, Dong-Young Woo, Taejung Kim, Jungyeob Ham, Young-Joo Kim. Ginsenoside Rh3 increases the susceptibility of regorafenib-mediated cancer cell death by inhibiting the JAK/STAT3 signaling pathway in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4572.

Abstract 4667: HDAC9 as a potential regulator of lenvatinib resistance in hepatocellular carcinoma

Abstract Lenvatinib is used as the first-line therapy for advanced hepatocellular carcinoma (HCC) patients. However, poor response and compromised therapeutic effect with prolonged treatment are frequently observed in HCC patients. To elucidate the underlying mechanisms, lenvatinib responsive and non-responsive stages were modeled in liver tumor-bearing immunocompetent mice which were divided into lenvatinib and vehicle control treatment groups. Tumor tissues after short and prolonged lenvatinib treatment were harvested for single-cell RNA sequencing. Results from single-cell RNA sequencing revealed heterogenous tumor cell sub-populations associated with tumor differentiation and identified an upregulated expression of class IIa histone acetylase HDAC9 in lenvatinib-treated tumor at the non-responsive stage. Upregulation of HDAC9 was similarly observed in lenvatinib-resistant human patient-derived xenograft (PDX). Functional studies suggested that suppressing HDAC9 could re-sensitize lenvatinib response in both in vitro and in vivo models. In sum, we identified a potential regulator of lenvatinib treatment response in HCC. Citation Format: Yunong Xie, Minghe Zhang, Yan Liu, Linglin Liu, Alfred Sze-Lok Cheng, Stephanie Ma, Man Tong. HDAC9 as a potential regulator of lenvatinib resistance in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4667.

Scutellaria baicalensis Induces Cell Apoptosis and Elicits Mesenchymal-Epithelial Transition to Alleviate Metastatic Hepatocellular Carcinoma via Modulating HSP90β.

Hepatocellular carcinoma is one of the most common malignant tumors in the world and shows strong metastatic potential. Current medicine for hepatocellular carcinoma therapy is invalid, while Scutellaria baicalensis Georgi exhibits the pharmaceutical potential to treat liver diseases and liver cancer. Herein, we verified the inhibitory properties and the pivotal molecules regimented by Scutellaria baicalensis on advanced hepatocellular carcinoma. At first, the viability of SK-Hep-1 cells was significantly reduced under treatment of Scutellaria baicalensis extract in a dose-dependent manner without affecting the growth of normal hepatocyte. Scutellaria baicalensis extract application could remarkably cause apoptosis of SK-Hep-1 cells through p53/cytochrome C/poly-ADP ribose polymerase cascades and arrest the cell cycle at the G1/S phase by downregulating cyclin-dependent kinases. Meanwhile, administration of Scutellaria baicalensis extract remarkably attenuated the migration capability as well as suppressed matrix metalloproteinase activity of advanced hepatocellular carcinoma cells. The proteome profiles and network analysis particularly implied that exposure to Scutellaria baicalensis extract downregulated the expression of HSP90β, and the clinical stage of hepatocellular carcinoma is also positively correlated with the HSP90β level. Combined treatment of Scutellaria baicalensis extract and HSP90β siRNAs could markedly enhance the ubiquitination activity and the degradation of vimentin to subsequently inhibit the metastatic property of SK-Hep-1 cells. Moreover, application of Scutellaria baicalensis extract and HSP90β siRNAs depleted phosphorylation of AKT, which stimulated the expression of p53 and consecutively triggered cell apoptosis. These findings suggest that HSP90β may be a prospective target for the effective therapy of advanced hepatocellular carcinoma via accelerating apoptosis of hepatocellular carcinoma cells and eliciting mesenchymal-epithelial transition with the administration of Scutellaria baicalensis extract.

Hepatocellular Carcinoma: Advances in Systemic Therapy.

Hepatocellular carcinoma (HCC) is a prevalent primary liver cancer, representing over 90% of cases globally and ranking as the third leading cause of cancer-related death. This article reviews the evolving landscape of systemic therapies for advanced HCC, emphasizing recent advancements and their impact on patient outcomes. The advent of molecular targeted therapies has transformed HCC management, with sorafenib being the first FDA-approved molecular targeted therapy, setting a standard for a decade. However, recent breakthroughs involve the combination of atezolizumab and bevacizumab, demonstrating superior outcomes over sorafenib, leading to FDA approval in 2020. Another notable combination is tremelimumab and durvalumab, showing efficacy in a multinational phase III trial. Beyond these combinations, this article explores the role of other first-line treatments and subsequent therapies after progression. The evolving landscape of systemic therapies for HCC reflects a paradigm shift, with immunotherapy combinations emerging as key players alongside targeted therapies. This article highlights the complexity of treatment decisions, considering individual patient characteristics and disease etiology, and underscores the ongoing quest to optimize both systemic and local-regional therapies for improved long-term outcomes in HCC patients.

An open-label, multicenter study investigating RP3 oncolytic immunotherapy in combination with first- or second-line systemic atezolizumab plus bevacizumab in patients with locally advanced unresectable or metastatic hepatocellular carcinoma.

TPS576 Background: Despite advances in treatment for unresectable hepatocellular carcinoma (HCC), long-term survival rates remain poor. The combination of atezolizumab (Atezo) plus bevacizumab (Bev) is approved frontline therapy for advanced HCC, but a minority of patients (pts) respond and secondary resistance usually occurs within months. HCC has an immune-suppressed tumor microenvironment (TME), mediated by activated immune checkpoint signaling and angiogenesis pathways, which may contribute to therapeutic resistance. RP3 is a genetically modified herpes simplex virus type 1 (HSV-1) that expresses the fusogenic gibbon ape leukemia virus glycoprotein with the R sequence deleted (GALV-GP-R–), an anti–CTLA-4 antibody-like molecule, CD40 ligand, and 4-1BB ligand. The direct oncolytic effect coupled with immune stimulation by RP3 in the TME is intended to provide systemic antitumor activity and synergize with anti–PD-1/PD-L1 agents, such as Atezo. Preclinical data have demonstrated improved distribution of oncolytic HSV within tumors in combination with Bev, supporting the clinical combination of RP3 with Bev. This study will evaluate the safety and efficacy of RP3 combined with Atezo plus Bev as first- (1L) and second-line (2L) systemic therapies for unresectable and advanced HCC (NCT05733598). Methods: The 1L and 2L cohorts will each enroll up to 30 pts. Pts in the 1L cohort may not have received prior systemic treatment; pts in the 2L cohort must have progressed on or following 1 prior line of systemic therapy, which must have included a PD-1/PD-L1–directed agent. Key inclusion criteria include advanced unresectable HCC with ≥1 measurable tumor of ≥1 cm in longest diameter, Child-Pugh class A, and an Eastern Cooperative Oncology Group performance status of 0 to 1. Key exclusion criteria include untreated esophageal and/or gastric varices with bleeding or at high risk for bleeding and macroscopic invasion of the tumor into any major blood vessel(s) and/or main bile ducts. Pts with a history of medically refractory hepatic encephalopathy and/or hepato-renal syndrome are also excluded. Pts in the 1L cohort will receive Atezo 1200 mg and Bev 15 mg/kg every 3 weeks (Q3W) together with RP3 intratumorally Q3W for a total of up to 8 doses. Pts in the 2L cohort will receive RP3 every 2 weeks for 4 doses with Bev Q3W starting on cycle (C)1 day (D)1, then RP3 and Bev Q3W for up to 4 more doses with Atezo Q3W being added on C4D1. The primary endpoint is the overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary endpoints are safety, ORR using HCC modified RECIST, duration of response, complete response rate, and progression-free survival. Clinical trial information: NCT05733598 .

Molecular predictors of response to first-line systemic therapies in advanced hepatocellular carcinoma.

534 Background: With numerous advances in systemic therapy for advanced hepatocellular carcinoma (HCC) over the past several years, there are now multiple first-line treatment options which can be considered. These options include combination atezolizumab with bevacizumab (atezo/bev), programmed cell death protein 1/programmed death ligand 1 (PD-1/PD-L1) targeted agents, and oral multikinase inhibitor monotherapy. However, further guidance is needed to predict which patients will respond to best to each regimen. Methods: We performed a single center, retrospective study to determine the association between responses to first-line therapies in advanced HCC and various molecular alterations. Patients received first-line therapy with either atezo/bev, PD-1/PD-L1 monotherapy, or oral multikinase inhibitor monotherapy with treatment responses determined by imaging. All patients underwent next-generation sequencing (NGS) with testing performed on peripheral blood or tumor tissue. Results: A total of 116 patients with advanced HCC were included in this study. For first-line therapies, 45 (38.8%) patients received atezo/bev, 41 (35.3%) received oral multikinase inhibitor monotherapy, and 30 (25.9%) received PD-1/PD-L1 monotherapy. There was no association between treatment responses and patient ethnicity, age, or underlying cirrhosis etiology for any regimen. However, when analyzing NGS results, atezo/bev recipients with telomerase reverse transcriptase (TERT) promoter alterations had significantly higher rates of disease progression (PD) compared those without TERT promoter alterations (91.7% vs 54.6%, p = 0.03). In addition, in the oral multikinase inhibitor monotherapy group, those with CTNNB1 alterations had significantly greater PD rates compared to patients without these alterations (66.7% vs 31%, p = 0.04). There were no significant correlations between molecular alterations and responses in the PD-1/PD-L1 monotherapy group (Table). Conclusions: In our study, advanced HCC patients who received first-line systemic therapies were found to have significant correlations between TERT promoter and CTNNB1 alterations and responses to atezo/bev and oral multikinase inhibitor monotherapy, respectively. Given the widespread use of these regimens in the HCC treatment paradigm, additional studies are needed to confirm these findings and determine their impact on survival outcomes.[Table: see text]

Cost-utility analysis of sequential therapy with sorafenib followed by regorafenib versus single-line therapies in advanced hepatocellular carcinoma.

529 Background: Regorafenib is the only licensed second-line therapy available for patients with advanced hepatocellular carcinoma (HCC) that progress on first-line sorafenib in the UK. We evaluated the lifetime cost-effectiveness of a sequence of treatment with sorafenib followed by regorafenib (SOR-REG) compared with licensed single-line therapies for which there is no clear sequencing options available, including atezolizumab plus bevacizumab (ATEZO+BEV), which has become the standard of care in first-line treatment, as well as lenvatinib (LEN), followed by best supportive care (BSC). Methods: Assuming a UK National Health Service and Social Services perspective, we developed a probabilistic individual-level semi-Markov model with states reflecting progression-free survival, progression following first-line treatment, further progression following second-line treatment, and death. First-line overall survival (OS) and progression free survival (PFS) were informed by fractional polynomials network meta-analysis of published trials. Individual patient data from a phase 3 trial (RESORCE) on regorafenib and BSC informed OS and PFS in the second-line setting. Costs and utilities were sourced from published studies. Cost-effectiveness was summarized using incremental net monetary benefit (INMB), which could be positive or negative depending on direction of expected benefit associated with SOR-REG, and cost-effectiveness acceptability curves at willingness-to-pay (WTP) thresholds. Results: We found 1000 probabilistic samples and 1000 patients were sufficient for convergence. Lifetime costs were highest with ATEZO-BEV ([£80,963 [95% CI: £11,022, £97,369]), followed by SOR-REG (£38,373 [£31,064, £43,420]) and LEN (£37,351 [£5,020, £55,800]). Quality-adjusted life years (QALYs) were highest with ATEZO+BEV (1.021 [0.152, 1.239), followed by SOR-REG (0.942 [0.802, 1.057]) and LEN (0.755, [0.094, 1.092]). At a WTP threshold of £30,000 / QALY gained, SOR-REG had an INMB of £40,211 (95% CI -£2,099, £52,731) and £4,589 (-£8,044, £14,481) versus ATEZO+BEV and LEN, respectively. Conclusions: A sequence of SOR-REG for patients with advanced HCC is cost-effective at WTP thresholds of £30,000 / QALY gained due to lower lifetime costs and broadly comparable QALY gains with single-line ATEZO-BEV and LEN in the UK. Broader second-line treatment options are needed for patients receiving ATEZO+BEV and LEN as first-line therapies.

Lenvatinib plus pembrolizumab versus lenvatinib alone as first-line therapy for advanced hepatocellular carcinoma: Longer-term efficacy and safety results from the phase 3 LEAP-002 study.

482 Background: The randomized, double-blind, phase 3 LEAP-002 study (NCT03713593) was conducted to evaluate the efficacy and safety of first-line (1L) lenvatinib (len) + pembrolizumab (pembro) vs len + placebo (pbo) in patients (pts) with advanced hepatocellular carcinoma (HCC). After a median follow-up (randomization to data cutoff) of 32.1 mo, LEAP-002 did not meet its primary end points of OS at final analysis (median, 21.2 vs 19.0 mo; HR, 0.840; 95% CI, 0.708-0.997) and PFS at interim analysis 1 (IA1; median, 8.2 vs 8.0 mo; HR, 0.867; 95% CI, 0.734-1.024). However, the study highlighted the activity of len + pembro and, given the late separation of Kaplan-Meier survival curves for OS and PFS between treatment arms from 12 mo onwards, outcomes with extended follow-up are of interest. We report results after 12 mo of additional follow-up (median 43.6 mo). Methods: Eligible pts with advanced HCC were randomized 1:1 to len (8 mg/day if bodyweight [BW] &lt;60 kg; 12 mg/day if BW ≥60 kg) + pembro (200 mg IV Q3W) or len + pbo. Dual primary end points were OS and PFS (per RECIST v1.1 by BICR). Secondary end points included ORR and DOR, both per RECIST v1.1 by BICR, and safety. Data cutoff was June 6, 2023. Results: 794 pts were randomly assigned to receive len + pembro (n = 395) or len + pbo (n = 399). Median follow-up was 43.6 mo (range, 37.3-52.6), and treatment was ongoing in 25 (3.2%) pts. Median OS was 21.1 mo with len + pembro vs 19.0 mo with len + pbo (HR, 0.836; 95% CI, 0.713-0.981). OS rates for len + pembro vs len + pbo were 43.4% vs 40.0% at 24 mo, 32.7% vs 24.3% at 36 mo, and 22.4% vs 15.3% at 48 mo. Median PFS was 8.2 mo with len + pembro vs 8.1 mo with len + pbo (HR, 0.810; 95% CI, 0.692-0.949). PFS rates for len + pembro vs len + pbo were 16.4% vs 9.7% at 24 mo and 14.1% vs 3.3% at 36 mo. ORR was 26.3% for len + pembro vs 17.5% for len + pbo. Median DOR was 16.6 mo (range, 2.0+ to 45.3+) for len + pembro vs 10.4 mo (range, 1.9 to 37.0+) for len + pbo. Grade 3-5 treatment-related adverse event (TRAE) rates were 62.8% in the len + pembro arm and 58.0% in the len + pbo arm. No additional deaths due to TRAEs were reported. The most common TRAEs of any grade in the len + pembro vs len + pbo arms were hypertension (43.8% vs 46.8%), diarrhea (40.8% vs 34.2%), and hypothyroidism (40.0% vs 35.9%). Overall, 46.6% vs 55.4% of pts received ≥1 poststudy systemic anticancer treatment. Conclusions: With an additional 12 mo of follow-up, the LEAP-002 primary end points of OS and PFS for len + pembro vs len + pbo remained consistent with the primary efficacy analyses; no new safety signals were observed. The median OS of 19.0 mo with len monotherapy continues to support its role as a standard-of-care treatment in 1L advanced HCC. The activity of len + pembro for pts with advanced HCC observed in this study supports the evaluation of TACE ± len + pembro for intermediate-stage HCC in the ongoing phase 3 LEAP-012 study (NCT04246177). Clinical trial information: NCT03713593 .

Hepatic arterial infusion therapy for advanced hepatocellular carcinoma after systemic treatment failure: Multicenter, real-world study.

The study was conducted to evaluate the feasibility and safety profile of hepatic arterial infusion chemotherapy with oxaliplatin, 5-fluorouracil, and leucovorin (HAIC-FOLFOX) as an alternative therapeutic choice for patients with advanced hepatocellular carcinoma (HCC) that is refractory to systemic treatment including immune checkpoint blockades or molecular targeting agents. Two hundred and forty five consecutive patients with advanced HCC who received HAIC-FOLFOX treatment after systemic treatment failure were retrospectively reviewed in six institutions and their survival, tumor response, and tolerance were assessed. The median overall survival (OS) and progression-free survival of the 209 included participants were 10.5months (95% confidence interval [CI], 8.1-12.9) and 6.0months (95% CI, 5.1-6.9), respectively. According to Response Evaluation Criteria in Solid Tumors 1.1 criteria, the objective response rate was 21.1%, and the disease control rate was 64.6%. Multivariate analysis of risk factors of OS were albumin-bilirubin grade (2 and 3 vs. 1, hazard ratio [HR] 1.57; 95% CI, 1.05-2.34; p=0.028), tumor number (>3 vs. 1-3, HR 2.18; 95% CI, 1.10-4.34; p=0.026), extrahepatic spread (present vs. absent, HR 1.61, 95% CI, 1.06-2.45; p=0.027), synchronous systemic treatment (present vs. absent, HR 0.55, 95% CI, 0.37-0.83; p=0.004) and treatment response (responder vs. nonresponder, HR 0.30, 95% CI, 0.17-0.53; p<0.001). Grade 3-4 adverse events (AEs) occurred in 59 (28.2%) HCC patients. All AEs were manageable, and deaths related to hepatic artery infusion chemotherapy treatment were not observed. Our findings support the effectiveness and safety of HAIC-FOLFOX treatment for patients with advanced HCC who have failed systemic treatment.

First-Line Treatment for Advanced Hepatocellular Carcinoma: A Three-Armed Real-World Comparison.

There are several existing systemic 1st- line therapies for advanced hepatocellular carcinoma (HCC), including atezolizumab/bevacizumab (Atez/Bev), sorafenib and lenvatinib. This study aims to compare the effectiveness of these three 1st-line systemic treatments in a real-world setting for HCC, focusing on specific patient subgroups analysis. A total of 177 patients with advanced HCC treated with Atez/Bev (n = 38), lenvatinib (n = 21) or sorafenib (n = 118) as 1st line systemic therapy were retrospectively analyzed and compared. Primary endpoints included objective response rate (ORR), progression-free survival (PFS) and 15-month overall survival (15-mo OS). Subgroups regarding liver function, etiology, previous therapy and toxicity were analyzed. Atez/Bev demonstrated significantly longer median 15-month OS with 15.03 months compared to sorafenib with 9.43 months (p = 0.04) and lenvatinib with 8.93 months (p = 0.05). Similarly, it had highest ORR of 31.6% and longest median PFS with 7.97 months, independent of etiology. However, significantly superiority was observed only compared to sorafenib (ORR: 4.2% (p < 0.001); PFS: 4.57 months (p = 0.03)), but not comparing to lenvatinib (ORR: 28.6% (p = 0.87); PFS: 3.77 months (p = 0.10)). Atez/Bev also resulted in the longest PFS in patients with Child-Pugh A and ALBI 1 score and interestingly in those previously treated with SIRT. Contrary, sorafenib was non inferior in patients with impaired liver function. Atez/Bev achieved longest median PFS and 15-mo OS independent of etiology and particularly in patients with stable liver function or prior SIRT treatment. Regarding therapy response lenvatinib was non-inferior to Atez/Bev. Finally, sorafenib seemed to perform best for patients with deteriorated liver function.

Phase I/II trial of BMS-986,205 and nivolumab as first line therapy in hepatocellular carcinoma

BackgroundIndoleamine-2,3-dioxygenase (IDO) helps orchestrate immune suppression and checkpoint inhibitor resistance in hepatocellular carcinoma (HCC). BMS-986,205 is a novel oral drug that potently and selectively inhibits IDO. This Phase I/II study evaluated the safety and tolerability of BMS-986,205 in combination with nivolumab as first-line therapy in advanced HCC.MethodsAdults with untreated, unresectable/metastatic HCC received BMS-986,205 at two dose levels (50–100 mg orally daily) in combination with fixed dose nivolumab (240mg/m2 IV on Day 1 of each 14-day cycle). The primary objective was to determine the safety and tolerability of this combination; secondary objectives were to obtain preliminary efficacy.ResultsEight patients received a total of 91 treatment cycles in the dose escalation phase. All patients were Child Pugh A and 6 patients had underlying viral hepatitis. In the 6 evaluable patients, no dose-limiting toxicities (DLTs) were observed. The most common treatment-related adverse events (TRAEs) were aspartate transaminase (AST) and alanine transaminase (ALT) elevation (3 patients) and diarrhea, maculopapular rash and increased alkaline phosphatase (2 patients each). Grade 3 events were diarrhea and AST elevation (1 patient), and hyperglycemia and pancreatitis requiring treatment discontinuation (1 patient). No grade 4–5 events occurred. Partial response was observed in 1 patient (12.5%) and stable disease in 3 patients (37.5%), yielding a disease control rate of 50%. Median PFS was 8.5 weeks; median OS was not reached.ConclusionCombination BMS-986,205 and nivolumab showed a manageable safety profile with durable benefit as first-line therapy in a meaningful subset of advanced HCC patients.