Advanced Unresectable Hepatocellular Carcinoma Research Articles

Expanded biomarker analysis of an international, open-label phase 2 study of regorafenib plus pembrolizumab in patients with advanced hepatocellular carcinoma (HCC) previously treated with immune checkpoint inhibitors (ICI).

635 Background: The optimal treatment for patients (pts) with advanced HCC who progress on an ICI-containing regimen has not been defined. In pts who progressed on one prior ICI regimen, regorafenib plus pembrolizumab (rego + pembro) showed modest anti-tumor activity (primary completion analysis: overall objective response rate 7.4%, all partial responses [PR]) and an expected safety profile (NCT04696055; El-Khoueiry, ASCO 2024). We conducted additional exploratory analyses of tumor markers to gain insights into the clinical results. Methods: Overall, 95 adults with unresectable advanced HCC (C-P Class A, BCLC stage B/C, ECOG PS 0/1) received oral regorafenib 90 mg once daily 3 weeks on/1 week off plus pembrolizumab 400 mg i.v. every 6 weeks. Prior treatment: Cohort 1 = atezolizumab + bevacizumab (n=68); Cohort 2 = any other ICI alone or in combination (n=27). Biomarker analyses in subsets of pts explored potential correlations with clinical benefit (defined as tumor response or stable disease [SD] ≥ 4 months). Immune cell subtypes in blood were analyzed by flow cytometry. Tumor immune markers were assessed by immunohistochemistry. Gene expression profiling in tumor samples was by RNAseq. Results: Twenty-one pts had baseline samples for RNAseq, 7 of whom had clinical benefit (n= 3 Cohort 1 [including 1 PR], n=4 Cohort 2). Pts with clinical benefit had differential gene expression at baseline including enriched expression of genes associated with Notch, Hedgehog, fibroblast, TGF-β, and insulin-like growth factor binding protein signaling; in contrast, there was higher expression of genes associated with myeloid derived suppressor cells in pts without clinical benefit. Of note, tumor samples from pts in this study had increased Tregs and T-cell exhaustion signatures compared with pts treated with rego + pembro in a first-line study (NCT03347292).Analyses of available paired tumor samples from 4 patients (n=2 SD, n=2 progressive disease) found reductions in activated fibroblast, TGF-β, and collagen gene expression signatures from baseline to Week 6 Day 1 of treatment. Conclusions: Rego + pembro had modest activity in pts who progressed on one prior ICI-based regimen. Exploratory biomarker analyses suggest different gene expression in pts with or without clinical benefit. Clinical benefit was associated with enriched expression of genes in Notch, Hedgehog, fibroblast, and TGF-β pathways. Pre- and post-treatment biopsies showed reductions in fibroblast, TGF-β, and collagen gene expression, which are known features of HCC. In the context of the limitations of small sample size and absence of a control arm, these findings are hypothesis generating and consistent with HCC biology and regorafenib mechanism of action. Clinical trial information: NCT04696055 .

A multicenter, open-label study investigating RP2 oncolytic immunotherapy in combination with second-line systemic atezolizumab plus bevacizumab in patients with locally advanced unresectable or metastatic hepatocellular carcinoma (HCC).

TPS649 Background: Despite advances in unresectable HCC treatment, long-term survival rates remain poor. The combination of atezolizumab (Atezo) plus bevacizumab (Bev) is approved as frontline therapy for advanced HCC, but only a minority of patients (pts) respond, and secondary resistance usually occurs within months. HCC has an immune-suppressed tumor microenvironment (TME) mediated by the expression of immune checkpoint signals and angiogenesis pathways, which may contribute to therapeutic resistance. RP2 is an enhanced potency oncolytic herpes simplex virus type 1 (HSV-1) that expresses GM-CSF, a fusogenic glycoprotein (GALV-GP-R–), and an anti–CTLA-4 antibody-like molecule. RP2 showed preliminary clinical activity alone or combined with anti–PD-1 in a phase 1 study in pts with advanced solid tumors. The direct oncolytic effect coupled with immune stimulation by RP2 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 when administered with Bev, supporting the clinical combination of RP2 with Bev. This study will evaluate the safety and efficacy of RP2 combined with Atezo plus Bev as second-line systemic therapy for unresectable advanced HCC (NCT05733598). Methods: This is an open-label, single arm, phase 2 trial. Up to 30 pts will be enrolled and receive RP2 in combination with Atezo plus Bev. Key inclusion criteria include advanced unresectable HCC with ≥1 measurable tumor of ≥1 cm in longest diameter, Child-Pugh class A, an Eastern Cooperative Oncology Group performance status of 0 to 1, and progression on 1 prior systemic treatment, which must have included a PD-1/PD-L1–directed agent. Key exclusion criteria include untreated/incompletely treated 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 will receive intratumoral RP2 Q2W for 4 doses, then Q3W for up to 4 doses. Bev will be given at 10 mg/kg Q2W starting with the first dose of RP2, then at 15 mg/kg Q3W starting with cycle 4; Atezo will be given at 840 mg Q2W for cycles 2 and 3, then at 1200 mg Q3W starting with cycle 4. Pts will receive treatment until confirmed progressive disease, loss of clinical benefit, or unacceptable toxicity. The primary endpoint is overall response rate (ORR), defined as the proportion of pts achieving a best overall response of complete response or partial response per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 as modified for this study. Secondary endpoints include safety, ORR using HCC-modified RECIST, duration of response, complete response rate, and progression-free survival. Clinical trial information: NCT05733598 .

Real-world experience with atezolizumab plus bevacizumab (A+/-B) in Hispanic patients with advanced hepatocellular carcinoma (HCC) at a Hispanic-majority cancer center.

549 Background: Combination of atezolizumab (A), a programmed death-ligand 1 (PD-L1) inhibitor, and bevacizumab (B), a vascular endothelial growth factor (VEGF) inhibitor, has demonstrated efficacy for first-line treatment for HCC. However, real-world data on the outcomes of this combination therapy in diverse patient populations, particularly in Hispanic U.S. patients, remains limited. This study aims to evaluate the clinical outcomes of patients intended to treat with A+/-B at a Hispanic-majority U.S. cancer center. Methods: This retrospective study of patients diagnosed with advanced unresectable HCC who received treatment with A+B at a Hispanic-serving NCI-designated cancer center. Patients were included if they received at least one dose of A, either as monotherapy or in combination with B, between January 2019 and April 2022. Demographic and clinical data, including age, gender, ethnicity, liver disease etiology, Child-Pugh (CP) classification, comorbidities, and treatment details, were collected. The primary endpoints were the overall response rate (ORR) and complete response (CR) rate. Statistical analyses were conducted to evaluate the association between baseline characteristics and clinical outcomes. The median overall survival (mOS) evaluated by Kaplan-Meier Method. Results: 38 patients received at least A (84% A+B, 6 patients had B held due to bleeding risk after consent). Median age 65 years (45-90). 32 (84%) patients were male. 22 (58%) patients were Hispanic. 45% had HCV-related liver disease. 32% had CP B with no statistically significant association between CP Class and ethnicity. 53% had concurrent diabetes. 26% patients had obesity. The median time on treatment was 7.5 mo (1- 24 mo) with no statistical difference between Hispanics and non-Hispanics (9 vs 6 mo, p 0.70). CR 37% with ORR of 42%. Using Fisher’s exact test, no association was noted between obesity, ethnicity, treatment option or CP class to occurrence of complete or partial response. mOS was 19 mo. There was no statistical difference in mOS between CP A and CP B (19 vs 10 mo, p value 0.6) and no difference between Hispanics (14 mo) vs non-Hispanics (19 mo) (p 0.5), using log rank test. Conclusions: This real-world analysis of a Hispanic-majority U.S. cohort of patients with advanced HCC shows 42% ORR and 37% CR. The findings suggest that this regimen is effective across a diverse patient population, including those with comorbid conditions, such as liver dysfunction (CP B 32%), HCV (45%), diabetes (53%, and obesity (26%). Limitations are the small study population and retrospective nature of the study. Evaluation of toxicity data is ongoing. Further prospective studies are needed to identify biomarkers of outcomes in Hispanic patients with HCC, which is ongoing at our cancer center (NCT03894917).

Current status of physicians’ perception of HCC conversion/downstaging therapy: A nationwide survey in China.

585 Background: Conversion or downstaging therapy for intermediate and advanced unresectable hepatocellular carcinoma (HCC) has emerged as a significant exploring area of clinical practice and research in recent years. Nonetheless, there exists considerable variability in both the selection criteria for patients undergoing conversion therapy and the regimens selected for conversion across different regions and medical institutions. The present study aims to elucidate the current clinical application of conversion therapy in China, as well as to identify the considerations that physicians take into account when selecting eligible patients for conversion therapy and determining the appropriate conversion modality. Methods: Physicians meeting predefined inclusion criteria were invited to complete an online questionnaire from January to July, 2024. The collected data were subsequently pooled and analyzed descriptively. Results: A total of 120 valid questionnaires were retrieved, mainly form surgical (69.2%, n=83) and interventional (30.8%, n=37) departments. Generally, the study showed that approximately 51% of stage Ib-IIIa patients will be selected for the treatment goal of conversion or downstaging, and the overall successful rate as meeting criteria for surgical resection after treatment was 36%. Three primary factors were prioritized by physicians for determination of conversion therapy: the type of portal vein tumor thrombus (PVTT) (97%, 116/120), the future liver volume (90%, 108/120), and Child-Pugh classification (90%,108/120). In the specific physician group who selected the following attributes, patients classified as Child-Pugh A (82%, 89/108) or Child-Pugh B7 (66%, 71/108), those with tumor diameter exceeding 5 cm (92%, 98/106) and Eastern Cooperative Oncology Group (ECOG) performance score of 0 to 1 (89%, 76/85) were most frequently selected for conversion therapy. Additionally, study showed that patients presenting with Vp1-2 (72%, 83/116) and Vp3 (71%, 82/116) could also be considered for conversion therapy. Currently, the prevalent treatment approach of conversion therapy involves a combination of local and systemic therapies, which is utilized in approximately 73% of cases. Among systemic treatment methodologies, the combination of Lenvatinib and immunotherapy is the most widely adopted by physicians. Besides, higher ORR was the foremost consideration for 83% (99/120) of physicians, followed by rapid response (68%, 82/120), adherence to guidelines and consensus (63%, 76/120), and lower tumor progression rate (58%, 70/120). Conclusions: This study elucidates the current status of conversion therapy for HCC in China. The findings underscore the necessity for optimizing conversion modalities and advancing standardized practices in the application of conversion therapy.

Transarterial Chemoembolization With or Without Systemic Therapy for Unresectable Hepatocellular Carcinoma: A Retrospective Comparative Study.

Standard treatments provide limited benefits for patients with intermediate- or advanced-stage hepatocellular carcinoma (HCC). This retrospective observational study aimed to assess the potential improvements in outcomes associated with systemic therapies in patients receiving transarterial chemoembolization (TACE) for initially unresectable HCC. Between February 2019 and March 2023, we reviewed patients diagnosed with intermediate-to-advanced HCC who were treated with either TACE or TACE combined with antiangiogenic agents and immune checkpoint inhibitors (combination therapy) as their initial treatment. To address potential confounding biases, patients were further stratified into surgical and non-surgical cohorts, and separate analyses were conducted. The primary endpoints were progression-free survival (PFS) and overall survival (OS), with safety profiles also evaluated. Among 279 patients with initially unresectable intermediate or advanced HCC, 156 successfully underwent curative-intent liver resection after preoperative treatments (TACE group, n = 69; combination group, n = 87), while 123 patients continued with non-surgical treatments (TACE group, n = 31; combination group, n = 92). After propensity score matching, 26 matched patient pairs were generated within the non-surgical cohort. The combination group exhibited significantly improved PFS in non-surgical patients compared with the TACE group (9.4 vs. 7.2 months, p = 0.043). Cox proportional hazards analysis further confirmed that combination therapy was associated with improved PFS (hazard ratio = 0.476, 95% confidence interval: 0.257-0.883, p = 0.019). For surgical patients exceeding the up-to-seven criteria, the combination group demonstrated superior median PFS (18.0 vs. 14.6 months, p = 0.03) and OS (not reached vs. 50.1 months, p = 0.049) compared with the TACE group. Adverse events were manageable, with no treatment-related fatalities reported. Combination therapy with TACE demonstrated enhanced survival benefits for patients with intermediate to advanced HCC, particularly in surgical patients with higher tumor burdens.

Tiragolumab in combination with atezolizumab and bevacizumab in patients with unresectable, locally advanced or metastatic hepatocellular carcinoma (MORPHEUS-Liver): a randomised, open-label, phase 1b-2, study.

PD-L1 and VEGF blockade with atezolizumab plus bevacizumab has been shown to improve survival in unresectable hepatocellular carcinoma. TIGIT is an immune checkpoint regulator implicated in many cancers, including unresectable hepatocellular carcinoma. Here, we evaluate the clinical activity and safety of the addition of tiragolumab, an anti-TIGIT monoclonal antibody, to atezolizumab plus bevacizumab. This randomised, open-label, phase 1b-2 umbrella study was conducted at 26 centres across China, France, Israel, New Zealand, South Korea, Taiwan, and the USA. Eligible patients were adults aged 18 years old or older with previously untreated locally advanced unresectable hepatocellular carcinoma, an Eastern Cooperative Oncology Group performance status of 0-1, Child-Pugh class A disease, and a life expectancy of at least 3 months. Eligible patients were randomly assigned (2:1) using permuted block randomisation to receive either tiragolumab 600 mg plus atezolizumab 1200 mg plus bevacizumab 15 mg/kg or atezolizumab 1200 mg plus bevacizumab 15 mg/kg, administered via intravenous infusion every 3 weeks on day 1 of each 21-day cycle. Patients received treatment until unacceptable toxic effects or loss of clinical benefit, whichever occurred first. The primary endpoint was objective response rate. Analysis of clinical activity was done in the efficacy-evaluable population (all patients who received at least one dose of each drug for their assigned treatment regimen) and safety was assessed in all patients who received any study treatment. The trial is registered with ClinicalTrials.gov, NCT04524871, and is ongoing. Between Aug 20, 2020, and Feb 10, 2022, we assessed 154 patients for eligibility and 59 eligible patients were randomly assigned to receive tiragolumab plus atezolizumab plus bevacizumab (n=41) or atezolizumab plus bevacizumab (n=18); one patient in the tiragolumab plus atezolizumab plus bevacizumab group experienced an adverse event before receiving any treatment and withdrew from the study. Median age was 65·0 years (IQR 61·0-73·0). 46 (79%) of 58 patients were male and 12 (21%) were female. Most patients were Asian (23 [40%]) or White (21 [36%]). At the time of clinical cutoff (Aug 21, 2023), median follow-up was 20·6 months (IQR 10·6-28·0) in the tiragolumab plus atezolizumab plus bevacizumab group and 14·0 months (4·2-18·5) in the atezolizumab plus bevacizumab group. The confirmed objective response rate was 43% (95% CI 27-59, n=17) in the tiragolumab plus atezolizumab plus bevacizumab group and 11% (1-35, n=2) in the atezolizumab plus bevacizumab group. All patients in both groups experienced an adverse event. The incidence of pruritis (20 [50%] of 40 patients vs three [17%] of 18 patients), arthralgia (13 [33%] vs two [11%]), and diarrhoea (12 [30%] vs one [6%]) was notably higher in the tiragolumab plus atezolizumab plus bevacizumab group than in the atezolizumab plus bevacizumab group, although these were mainly grade 1-2. The most common grade 3-4 adverse events were hypertension (six [15%] of 40 patients in the tiragolumab plus atezolizumab plus bevacizumab group vs two [11%] of 18 patients in the atezolizumab plus bevacizumab group), aspartate aminotransferase increased (three [8%] of 40 patients vs one [6%] of 18 patients), and proteinuria (two [5%] of 40 patients vs two [11%] of 18 patients). Serious adverse events occurred in 21 (53%) of 40 patients in the tiragolumab plus atezolizumab plus bevacizumab group and in ten (56%) of 18 patients in the atezolizumab plus bevacizumab group. Treatment-related deaths occurred in one patient in the tiragolumab plus atezolizumab plus bevacizumab group (due to cholestasis) and two patients in the atezolizumab plus bevacizumab group (due to oesophageal varices haemorrhage and upper gastrointestinal haemorrhage). The addition of tiragolumab to atezolizumab plus bevacizumab did not appear to result in a substantial worsening of treatment-related or immune-mediated adverse events, and no new safety signals were identified. This signal-seeking study suggests that the addition of tiragolumab to atezolizumab and bevacizumab might be more clinically active than atezolizumab plus bevacizumab alone in unresectable hepatocellular carcinoma. Based on these data, further study of combination tiragolumab plus atezolizumab plus bevacizumab is warranted. F Hoffmann-La Roche and Genentech.

A real-world drug safety surveillance study from the FAERS database of hepatocellular carcinoma patients receiving pembrolizumab alone and plus lenvatinib

Pembrolizumab plus Lenvatinib is regarded as a significant treatment option for advanced unresectable hepatocellular carcinoma (HCC). This study aims to meticulously monitor and identify adverse events (AEs) related to this combined therapy, enhance patient safety, and offer evidence-based recommendations for the appropriate use of these drugs. We gathered adverse drug reactions (ADRs)-related data from the FAERS database for HCC patients who received Pembrolizumab, both alone and in combination with Lenvatinib from the first quarter of 2014 to the fourth quarter of 2023. ADRs signal detection was performed using the ROR, PRR, BCPNN, MHRA, and MGPS methods. We gathered data on 459 and 358 AEs from patients with HCC treated with pembrolizumab alone and in combination with lenvatinib, respectively. Using four signal quantification techniques, we identified 50 and 38 distinct AEs, which were classified into 15 different System organ class (SOC) categories. Notably, the most common AEs associated with pembrolizumab were gastrointestinal disorders and hepatobiliary disorders. In both patient groups, the most frequently reported AEs were hepatic encephalopathy, blood bilirubin increased and diarrhea. We also observed some unexpected significant AEs, such as dehydration, skin ulcers, and intestinal perforation. The countries reporting the highest number of AEs were the United States, followed by China, France, and Japan. The median onset time for AEs related to pembrolizumab alone and its combination with lenvatinib was 80.5 days (interquartile range 20.0–217.3 days) and 77.5 days (interquartile range 19.7–212.3 days), respectively. This study offers new insights into the monitoring and management of ADRs in HCC patients receiving pembrolizumab alone or in combination with lenvatinib. It is crucial to closely monitor the safety of this treatment regimen in HCC patients to avoid serious AEs.

ASO Author Reflections: The Role of Salvage Surgery in Multidisciplinary Treatment for Unresectable Advanced Hepatocellular Carcinoma.

ASO Author Reflections: The Role of Salvage Surgery in Multidisciplinary Treatment for Unresectable Advanced Hepatocellular Carcinoma.

Disulfiram/Cu targeting FOXO6 modulates sensitivity of hepatocellular carcinoma to lenvatinib via disrupt choline metabolic.

Disulfiram/Cu(DSF/Cu) has a known pharmacokinetic and safety profile, exerting a strong antitumor effect. Oral tyrosine kinase inhibitors including lenvatinib are approved as first-line therapy for treating advanced unresectable hepatocellular carcinoma (HCC). These patients still have limited survival due to drug resistance. Disulfiram/Cu and lenvatinib are the promising antitumor treatments. In this study, we studied whether Disulfiram/Cu increased lenvatinib sensitivity in HCC cells. Moreover, the potential drug targets of Disulfiram/Cu and associated mechanisms were explored. We mainly investigated Autophagic flux was determined via immunofluorescence analysis and confocal microscopy. p-PI3K, p-AKT, p62, LC3B, FOXO6, and CHKA proteins associated with autophagy were detected by immunoblotting. In addition, antitumour activity of Disulfiram/Cu in combination with lenvatinib was examined in vivo through construction of the nude mouse transplant tumor model. Furthermore, our results show disulfiram/Cu combined with lenvatinib exerted the synergistic impact on treating HCC in vitro. Mechanistically, transcriptome combined with metabolome reveals Disulfiram/Cu targeting FOXO6 induction of autophagy mediated inhibits cell growth in hepatocellular carcinoma by downregulating CHKα for inhibiting AKT pathway activation while blocking choline metabolic reprogramming in HCC. These effects mostly explain the tumor-promoting effect of FOXO6 on HCC. In general, the results illustrate the mechanistic associations between metabolites and tumor cell malignant phenotype, contributing to developing new anti-HCC pharmacological treatments by Inhibiting FOXO6 for disrupting choline metabolic pathway.

A Novel Combinatorial Regimen Using Sorafenib and Uttroside B, A US FDA-designated 'Orphan Drug', for the Treatment of Hepatocellular Carcinoma.

Sorafenib (Sor) is the first-line treatment option in clinics for treating advanced unresectable hepatocellular carcinoma (HCC). However, acquired chemoresistance and adverse side effects associated with Sor monotherapy limit its clinical benefits. We have previously reported the exceptional anti-HCC potential of uttroside B (Utt-B), a furostanol saponin isolated in our lab from Solanum nigrum Linn. leaves. The current study has evaluated the supremacy of a combinatorial regimen of Sor and Utt-B over Sor monotherapy. MTT assay was used for In vitro cytotoxicity studies. A clonogenic assay was conducted to assess the anti-proliferative effect of the combination. Annexin V/PI staining, confocal microscopy, FACS cell cycle analysis, and Western blotting experiments were performed to validate the pro-apoptotic potential of the combination in HepG2 and Huh7 cell lines. Pharmacological safety evaluation was performed in Swiss albino mice. Our results indicate that Utt-B augments Sor-induced cytotoxicity in HepG2 and Huh7 cells. The combination inhibits the proliferation of liver cancer cells by inducing apoptosis through activation of the caspases 7 and 3, leading to PARP cleavage. Furthermore, the combination does not induce any acute toxicity in vivo, even at a dose five times that of the effective therapeutic dose. Our results highlight the potential of Utt-B as an effective chemosensitizer, which can augment the efficacy of Sor against HCC and circumvent Sor-induced toxic side effects. Moreover, this is the first and only report to date on the chemosensitizing potential of Utt-B and the only report that demonstrates the therapeutic efficacy and pharmacological safety of a novel combinatorial regimen involving Utt-B and Sor for combating HCC.

Mitochondria-Targeted Icaritin Nanoparticles Induce Immunogenic Cell Death in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a highly malignant tumor that is resistant to chemotherapy and immunotherapy. Icaritin (ICT), a traditional Chinese medicine, has been reported as an immunoregulatory agent for treating advanced unresectable HCC. ICT induces mitophagy to cause immunogenic cell death (ICD); however, the poor bioavailability of ICT limits its therapeutic efficacy and clinical use. Therefore, this study aimed to assess the effect of using the poly(2-(N-oxide-N,N-diethylamino) ethyl methacrylate)-b-poly(ε-caprolactone) copolymer (OPDEA-PCL) to encapsulate ICT into nanoparticles (ICT NPs). OPDEA-PCL/ICT NPs colocalized with the mitochondria, promoting the ICD induction effect of ICT in mouse HCC H22 cells. In the H22 subcutaneous tumor model, intravenously injected OPDEA-PCL/ICT NPs quickly accumulated in the tumor and efficiently activated systemic anticancer immunogenicity through their effects on mitophagy. The resulting tumor suppression rate was 60%, which was significantly higher than that of free ICT and poly(ethylene glycol) (PEG)-PCL/ICT NPs. Furthermore, mouse survival was also prolonged by nearly 2-fold with OPDEA-PCL/ICT NPs compared with PBS. In summary, this approach provides valuable insights into improving the immunotherapeutic efficacy of ICT for HCC.

Tislelizumab: a promising alternative first-line systemic therapy in unresectable advanced hepatocellular carcinoma

Tislelizumab: a promising alternative first-line systemic therapy in unresectable advanced hepatocellular carcinoma

The impact of lenvatinib on sarcopenia in patients with advanced unresectable hepatocellular carcinoma.

Lenvatinib is a multiple receptor tyrosine kinase inhibitor (TKI) approved for first-line treatment of patients with unresectable hepatocellular carcinoma (HCC). TKI are suspected of exacerbating muscle loss in patients with cancer. In this study, we analyze the role of muscle loss in patients with advanced HCC treated with lenvatinib. This is a retrospective analysis of a real-life cohort of 25 patients with advanced HCC who were treated with lenvatinib from 2018 to March 2021 in Germany. Patients were stratified for loss of skeletal muscle area during the first three months of lenvatinib therapy. Overall survival (OS), progression-free survival (PFS) and toxicity were analyzed for all patients, especially regarding loss of muscle before and during the first three months of therapy with lenvatinib. Three months after beginning of therapy with lenvatinib, a significant reduction of muscle mass was observed in 60% of patients (p = 0.035). Despite increase of loss of skeletal muscle, patients benefitted from lenvatinib in our cohort of patients in terms of OS and PFS and did not experience increased toxicity. Furthermore, muscle loss was not a negative predictor of survival in the univariate analysis (p = 0.675). Patients with advanced hepatocellular carcinoma experience muscle loss with lenvatinib therapy. However, despite progressive muscle loss, patients benefit from a therapy with lenvatinib in terms of OS and PFS without increased toxicity. However, assessment and prophylaxis of skeletal muscle status should be recommended during a therapy with lenvatinib.

Complete Response to Locoregional Therapy Plus Immunotherapy for Hepatocellular Carcinoma

Previous studies showed that 42% to 50% of patients with locally advanced hepatocellular carcinoma (HCC) achieved complete remission (CR) after combined locoregional therapy (LRT) plus immunotherapy (IO). However, data on predictors of CR and long-term clinical outcomes without surgery and after discontinuation of IO are lacking. To assess the long-term clinical outcomes among patients with unresectable HCC who achieved CR after LRT-IO and were placed on a watch-and-wait protocol. This cohort study included patients with unresectable HCC who achieved CR after LRT-IO in 2 prospective studies between January 2018 and December 2022. The time of data cutoff was June 2023. Radiologic CR was defined per modified Response Evaluation Criteria in Solid Tumors. All patients underwent close surveillance after CR without surgical interventions, and IO was discontinued. All patients had received stereotactic body radiotherapy followed by anti-programmed cell death protein 1 or anti-programmed death ligand 1 therapy. Forty-nine patients had received a dose of transarterial chemoembolization before stereotactic body radiotherapy. The primary outcome was the 3-year overall survival (OS) rate. Secondary outcomes included the 3-year time-to-progression rate, 3-year local control rate, and relapse pattern. Factors associated with CR were analyzed using multivariate analyses. A total of 63 patients were enrolled (58 male [92.1%]; median age, 69 years [range, 18-90 years]); 38 patients (60.3%) had macrovascular invasion, and the median tumor diameter was 10 cm (range, 3.8-31.1 cm). The median follow-up time was 34.7 months (95% CI, 6.5-64.6 months). Twenty-nine patients (46.0%) achieved CR. The patients achieving CR had a significantly better 3-year OS rate than patients not achieving CR (75.5% [95% CI, 58.2%-98.3%] vs 28.1% [95% CI, 7.4%-29.4%]; P < .001). Among the 29 patients with CR, the 3-year time-to-progression rate was 58.7% (95% CI, 38.7%-79.1%) and the 3-year local control rate was 90.5% (95% CI, 78.2%-100%). Ten patients (34.5%) developed recurrence; among them, 6 (60.0%) with solitary intrahepatic disease relapse underwent curative surgical treatment. The absence of tumor vascular invasion (odds ratio, 0.30; 95% CI, 0.10-0.89) and the sum of the largest lesion diameters of 8 cm or less (odds ratio, 0.26; 95% CI, 0.07-0.98) were associated with CR. This cohort study of LRT-IO with long-term follow-up data found a durable response in patients with locally advanced unresectable HCC. Long-term survival was attainable in patients with radiologic CR. Further randomized clinical trials are warranted.

986P Fostrox (fostroxacitabine bralpamide) plus lenvatinib in patients with locally advanced unresectable or metastatic hepatocellular carcinoma (HCC) progressed on immunotherapy combinations: Results from a multi-center phase Ib/IIa study

986P Fostrox (fostroxacitabine bralpamide) plus lenvatinib in patients with locally advanced unresectable or metastatic hepatocellular carcinoma (HCC) progressed on immunotherapy combinations: Results from a multi-center phase Ib/IIa study

Efficacy of Combination Therapy of Lenvatinib and New FP for the Treatment of Unresectable Advanced Hepatocellular Carcinoma: A Case Report

Efficacy of Combination Therapy of Lenvatinib and New FP for the Treatment of Unresectable Advanced Hepatocellular Carcinoma: A Case Report

CVM-1118: An oral anti-vasculogenic mimicry (VM) agent in combination with nivolumab in patients with unresectable advanced hepatocellular carcinoma (HCC)—A phase IIa study.

92 Background: CVM-1118 is a potent anti-tumor new chemical entity with multiple mechanisms of action including induction of apoptosis, cell cycle arrest, and inhibition of VM network formation. This study evaluated the anti-tumor effect and safety profile of CVM-1118 plus nivolumab in patients with progressive unresectable advanced HCC following the first-line therapy with TKIs. Methods: Eligible pts had unresectable advanced HCC and were refractory to prior systemic therapy (e.g., sorafenib, lenvatinib, regorafenib, and/or ramucirumab), with the exception of prior immunotherapy. Patients received oral CVM-1118 at 200 mg BID (400 mg daily) in combination with intravenous nivolumab at 240 mg Q2W in 28-day cycles. The primary endpoint of objective response rate was evaluated using mRECIST. The secondary endpoints were overall response rate (ORR) (per RECIST 1.1), progression free survival (PFS), disease control rate (DCR), and duration of overall response (DoR). Results: A total of 31 evaluable pts were enrolled (25 M/6 F; median age 65 y, range 44–80 y). All patients were Child Pugh A, BCLC stage B (13%, n=4) or C (87%, n=27) at the start of treatment. The median number of prior lines of therapy was 1 (range 1–2). The duration of CVM-1118 and nivolumab treatment ranged from 1.5–17.7 mos (median 3.1 mos) with 5/31 (16%) pts remaining on treatment for ≥ 5.2 mos (range 5.2–17.7 mos). The best ORR was 19.4% (mRECIST) (2 CR (6%), 4 PR (13%)), with remaining responses including 11 SD (36%) and 14 PD (45%). The DCR was 54.8% (95% CI 37.3–72.3%), the median PFS was 3.53 mos (95% CI 1.9–5.4 mos) and the median DoR was 12.1 mos (95% CI 5.2–16.1 mos). The most common treatment-related AEs ³ grade 3 included AST increased (12.9%), neutrophil count decreased (9.7%), anemia (6.5%), and WBC decreased (6.5%). As opposed to therapy with atezolizumab plus bevacizumab, gastrointestinal hemorrhage and hypertension were not observed in this study. Pharmacokinetics data demonstrated that CVM-1118 was rapidly metabolized to CVM-1125 in all pts following administration. On Day 1, the mean drug exposure of CVM-1125 was Cmax 564 ng/mL and the AUC0-24 was 2154 ng·hr/mL. Intersubject variability of drug exposure appeared to be high; the T1/2 of CVM-1125 was ~1.7 hr. Conclusions: CVM-1118 combined with nivolumab demonstrated clinical activity in advanced HCC pts with a safety profile that appears favorable compared to atezolizumab plus bevacizumab. These data support further development of the combination of CVM-1118 and nivolumab in pts with unresectable advanced HCC. Clinical trial information: NCT05257590 .

The current status and future of targeted-immune combination for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common cancers and the third leading cause of death worldwide. surgery, transarterial chemoembolization (TACE), systemic therapy, local ablation therapy, radiotherapy, and targeted drug therapy with agents such as sorafenib. However, the tumor microenvironment of liver cancer has a strong immunosuppressive effect. Therefore, new treatments for liver cancer are still necessary. Immune checkpoint molecules, such as programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T lymphocyte antigen-4 (CTLA-4), along with high levels of immunosuppressive cytokines, induce T cell inhibition and are key mechanisms of immune escape in HCC. Recently, immunotherapy based on immune checkpoint inhibitors (ICIs) as monotherapy or in combination with tyrosine kinase inhibitors, anti-angiogenesis drugs, chemotherapy agents, and topical therapies has offered great promise in the treatment of liver cancer. In this review, we discuss the latest advances in ICIs combined with targeted drugs (targeted-immune combination) and other targeted-immune combination regimens for the treatment of patients with advanced HCC (aHCC) or unresectable HCC (uHCC), and provide an outlook on future prospects. The literature reviewed spans the last five years and includes studies identified using keywords such as "hepatocellular carcinoma," "immune checkpoint inhibitors," "targeted therapy," "combination therapy," and "immunotherapy".

Validation of a Machine Learning Algorithm, EVendo, for Predicting Esophageal Varices in Hepatocellular Carcinoma

BackgroundTreatment with atezolizumab and bevacizumab has become standard of care for advanced unresectable hepatocellular carcinoma (HCC) but carries an increased gastrointestinal bleeding risk. Therefore, patients are often required to undergo esophagogastroduodenoscopy (EGD) to rule out esophageal varices (EV) prior to initiating therapy, which can delay care and lead to unnecessary procedural risks and health care costs. In 2019, the EVendo score was created and validated as a noninvasive tool to accurately screen out patients who were at low risk for having EV that required treatment. We sought to validate whether the EVendo score could be used to accurately predict the presence of EV and varices needing treatment (VNT) in patients with HCC.MethodsThis was a retrospective multicenter cohort study of patients with HCC from 9/2004 to 12/2021. We included patients who underwent EGDs within 1 year after their HCC diagnosis. We collected clinical parameters needed to calculate an EVendo score at the time of EGD and compared the EVendo model prediction to the gold standard endoscopic report in predicting presence of VNT.Results112 with HCC were recruited to this study, with 117 qualifying EGDs. VNT occurred in 39 (33.3%) patients. The EVendo score had a sensitivity of 97.4% and a negative predictive value of 96.9%, supporting the validity in applying EVendo in predicting VNT in HCC.ConclusionIn this study, we validated the use of the EVendo score in ruling out VNT in patients with HCC. The application of the EVendo score could safely defer about 30% of EGDs for EV screening in HCC patients. Although additional validation cohorts are needed, this suggests that EVendo score can potentially be applied in patients with HCC to avoid unnecessary EGDs, which can ultimately mitigate healthcare costs and delays in initiating HCC treatment with atezolizumab and bevacizumab.

CVM-1118: A potent oral anti-vasculogenic mimicry (VM) agent in combination with nivolumab in patients with unresectable advanced hepatocellular carcinoma (HCC)—A phase IIa study.

e16150 Background: CVM-1118 is a potent anti-tumor new chemical entity with multiple mechanisms of action including induction of apoptosis, cell cycle arrest, and inhibition of VM network formation. This study evaluated the anti-tumor effect and safety profile of CVM-1118 plus nivolumab in patients with progressive unresectable advanced HCC following the first-line therapy with TKIs. Methods: Eligible pts had unresectable advanced HCC and were refractory to prior systemic therapy (e.g., sorafenib, lenvatinib, regorafenib, and/or ramucirumab), with the exception of prior immunotherapy. Patients received oral CVM-1118 at 200 mg BID (400 mg daily) in combination with intravenous nivolumab at 240 mg Q2W in 28-day cycles. The primary endpoint of objective response rate was evaluated using mRECIST. The secondary endpoints were overall response rate (ORR) (per RECIST 1.1), progression free survival (PFS), disease control rate (DCR), and duration of overall response (DoR). Results: A total of 31 evaluable pts were enrolled (25 M/6 F; median age 65 y, range 44–80 y). All patients were Child Pugh A, BCLC stage B (13%, n = 4) or C (87%, n = 27) at the start of treatment. The median number of prior lines of therapy was 1 (range 1–2). The duration of CVM-1118 and nivolumab treatment ranged from 1.5–15.0 mos (median 3.1 mos) with 5/31 (16%) pts remaining on treatment for ≥ 4.6 mos (range 4.67–15.0 mos). The best ORR was 19.4% (mRECIST) (2 CR (6%), 4 PR (13%)), with remaining responses including 11 SD (36%) and 14 PD (45%). The DCR was 54.8% (95% CI 37.3–72.3%), the median PFS was 3.53 mos (95% CI 1.9–5.4 mos) and the median DoR was 10.4 mos (95% CI 2.8–13.7 mos). The most common treatment-related AEs ³ grade 3 included AST increased (12.9%), neutrophil count decreased (9.7%), anemia (6.5%), and WBC decreased (6.5%). As opposed to therapy with atezolizumab plus bevacizumab, gastrointestinal hemorrhage and hypertension were not observed in this study. Pharmacokinetics data demonstrated that CVM-1118 was rapidly metabolized to CVM-1125 in all pts following administration. On Day 1, the mean drug exposure of CVM-1125 was Cmax 564 ng/mL and the AUC0-24 was 2154 ng·hr/mL. Intersubject variability of drug exposure appeared to be high; the T1/2 of CVM-1125 was ~1.7 hr. Conclusions: CVM-1118 combined with nivolumab demonstrated clinical activity in advanced HCC pts with a safety profile that appears favorable compared to atezolizumab plus bevacizumab. These data support further development of the combination of CVM-1118 and nivolumab in pts with unresectable advanced HCC. Clinical trial information: NCT05257590 .