Treatment Of Unresectable Hepatocellular Carcinoma Research Articles

Beneficial effects of maintaining liver function during hepatic arterial infusion chemotherapy combined with tyrosine kinase and programmed cell death protein-1 inhibitors on the outcomes of patients with unresectable hepatocellular carcinoma

Background and aimCombination therapy is the primary treatment for unresectable hepatocellular carcinoma (u-HCC). The hepatic functional reserve is also critical in the treatment of HCC. In this study, u-HCC was treated with combined hepatic arterial infusion chemotherapy (HAIC), tyrosine kinase inhibitors (TKIs), and programmed cell death protein-1 (PD-1) inhibitors to analyze the therapeutic response, progression-free survival (PFS), and safety.MethodsOne hundred sixty-two (162) patients with u-HCC were treated by combination therapy of HAIC, TKIs, and PD-1 inhibitors. PFS was assessed by Child–Pugh (CP) classification subgroups and the change in the CP score during treatment.ResultsThe median PFS was 11.7 and 5.1 months for patients with CP class A (CPA) and CP class B (CPB), respectively (p = 0.013), with respective objective response rates of 61.1 and 27.8% (p = 0.002) and conversion rates of 16 and 0% (p = 0.078). During treatment, the CP scores in patients with CPA worsened less in those with complete and partial response than in those with stable and progressive disease. In the CP score 5, patients with an unchanged CP score had longer PFS than those with a worsened score (Not reached vs. 7.9 months, p = 0.018). CPB was an independent factor negatively affecting treatment response and PFS. Patients with CPA responded better to the combination therapy and had fewer adverse events (AEs) than those with CPB.ConclusionsThus, triple therapy is more beneficial in patients with good liver function, and it is crucial to maintain liver function during treatment.

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.

Efficacy and safety of tislelizumab plus lenvatinib as first-line treatment in patients with unresectable hepatocellular carcinoma: a multicenter, single-arm, phase 2 trial

BackgroundLenvatinib is widely used in treatment of unresectable hepatocellular carcinoma (uHCC), but the benefit of its combination with immunotherapy needs to be verified. This study evaluated the efficacy and safety of tislelizumab plus lenvatinib in systemic treatment-naïve patients with uHCC.MethodsIn this multicenter, single-arm, phase 2 study, systemic treatment-naïve patients with uHCC received tislelizumab 200 mg every three weeks plus lenvatinib (bodyweight ≥ 60 kg: 12 mg; < 60 kg: 8 mg; once daily). Dose-limiting toxicities (DLTs) were evaluated in safety run-in phase to determine whether to enter the expansion phase. The primary endpoint was objective response rate (ORR) assessed by independent review committee (IRC) per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1). Based on Simon’s two-stage design, > 6 responders were needed in stage 1 (n = 30) to continue the study, and ≥ 18 responders were needed by the end of stage 2 (n = 60) to demonstrate statistical superiority to a historical control of lenvatinib monotherapy.ResultsSixty-four patients were enrolled. No DLTs were reported. The study achieved statistical superiority (p = 0.0003) with 23 responders assessed by IRC per RECIST v1.1 in the first 60 patients of the efficacy evaluable analysis set (n = 62). After a median follow-up of 15.7 months, confirmed ORR and disease control rate were 38.7% (24/62, 95% confidence interval [CI], 26.6–51.9) and 90.3% (56/62, 95% CI, 80.1–96.4), respectively. Median progression-free survival was 8.2 months (95% CI, 6.8–not evaluable). Overall survival rate at 12 months was 88.6% (95% CI, 77.7–94.4). Grade ≥ 3 treatment-related adverse events occurred in 18 (28.1%) patients.ConclusionsTislelizumab plus lenvatinib demonstrated promising antitumor activity with favourable tolerability as first-line therapy for patients with uHCC.Trial registrationClinicalTrials.gov (NCT 04401800).

Role of Flex-Dose Delivery Program in Patients Affected by HCC: Advantages in Management of Tare in Our Experience.

Background: Introduced in the latest BCLC 2022, endovascular trans-arterial radioembolization (TARE) has an important role in the treatment of unresectable hepatocellular carcinoma (HCC) as a "bridge" or "downstaging" of disease. The evolution of TARE technology allows a more flexible and personalized target treatment, based on the anatomy and vascular characteristics of each HCC. The flex-dose delivery program is part of this perspective, which allows us to adjust the dose and its radio-embolizing power in relation to the size and type of cancer and to split the therapeutic dose of Y90 in different injections (split-bolus). Methods: From January 2020 to January 2022, we enrolled 19 patients affected by unresectable HCC and candidates for TARE treatment. Thirteen patients completed the treatment following the flex-dose delivery program. Response to treatment was assessed using the mRECIST criteria with CT performed 6 and 9 months after treatment. Two patients did not complete the radiological follow-up and were not included in this retrospective study. The final cohort of this study counts eleven patients. Results: According to mRECIST criteria, six months of follow-up were reported: five cases of complete response (CR, 45.4% of cases), four cases of partial response (PR, 36.4%), and two cases of progression disease (PD, 18.2%). Nine months follow-up reported five cases of complete response (CR, 45.4%), two cases of partial response (PR, 18.2%), and four cases of progression disease (PD, 36.4%). No intra and post-operative complications were described. The average absorbed doses to the hepatic lesion and to the healthy liver tissue were 319 Gy (range 133-447 Gy) and 9.5 Gy (range 2-19 Gy), respectively. Conclusions: The flex-dose delivery program represents a therapeutic protocol capable of "saving" portions of healthy liver parenchyma by designing a "custom-made" treatment for the patient.

WITHDRAWN: Preparation, evaluation and application of MRI detectable sunitinib-loaded calcium alginate/poly(acrylic acid) hydrogel microspheres

Transcatheter arterial chemoembolization (TACE) is an effective method for the treatment of unresectable hepatocellular carcinoma. Although many embolic agents have been developed in TACE, there are few ideal embolic agents that combine drug loading, imaging properties and vessel embolization. Here, we developed novel magnetic embolic microspheres that could simultaneously load sunitinib malate (SU), be detected by magnetic resonance imaging (MRI) and block blood vessels. Calcium alginate/poly (acrylic acid) hydrogel microspheres (CA/PAA-MDMs) with superparamagnetic iron oxide nanoparticles (SPIONs) modified by citric acid were prepared by a drip and photopolymerization method. The embolization and imaging properties of CA/PAA-MDMs were evaluated through a series of experiments such as morphology, X-ray diffraction and X-ray photoelectron spectroscopy, magnetic responsiveness analysis, elasticity, cytotoxicity, hemolysis test, in vitro MRI evaluation, rabbit ear embolization and histopathology. In addition, the ability of drug loading and drug release of CA/PAA-MDMs were investigated by using sunitinib (SU) as the model drug. In conclusion, CA/PAA-MDMs showed outstanding drug loading capability, excellent imaging property and embolization effect, which would be expected to be used as a potential biodegradable embolic agent in the clinical interventional therapy.

Stereotactic Body Radiotherapy Combined With Lenvatinib With or Without PD-1 Inhibitors as Initial Treatment for Unresectable Hepatocellular Carcinoma

PurposeThe aim of this study was to compare the clinical benefit and safety of the triple combination of stereotactic body radiotherapy (SBRT), lenvatinib and programmed death 1 (PD-1) inhibitors with the dual combination of SBRT and lenvatinib in patients with unresectable hepatocellular carcinoma (uHCC). Methods and MaterialsPatients with uHCC who received SBRT in combination with lenvatinib and PD-1 inhibitors or SBRT in combination with lenvatinib alone as first-line treatment from October 2018 to July 2022 were reviewed in this study. The primary endpoints were overall survival (OS), and progression-free survival (PFS). The second endpoints were intra-hepatic PFS (IHPFS), extra-hepatic PFS (EHPFS) and objective remission rate (ORR). In addition, safety profiles were assessed by analyzing treatment-related adverse events (TRAEs) between the two groups to assess safety profiles. ResultsIn total, 214 patients with uHCC who received combination therapy were included in this retrospective study. Among them, 146 patients received triple combination therapy of SBRT, lenvatinib and PD-1 inhibitors (SBRT-L-P group), and 68 patients received dual therapy of SBRT and lenvatinib (SBRT-L group). The median OS times of the two groups were 31.2 months and 17.4 months, respectively (P<0.001). The median PFS time was significantly longer in the SBRT-L-P group than that in SBRT-L group (15.6 months vs. 8.8 months, p<0.001). Additionally, the median IHPFS (17.5 vs. 9.9 months, p<0.001) and EHPFS (20.9 vs. 11.6 months, p<0.001) were significantly longer in the SBRT-L-P group than that in SBRT-L group. The ORR in the SBRT-L-P group was higher than that in the SBRT-L group (63.0 vs. 39.7%, p=0.002). The incidence and severity of TRAEs in the SBRT-L-P group were comparable to those in the SBRT-L group. ConclusionThe use of both lenvatinib and PD-1 inhibitors with SBRT in patients with uHCC was associated with improved overall survival compared to lenvatinib and SBRT alone with a manageable safety profile.

The efficacy and safety of PD-1 inhibitor combined with TACE in the first-line treatment of unresectable hepatocellular carcinoma.

The application of immune checkpoint inhibitors (ICIs) has changed the treatment of advanced hepatocellular carcinoma. Transcatheter arterial chemoembolization (TACE) is a first-line treatment for intermediate hepatocellular carcinoma. Serving as a local treatment modality that can induce immunogenic cell death, the efficacy and safety of combined use with ICI have not been evaluated. Although there have been prospective studies aimed at evaluating the efficacy and safety of ICI combined with TACE in BCLC stage B HCC patients, there are few reports on the evaluation of BCLC stage C patients with distant metastasis or portal vein cancer thrombus. Data of unresectable hepatocellular carcinoma patients received PD-1 inhibitor and TACE were collected in Xijing Hospital from June 2019 to December 2022. The tumor response was evaluated according to the Solid Tumor Modified Response Evaluation Standard (mRECIST), including complete response (CR), partial response (PR), disease stability (SD), disease progression (PD), objective response rate (ORR), and disease control rate (DCR). The progression-free survival (PFS) and overall survival (OS) were used to estimate therapy efficacy. The treatment-related adverse events were evaluated based on National Cancer Institute Common Adverse Event Evaluation Criteria (CTCAE) version 5.0. A total of 42 patients with unresectable hepatocellular carcinoma were included in this study, including 34 males (80.5%) and 8 females (19.5%). The average age is 54.5years, ranging from 34 to 72. The median follow-up time was 12.3months, with an ORR of 42.9% and a DCR of 90.5% as of the follow-up time. The median PFS is 7.5months (95% CI: 5.76-9.23), and the median OS has not yet been reached; 6-month PFS was 62.2%. Safety analysis showed that 41 (97.6%) patients experienced treatment-related adverse reactions, mainly including elevated AST and ALT, fever, elevated bilirubin, hypothyroidism, nausea, abdominal pain, and rash. 40 patients had grade 1/2 adverse reactions, and only one patient had grade 3 adverse reactions, manifested as intolerable rash, nausea, and vomiting. Treatment is terminated when symptomatic treatment and drug suspension cannot be alleviated. In this study, thre patients with unresectable hepatocellular carcinoma were treated with PD-1 inhibitor combined with TACE to achieve good tumor reduction effect and underwent liver cancer resection surgery. For patients with unresectable hepatocellular carcinoma, whether in BCLC stage B or stage C, effective systemic therapy (PD-1 inhibitor) combined with local therapy (TACE) can achieve a high rate of tumor regression and objective response. Some patients may even pursue surgical treatment opportunities, and the treatment-related adverse reactions are controllable, which is expected to provide new options for extending the survival of unresectable hepatocellular carcinoma patients.

Abstract 5097: Effectiveness and safety of atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma: A multicenter, retrospective real-world study in China

Abstract Background: Atezolizumab plus bevacizumab (Atezo+Bev) has shown better benefits than sorafenib as the first-line treatment for unresectable hepatocellular carcinoma (uHCC) in IMbrave 150. However, the real-world evidence of Atezo+Bev in uHCC is limited, especially in China. We aimed to investigate the real-world effectiveness and safety of Atezo+Bev in Chinese patients with uHCC. Methods: Patients with uHCC treated with Atezo+Bev were included at 5 centers in China from Jan. 2021 to Jan. 2023. Overall response (ORR), organ-specific response rate (OSRR), disease control rates (DCR), time to disease progression (TPP), progression-free survival (PFS), metastasis-specific PFS and overall survival (OS) were calculated. Results: Among 48 patients, the median age was 58.4 years with 85.4% being male. A total of 35 and 13 patients received Atezo+Bev as 1st and 2nd line treatment, respectively. The median number of treatment cycles were 8, and 27 (56.3%) patients received locoregional therapies. Detailed treatment response is in the Table. The overall ORR and DCR assessed by mRECIST were 60.4% and 75.0%, while the intra- and extrahepatic OSRR were 59.4% and 62.5%, respectively. With a median follow-up of 14.5 months, the median PFS was 8.5 months (95%CI: 4.4, 11.2) in 1st line setting and 5.1 months (95%CI: 2.1, 7.9) in 2nd line setting. Median intra- and extrahepatic metastasis-specific PFS were 7.9 and 7.6 months, respectively. Median overall TTP was 7.6 months. The median OS was not reached. A total of 36 patients (75%) experienced any grade adverse events, most commonly being thrombocytopenia (27.1%, n=13), lymphopenia (25%, n=12) and abnormal liver function (14.6%, n=7). Conclusion: This study confirmed effectiveness and safety of Atezo+Bev in the 1st line treatment of uHCC, and observed its potential in 2nd line in a real-world setting. Further studies are warranted to confirm these observations and refine treatment strategies. Table. Treatment response N (%) Response Evaluation Criteria in Solid Tumors (RECIST) 1.1(N=48) Modified RECIST(N=48) Complete response (CR) 7 (14.6) 9 (18.8) Partial response (PR) 12 (25.0) 20 (41.7) Stable disease (SD) 15 (31.2) 7 (14.6) Progressive disease 11 (22.9) 12 (25.0) Not evaluated 3 (6.2) 0 ORR (CR+PR) 19 (39.6) 29 (60.4) DCR (CR+PR+SD) 34 (70.8) 36 (75.0) Citation Format: Hui Zhang, Minghua Shao, Binbin Tan, Yin Fu, Yuan, Hailei Chen. Effectiveness and safety of atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma: A multicenter, retrospective real-world study in China [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 5097.

Abstract 3840: Can serum exosomal content predict response to immunotherapy in hepatocellular carcinoma

Abstract While atezolizumab and bevacizumab combination has received FDA approval for the treatment of unresectable hepatocellular carcinoma (HCC), and recently durvalumab + tremelimumab also showed activity over sorafenib, there is no biomarker which can guild which patients can benefit from these regimens. The traditional PD-L1 positivity in the tumor by immunohistochemical staining which can predict possible response to immune checkpoint inhibitor in other solid tumors, such as melanoma and NSCLC, does not appear to apply to HCC. Thus, we attempt to explore whether exosomal content can be useful to predict response. HCC tumors exist in a complex microenvironment and serum exosomes can be generated from either tumor cells, macrophages, or other immune cells. Exosome act as new mediators for cell-cell communication transporting molecules such as lipids, proteins, and RNAs in vivo. Exosomal PD1 and PD-L1 have been implicated for possible biomarkers for immune checkpoint sensitivity. We isolated exosome from serum of unresectable HCC patients who underwent treatment with atezolizumab and bevacizumab. Blood sample was obtained prior to treatment, and then on cycle 3 and at the time of disease progression. Exosomes were isolated using the kit from System BioScience. Twenty patients were entered into the study. Five patients were not treated (received SBRT or other regional treatment), one was lost to follow up and one had atezolizumab only. In terms of antitumor response, eight patients had stable disease, three patients had partial response and two patients had progressive disease. Serum exosomal content data was available in 16 patients. Both PD1 and PDL1 are lowest in the three patients who had response followed by the group who had stable disease. In the two patients who had progressive disease, both exosomal PD-L1 and PD1 appeared to be the highest and did not change during treatment. Unlike in melanoma patients we have studied, other proteins in the antiapoptotic family such as Bcl-2 do not show any differences. While the number of patients are small and accrual is still ongoing, it appears that exosomal PD-L1/PD1 may have clinical value in predicting response to atezolizumab + bevacizumab therapy. Supported by Sylvester Comprehensive Cancer Center grant. Citation Format: Niramol Savaraj, Pablo Puente, Ying-Ying Li, Chunjing Wu, Jonathan D. Nguyen, Medhi Wangpaichitr, Peter J. Hosein, Lynn G. Feun. Can serum exosomal content predict response to immunotherapy 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 3840.

Aldehyde Dehydrogenase 2 (ALDH2): A novel sorafenib target in hepatocellular carcinoma unraveled by the proteome-wide cellular thermal shift assay

Sorafenib is a multikinase inhibitor indicated for first-line treatment of unresectable hepatocellular carcinoma. Despite its widespread use in the clinic, the existing knowledge of sorafenib mode-of-action remains incomplete. To build upon the current understanding, we used the Cellular Thermal Shift Assay (CETSA) coupled to Mass Spectrometry (CETSA-MS) to monitor compound binding to its target proteins in the cellular context on a proteome-wide scale. Among the potential sorafenib targets, we identified aldehyde dehydrogenase 2 (ALDH2), an enzyme that plays a major role in alcohol metabolism. We validated the interaction of sorafenib with ALDH2 by orthogonal methods using pure recombinant protein, proving that this interaction is not mediated by other cellular components. Moreover, we showed that sorafenib inhibits ALDH2 activity, supporting a functional role for this interaction. Finally, we were able to demonstrate that both ALDH2 protein expression and activity were reduced in sorafenib-resistant cells compared to the parental cell line. Overall, our study allowed the identification of ALDH2 as a novel sorafenib target and sheds light on its potential role in both hepatocellular carcinoma and sorafenib resistance condition.

Predictive factors for transition to conversion therapy in hepatocellular carcinoma using atezolizumab plus bevacizumab.

To identify predictive factors associated with successful transition to conversion therapy following combination therapy with atezolizumab and bevacizumab in the treatment of unresectable hepatocellular carcinoma (HCC). In total, 188 patients with HCC, who received atezolizumab plus bevacizumab combination therapy as the first-line chemotherapy, were studied. Patients who achieved complete response (CR) with systemic chemotherapy alone were excluded. Clinical factors possibly linked to successful transition to conversion therapy and the achievement of cancer-free status were identified. Fifteen (8.0%) patients underwent conversion therapy. In the conversion group, there was a significantly higher proportion of patients with Barcelona Clinic Liver Cancer (BCLC) stage A or B (73.3% versus [vs.] 45.1%; p = .03) and tended to have lower Child-Pugh scores and alpha-fetoprotein levels. Multivariate analysis revealed that BCLC stage was a predictive factor for the implementation of conversion therapy (A or B; odds ratio 3.7 [95% CI: 1.1-13]; p = .04). Furthermore, 10 (66.7%) patients achieved cancer-free status and exhibited a smaller number of intrahepatic lesions at the start of treatment (3.5 vs. 7; p < .01), and a shorter interval between systemic chemotherapy induction and conversion therapy (131 vs. 404 days; p < .01). In addition, the rate of achieving cancer-free status by undergoing surgical resection or ablation therapy was significantly higher (p = .03). BCLC stage was the sole predictive factor for successful transition to conversion therapy when using combination therapy with atezolizumab and bevacizumab to treat HCC. Furthermore, a small number of intrahepatic lesions and early transition to conversion therapy were associated with the achievement of cancer-free status.

The second-line treatment of hepatocellular carcinoma with CalliSpheres drug-eluting bead transarterial chemoembolization combined with regorafenib: A safety and efficacy analysis.

This study aimed to investigate the efficacy and safety of CalliSpheres drug-eluting beads transarterial chemoembolization (DEB-TACE) combined with regorafenib in the second-line treatment of unresectable hepatocellular carcinoma. A retrospective analysis was made of 34 patients with unresectable hepatocellular carcinoma (HCC) that had progressed after first-line treatment in Linyi Tumor Hospital from October 2019 to June 2021. These patients were divided into observation group (n = 15) and control group (n = 19) based on their treatment plans, who were respectively treated with regorafenib alone and regorafenib combined with DEB-TACE. The objective response rate (ORR) and the disease control rate (DCR) were evaluated by the modified Response Evaluation Criteria in Solid Tumors (mRECIST), and the progression-free survival (PFS) and the overall survival (OS) were calculated; the factors influencing PFS and OS of patients were analyzed by the Cox proportional hazards model; and the adverse reactions to the treatments were observed and recorded. After 2months of treatment, the ORR and the DCR of the observation group were 73.3% (11/15) and 86.7% (13/15) respectively, both higher than 10.5% (2/19) and 47.4% (9/19) of the control group. Their differences are statistically significant (P < 0.05). There were no statistically significant differences in the incidences of regorafenib-related adverse reactions including hand-foot skin reactions, fatigue, hypertension, diarrhea, and proteinuria between the two groups (P > 0.05). In the observation group, the main adverse reactions to DEB-TACE such as fever, pain, nausea, and vomiting were relieved after symptomatic treatment, and no serious complications such as ectopic embolization of CalliSpheres drug-eluting beads occurred. As of July 31, 2022, the median follow-up time was 12.5months, and the average was (14.00 ± 5.69) months. The median PFS was 9months in the observation group, and 6months in the control group, presenting a statistically significant difference (P < 0.05), and the median OS was 18months in the observation group, and 12months in the control group, also presenting a statistically significant difference (P < 0.05). The results of monofactor prognostic analysis showed that Child grade, AFP level, and treatment method had an influence on the PFS and the OS of liver cancer patients receiving regorafenib second-line treatment (P < 0.05), and the results of multifactor prognostic analysis showed that child grade and treatment method independently influenced the PFS of patients, while treatment method independently influenced the OS of patients (P < 0.05). DEB-TACE combined with regorafenib is safe and feasible in the treatment of unresectable HCC, with good efficacy and mild adverse reactions.

90Y]Yttria Alumino Silicate Glass Microspheres: A Biosimilar Formulation to "TheraSphere" for Cost-Effective Treatment of Liver Cancer.

Background: Selective internal radiation therapy (SIRT) using a suitable β--emitting radionuclide is a promising treatment modality for unresectable liver carcinoma. Yttrium-90 (90Y) [T1/2 = 64.2 h, Eβ(max) = 2.28 MeV, no detectable γ-photon] is the most preferred radioisotope for SIRT owing to its favorable decay characteristics. Objective: The present study describes indigenous development and evaluation of intrinsically radiolabeled [90Y]yttria alumino silicate ([90Y]YAS) glass microsphere, a formulation biosimilar to "TheraSphere" (commercially available, U.S. FDA-approved formulation), for SIRT of unresectable liver carcinoma in human patients. Methods: YAS glass microspheres of composition 40Y2O3-20Al2O3-40SiO2 (w/w) and diameter ranging between 20 and 36 μm were synthesized with almost 100% conversion efficiency and >99% sphericity. Intrinsically labeled [90Y]YAS glass microspheres were produced by thermal neutron irradiation of cold YAS glass microspheres in a research reactor. Subsequent to in vitro evaluations and in vivo studies in healthy Wistar rats, customized doses of [90Y]YAS glass microspheres were administered in human patients. Results: [90Y]YAS glass microspheres were produced with 137.7 ± 8.6 MBq/mg YAS glass (∼6800 Bq per microsphere) specific activity and 99.94% ± 0.02% radionuclidic purity at the end of irradiation. The formulation exhibited excellent in vitro stability in human serum and showed >97% retention in the liver up to 7 d post-administration when biodistribution studies were carried out in healthy Wistar rats. Yttrium-90 positron emission tomography scans recorded at different time points post-administration of customized dose of [90Y]YAS glass microspheres in human patients showed near-quantitative retention of the formulation in the injected lobe. Conclusions: The study confirmed the suitability of indigenously prepared [90Y]YAS glass microspheres for clinical use in the treatment of unresectable hepatocellular carcinoma.

The efficacy and safety of transarterial chemoembolization combined with cadonilimab and lenvatinib for unresectable hepatocellular carcinoma: A phase II clinical trial.

478 Background: Immune-checkpoint inhibitors, in combination with targeted therapy and local therapy, have been developed as promising treatment for unresectable hepatocellular carcinoma (uHCC) of intermediate stage. This study aimed to assess the efficacy and safety of cadonilimab(a tetravalent PD-1/CTLA-4 bispecific antibody) plus Lenvatinib (Len) and transarterial chemoembolization (TACE) in the treatment of intermediate HCC. Methods: This open label, multicenter phase II trial enrolled patients with histologically or clinically confirmed intermediate uHCC to receive TACE followed by cadonilimab 10mg/kg every 3 weeks plus Len until disease progression or intolerable toxicity. The primary endpoint was progression free disease (PFS) according to RECIST v1.1. The secondary endpoint includes safety, overall survival (OS), PFS according to modified RECIST (mRECIST), and objective response rate (ORR), disease control rate (DCR) and duration of response (DoR) by both RECIST v1.1 and mRECIST. Results: From June 2022 to May 2023, 78 patients were screened and 60 patients enrolled. As of August 15, 2023, 60 patients received at least once cadonilimab and the median duration of follow-up was 5.1 months. The average number of TACE procedures per patient was 1.70. The median PFS and OS were not reached, while the 6-month PFS rate was 77.1% (95% CI, 60.8-87.3) per RECIST v1.1 and 75.6% (95% CI, 59.5-86.0) per mRECIST. The ORR and DCR were 35.0% (95% CI, 23.1-48.4) and 96.7% (95% CI, 88.5-99.6) according to RECIST v1.1 and 85.0% (95% CI, 73.4-92.9) and 95.0% (95% CI, 86.1-99.0) according to mRECIST. 9 patients (15.0%) achieved complete response per mRECIST. The incidence of grade≥3 treatment-related adverse events (TRAEs) was 68.9%. The incidence of grade≥3 adverse events related to cadonilimab was 45.9%.The most common TRAEs included thrombocytopenia, aspartate aminotransferase increased, and alanine aminotransferase increased. Conclusions: Combination of TACE and cadonilimab plus len showed promising efficacy and manageable toxicity in intermediate uHCC. Benefit of control on tumor progression after TACE and lasting survival can be expected. Clinical trial information: NCT05319431 . [Table: see text]

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 .

Comparison of the treatment effect between lenvatinib and atezolizumab plus bevacizumab for unresectable hepatocellular carcinoma in pathologically diagnosed metabolic dysfunction–associated steatotic liver disease.

493 Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is one of the leading etiologies of HCC. Recent evidence indicates that MASLD might affect the response to immune checkpoint inhibitors and multi-receptor tyrosine kinase inhibitors in the treatment for unresectable hepatocellular carcinoma (HCC), yet real-world data with accurate pathological diagnosis of MASLD has not been confirmed. Methods: Patients with unresectable HCC who had been pathologically diagnosed with MASLD by liver biopsy and/or hepatectomy and later received treatment with lenvatinib (LEN) or atezolizumab plus bevacizumab (ATZ/Bev) as first-line systemic treatment for HCC were included. Outcomes of treatment with LEN or ATZ/Bev were compared. Results: A total of 48 patients who received LEN (n=26) and ATZ/Bev (n=22) were included. The mean time from pathological diagnosis to the initiation of treatment was not different (LEN 1,542 days, ATZ/Bev 1,260 days; p=0.48). The degree of steatosis, inflammation, ballooning hepatocytes and fibrosis did not differ between LEN and ATZ/Bev. At the initiation of treatment, BCLC stage, albumin–bilirubin grade, and Child–Pugh grade did not differ between LEN and ATZ/Bev. The overall response rate and disease control rate evaluated with modified RECIST criteria were not different between LEN and ATZ/Bev (26.1% and 77.2% for LEN, and 22.7% and 70.8% for ATZ/Bev). Median progression-free survival (PFS) was not different between LEN and ATZ/Bev (266 days vs 287 days, p=0.278). Median overall survival (OS) of LEN tended to be longer than that of ATZ/Bev (1364 days vs 663 days, p=0.081). The potential advantage of LEN in OS was statistically significant in the patients with Child-Pugh score = 5 (P=0.0443). A total of 17 patients received both LEN and ATZ/Bev treatment and order of the treatment did not associate with PFS and OS. Conclusions: Outcomes of LEN and ATZ/Bev treatment for advanced HCC were not different in pathologically confirmed MASLD. Longer OS of LEN than ATZ/Bev was observed in the patients with relatively better liver function, suggesting that LEN might be a suitable first-line treatment for HCC with compensated liver function in the patients with pathologically confirmed MASLD.

Anlotinib combined with penpulimab and hepatic artery infusion chemotherapy (HAIC) in the first-line treatment of unresectable hepatocellular carcinoma.

TPS579 Background: Hepatic arterial infusion chemotherapy (HAIC) is recommended as a treatment option in patients with advanced hepatocellular carcinoma (HCC). Anlotinib plus penpulimab, a humanized anti-PD-1 IgG1 antibody, has shown encouraging activity in the treatment of advanced HCC in an open-label phase II trial (NCT 04172571). Considering different anti-malignancy mechanisms, combining systemic and locoregional therapies may show a potential synergic effect and promising preliminary efficacy results in advanced HCC. Consequently, the aim of this study is to assess the efficacy and safety of Anlotinib, Penpulimab, plus HAIC for advanced HCC. Methods: Trial design: This single-arm, prospective, phase II study will include treatment-naive adult (≥18 years) patients with advanced HCC, ECOG PS 0-2, and Child-Pugh class A-B. A total number of 26 patients will be enrolled for treatment until disease progression or intolerable toxicity. Patients will receive anlotinib(10 mg, p.o., qd, d1-14, q3w), penpulimab (200 mg, i.v., d1, q3w) and HAIC (d1- d2) with the FOLFOX regimen (oxaliplatin 85-130 mg/m2, leucovorin 400 mg/m2, 5-fluorouracil bolus 400 mg/m2 on day 1, and 5-fluorouracil infusion 2400 mg/m2 for 48 hours) for 4-6 cycles, followed by maintenance therapy with anlotinib and penpulimab for up to 2 years. The primary endpoint is objective response rate (ORR)), evaluated using RECIST 1.1. Secondary endpoints are median PFS and overall survival (OS), disease control rate (DCR) per RECIST 1.1, quality of life (QOL) and safety. Recruitment for this study will complete in December 2024.

Comparison of atezolizumab plus bevacizumab and lenvatinib for hepatocellular carcinoma with portal vein tumor thrombosis.

Atezolizumab plus bevacizumab and lenvatinib are currently available as first-line therapy for the treatment of unresectable hepatocellular carcinoma (HCC). However, comparative efficacy studies are still limited. This study aimed to investigate the effectiveness of these treatments in HCC patients with portal vein tumor thrombosis (PVTT). We retrospectively included patients who received either atezolizumab plus bevacizumab or lenvatinib as first-line systemic therapy for HCC with PVTT. Primary endpoint was overall survival (OS), and secondary endpoints included progressionfree survival (PFS) and disease control rate (DCR) determined by response evaluation criteria in solid tumors, version 1.1. A total of 52 patients were included: 30 received atezolizumab plus bevacizumab and 22 received lenvatinib. The median follow-up duration was 6.4 months (interquartile range, 3.9-9.8). The median OS was 10.8 months (95% confidence interval [CI], 5.7 to not estimated) with atezolizumab plus bevacizumab and 5.8 months (95% CI, 4.8 to not estimated) with lenvatinib (P=0.26 by log-rank test). There was no statistically significant difference in OS (adjusted hazard ratio [aHR], 0.71; 95% CI, 0.34-1.49; P=0.37). The median PFS was similar (P=0.63 by log-rank test), with 4.1 months (95% CI, 3.3-7.7) for atezolizumab plus bevacizumab and 4.3 months (95% CI, 2.6-5.8) for lenvatinib (aHR, 0.93; 95% CI, 0.51-1.69; P=0.80). HRs were similar after inverse probability treatment weighting. The DCRs were 23.3% and 18.2% in patients receiving atezolizumab plus bevacizumab and lenvatinib, respectively (P=0.74). The effectiveness of atezolizumab plus bevacizumab and lenvatinib was comparable for the treatment of HCC with PVTT.

Nomograms confirm serum IL-6 and CRP as predictors of immune checkpoint inhibitor efficacy in unresectable hepatocellular carcinoma.

Immunotherapy based on immune checkpoint inhibitors (ICIs) has become the first-line treatment for unresectable hepatocellular carcinoma (uHCC). However, only a small portion of patients are responsive to ICIs. It is important to identify the patients who are likely to benefit from ICIs in clinical practice. We aimed to examine the significance of serum IL-6 and CRP levels in predicting the effectiveness of ICIs for uHCC. We retrospectively recruited 222 uHCC patients who received ICIs treatment (training cohort: 124 patients, validation cohort: 98 patients). In the training cohort, patients are categorized into the response group (R) and no-response group (NR). The levels of serum IL-6 and CRP were compared between the two groups. Internal validation was performed in the validation cohort. Survival analysis was carried out using the Kaplan-Meier method and Cox proportional hazard regression model. The nomograms were developed and assessed using the consistency index (C-index) and calibration curve. Serum levels of IL-6 and CRP were significantly lower in the R group than in the NR group (9.94 vs. 36.85 pg/ml, p< 0.001; 9.90 vs. 24.50 mg/L, p< 0.001, respectively). An ROC curve was employed to identify the optimal cut-off values for IL-6 and CRP in both groups, resulting in values of 19.82 pg/ml and 15.50 mg/L, respectively. Multivariate Cox regression analysis revealed that MVI (HR 1.751, 95%CI 1.059-2.894, p=0.029; HR 1.530, 95%CI 0.955-2.451, p=0.077), elevated IL-6 (HR 1.624, 95%CI 1.016-2.596, p=0.043; HR 2.146, 95%CI 1.361-3.383, p =0.001) and high CRP (HR 1.709, 95%CI 1.041-2.807, p=0.034; HR 1.846, 95%CI 1.128-3.022, p = 0.015) were independent risk factors for PFS and OS, even after various confounders adjustments. Nomograms are well-structured and validated prognostic maps constructed from three variables, as MVI, IL6 and CRP. Low levels of IL-6 and CRP have a positive correlation with efficacy for uHCC patients receiving ICIs.

Organ-specific response with first-line atezolizumab-bevacizumab versus lenvatinib for patients with advanced hepatocellular carcinoma.

Immune checkpoint inhibitor (ICI)-based treatments have become the mainstay of first-line treatment for unresectable hepatocellular carcinoma (HCC), but there has been a concern that intrahepatic HCC lesions may be less responsive to ICI monotherapy. We aimed to investigate the organ-specific response patterns among unresectable HCC patients treated with first-line atezolizumab-bevacizumab or lenvatinib. This retrospective study included 386 patients with Child-Pugh A unresectable HCC who were treated with first-line atezolizumab-bevacizumab (n = 217) or lenvatinib (n = 169). The organ-specific response was separately evaluated according to the site of the lesions: liver, lung, lymph node (LN), and intraabdomen based on a radiological evaluation adopted from RECIST v 1.1. The median age was 60years. Hepatitis B infection was the most common etiology (n = 270, 69.9%), and 291 (75.4%) patients had a viral etiology. The proportion of patients achieving a ≥ 30% reduction in the tumor burden for each organ category was overall higher in the atezolizumab-bevacizumab group than that in the lenvatinib group: 20.2% vs. 11.8%, 23.0% vs. 12.2%, 27.9% vs. 17.9% and 33.3% vs. 15.0% for intrahepatic, lung, LN, and intraabdominal lesions, respectively. The corresponding values for the subgroup with a viral etiology were 17.3% vs. 8.1%, 18.8% vs. 13.3%, 28.9% vs. 3.6%, and 36.0% vs. 12.5%, respectively. Compared to lenvatinib, atezolizumab-bevacizumab was associated with a favorable organ-specific response regardless of the site of the tumor lesions. Unlike anti-PD-1 monotherapy, atezolizumab-bevacizumab had a comparable organ-specific response between intrahepatic and extrahepatic lesions, especially for those with viral etiology HCCs.