Treatment Of Unresectable Hepatocellular Carcinoma Research Articles

Drug-eluting beads versus conventional transarterial chemoembolization for the treatment of unresectable hepatocellular carcinoma: A meta-analysis.

Transarterial chemoembolization (TACE) consists of conventional TACE (cTACE) and drug-eluting beads TACE (DEB-TACE). The benefits of the 2 treatments remain controversial. We conduct this meta-analysis to assess the efficacy and safety of the 2 methods for the patients with unresectable hepatocellular carcinoma. In order to get a sound conclusion, we did thorough search all relevant studies with clear and stringent keyword criteria on the main databases. Objective tumor response rate, overall survival (OS) rate and adverse events were calculated and analyzed by RevMan 5.3 software. The random-effects or fixed-effects model was applied to pool the estimates according to Cochran Q test and I2 statistics. Twenty-four studies involving 2987 patients were eligible. DEB-TACE significantly improved objective tumor response rate (OR) (risk ratio [RR] = 1.27, 95% confidence interval [CI] [1.08, 1.48]; P = .003). While as for 1-year, 2-year, 3-year, 5-year OS rates, there were no evidences to indicate that DEB-TACE was significantly better than cTACE (RR = 1.05, 95% CI [0.99, 1.11]; P = .08), (RR = 1.02, 95% CI [0.93, 1.11]; P = .68), (RR = 0.92, 95% CI [0.77, 1.10]; P = .37), (RR = 0.92, 95% CI [0.47, 1.80]; P = .81), respectively. Adverse events rate (AE) was also similar in both groups (RR = 1.11, 95% CI [0.99,1.26]; P = .08). This meta-analysis demonstrates that DEB-TACE is not superior than cTACE regarding to OS and AE. However, DEB-TACE still be considered to provide a better objective tumor response rate for patients with unresectable hepatocellular carcinoma.

Potential tactics with certain gut microbiota for the treatment of unresectable hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) constitutes an extremely malignant form of primary liver cancer. Intricate connections linking to the immune system might be associated with the pathogenesis of HCC. Meanwhile, immunotherapy with immune checkpoint inhibitors has been established to be a favorable therapeutic possibility for advanced HCC. Although curative opportunities for advanced HCC are restricted, the immune checkpoint immunotherapy has developed as the main choice for treating HCC. However, patients with metabolic-associated fatty liver disease (MAFLD)-linked HCC might be less likely to benefit from the immunotherapy alone. The limitation of the effect of the immunotherapy might be owing to the impaired T cell activation in MAFLD patients, which could be well explained by a dysfunctional gut-liver axis. Gut microbiota and their metabolites including several bile acids could contribute to modulating the responses of the immune checkpoint immunotherapy. Roles of gut microbiota in the development of cancers have expected great interest in the latest studies. Here, an interplay between the gut and liver has been presented, which might suggest to affect the efficacy of immune checkpoint immunotherapy against HCC.

Efficacy and safety of transarterial chemoembolization plus lenvatinib with or without programmed death-1 inhibitors in the treatment of unresectable hepatocellular carcinoma: a systematic review and meta-analysis.

Programmed death-1 inhibitors plus lenvatinib and transarterial chemoembolization (TACE) (P-L-T) is a novel combination strategy. This systematic review and meta-analysis aimed to evaluate the efficacy and safety of P-L-T compared with lenvatinib and TACE (L-T) therapy in patients with unresectable hepatocellular carcinoma. A systematic literature search of the PubMed, Embase, Web of Science and Cochrane Library databases for studies investigating P-L-T therapy was performed. Data regarding outcome data, including overall survival (OS), progression-free survival (PFS), tumor response, and adverse events (AEs), were independently extracted by two authors using a standardized protocol. Eight cohort studies comprising 847 patients (P-L-T: 416, L-T: 431) were included in the meta-analysis. The P-L-T group exhibited significantly longer OS (hazard ratio (Page et al.) 0.51 [95% confidence interval (CI) 0.42-0.62]; I2 = 9.8%; p = 0.354] and PFS (HR 0.51 [95% CI 0.43-0.61]; I2 = 0%; p = 0.824), and higher objective response rate (risk ratio [RR] 1.54 [95% CI 1.33-1.78]; I2 = 0%, p = 0.858]) and disease control rate (RR 1.27 [95% CI 1.17-1.38]; I2 = 17.3%; p = 0.467). Grade 3/4 AEs were more prevalent in the P-L-T group, including hypertension (RR 1.91 [95% CI 1.16-3.15]), vomiting or nausea (RR 2.29 [95% CI 1.01-5.19]), and hypothyroidism (RR 12.21 [95% CI 1.63-91.23]). Compared with L-T combination therapy, P-L-T demonstrated a significant advantage in terms of OS, PFS, objective response rate, disease control rate, and manageable AEs.

Addition of transarterial chemoembolization improves outcome of tyrosine kinase and immune checkpoint inhibitors regime in patients with unresectable hepatocellular carcinoma.

Transarterial chemoembolization (TACE) is the standard treatment for hepatocellular carcinoma (HCC); the value of its combination with systemic therapy is worthy of further exploration. This study aimed to investigate the efficacy and safety of TACE combined with tyrosine kinase inhibitor (TKI) and immune checkpoint inhibitor (ICI) in the treatment of unresectable HCC. In this retrospective observational, single-center study, 147 patients with unresectable HCC were divided into a TACE group (n=98) and a non-TACE group (n=49) based on whether TACE was performed during TKI plus ICI therapy. The survival outcomes and adverse events (AEs) of the two groups were compared. Data from patients with unresectable HCC who received TKI plus ICI treatment between July 2017 and April 2020 were collected. The median intrahepatic tumor size was 8.7 cm [interquartile range (IQR), 5.9-12.4 cm]. At data cut-off, overall survival (OS) of the TACE group was significantly longer than that of the non-TACE group (19.5 and 10.8 months, respectively, P=0.005). In the high-risk cohort (with main or contralateral portal vein tumor thrombi and/or bile duct invasion and/or a tumor burden >50% of liver), the OS of the TACE group was still longer than that of the non-TACE group (14.9 and 8.7 months, respectively, P=0.031). Major AEs were tolerated in both groups, and there was no significant difference in their incidence (34.7% and 30.6%, respectively, P=0.621). TACE treatment combined with TKI plus ICI regime resulted in longer OS than treatment with TKI plus ICI alone for patients with unresectable HCC.

Tislelizumab versus sorafenib in first-line treatment of unresectable hepatocellular carcinoma: Impact on health-related quality of life in RATIONALE-301 population.

43 Background: RATIONALE-301 (NCT03412773), a global Phase 3 study, comparing tislelizumab (TIS) to sorafenib (SOR) as 1L treatment in adult patients (pts) with unresectable HCC (uHCC), met its primary endpoint of OS non-inferiority. This analysis examined the HRQoL outcomes in pts in both arms. Methods: Systemic therapy-naïve adults with histologically confirmed uHCC were randomized 1:1 to receive TIS (200 mg IV Q3W, n=342) or SOR (400 mg PO BID, n=332). HRQoL was assessed using EORTC QLQ-C30, QLQ-HCC18 and EQ5D-5L. A mixed model for repeated measures using key pre-specified PRO endpoints of global health status/quality of life (GHS/QoL), physical functioning and fatigue scales of the QLQ-C30, and HCC18 index score, fatigue and pain scores at the key pre-specified clinical cycles 4 and 6 were performed. Time to deterioration was examined with the Kaplan-Meier method using the PRO endpoints. Results: At both cycles, TIS had better HRQoL outcomes than SOR, as indicated by LS mean differences in GHS/QoL, physical functioning, fatigue and HCC symptom index, but not for pain. TIS had a lower risk for deterioration of QLQ-C30 GHS/QoL (hazard ratio [HR] 0.68 [95% CI, 0.49-0.94]), physical functioning (0.53 [0.39-0.73]) and fatigue (0.48 [0.37, 0.63]) as well as for deterioration in the HCC18 index (0.53 [0.34-0.81]) and fatigue (0.60 [0.46-0.80]). Both arms had a similar risk for deterioration in pain (HR 0.78 [0.56-1.09]). TIS maintained while SOR declined EQ-5D-5L VAS (general health status) scores at cycle 4 (mean change from baseline =-0.4 [SD = 14.52] vs -4.3 [12.92]) and cycle 6 (-0.2 [17.03] vs -5.4 [13.09]). Conclusions: Pts with HCC treated with 1L TIS had better HRQoL outcomes compared with pts treated with SOR, particularly in terms of fatigue and physical functioning. These results, along with effects on overall survival, response rate, and a favorable safety profile, support the benefit of TIS as a potential 1L treatment option for uHCC. Clinical trial information: NCT03412773 . [Table: see text]

Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma (CARES-310): a randomised, open-label, international phase 3 study

Immunotherapy with immune checkpoint inhibitors combined with an anti-angiogenic tyrosine-kinase inhibitor (TKI) has been shown to improve overall survival versus anti-angiogenic therapy alone in advanced solid tumours, but not in hepatocellular carcinoma. Therefore, a clinical study was conducted to compare the efficacy and safety of the anti-PD-1 antibody camrelizumab plus the VEGFR2-targeted TKI rivoceranib (also known as apatinib) versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma. This randomised, open-label, international phase 3 trial (CARES-310) was done at 95 study sites across 13 countries and regions worldwide. Patients with unresectable or metastatic hepatocellular carcinoma who had not previously received any systemic treatment were randomly assigned (1:1) to receive either camrelizumab 200 mg intravenously every 2 weeks plus rivoceranib 250 mg orally once daily or sorafenib 400 mg orally twice daily. Randomisation was done via a centralised interactive response system. The primary endpoints were progression-free survival, as assessed by the blinded independent review committee per Response Evaluation Criteria in Solid Tumours version 1.1, and overall survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of the study drugs. We report the findings from the prespecified primary analysis for progression-free survival and interim analysis for overall survival. This study is registered with ClinicalTrials.gov (NCT03764293). Between June 28, 2019, and March 24, 2021, 543 patients were randomly assigned to the camrelizumab-rivoceranib (n=272) or sorafenib (n=271) group. At the primary analysis for progression-free survival (May 10, 2021), median follow-up was 7·8 months (IQR 4·1-10·6). Median progression-free survival was significantly improved with camrelizumab-rivoceranib versus sorafenib (5·6 months [95% CI 5·5-6·3] vs 3·7 months [2·8-3·7]; hazard ratio [HR] 0·52 [95% CI 0·41-0·65]; one-sided p<0·0001). At the interim analysis for overall survival (Feb 8, 2022), median follow-up was 14·5 months (IQR 9·1-18·7). Median overall survival was significantly extended with camrelizumab-rivoceranib versus sorafenib (22·1 months [95% CI 19·1-27·2] vs 15·2 months [13·0-18·5]; HR 0·62 [95% CI 0·49-0·80]; one-sided p<0·0001). The most common grade 3 or 4 treatment-related adverse events were hypertension (102 [38%] of 272 patients in the camrelizumab-rivoceranib group vs 40 [15%] of 269 patients in the sorafenib group), palmar-plantar erythrodysaesthesia syndrome (33 [12%] vs 41 [15%]), increased aspartate aminotransferase (45 [17%] vs 14 [5%]), and increased alanine aminotransferase (35 [13%] vs eight [3%]). Treatment-related serious adverse events were reported in 66 (24%) patients in the camrelizumab-rivoceranib group and 16 (6%) in the sorafenib group. Treatment-related death occurred in two patients: one patient in the camrelizumab-rivoceranib group (ie, multiple organ dysfunction syndrome) and one patient in the sorafenib group (ie, respiratory failure and circulatory collapse). Camrelizumab plus rivoceranib showed a statistically significant and clinically meaningful benefit in progression-free survival and overall survival compared with sorafenib for patients with unresectable hepatocellular carcinoma, presenting as a new and effective first-line treatment option for this population. Jiangsu Hengrui Pharmaceuticals and Elevar Therapeutics.

Relationship between Plasma IP-10/CXCL10 Levels and the Initial Therapeutic Response in Patients Treated with Atezolizumab plus Bevacizumab for Unresectable Hepatocellular Carcinoma

Introduction: Atezolizumab plus bevacizumab combination therapy (AB) was the first-line treatment for unresectable hepatocellular carcinoma (u-HCC). IFN-γ-induced protein 10 (IP-10/CXCL10) is a chemokine to inhibit HCC proliferation by promoting the migration of cytotoxic T cells. We focused on the relationship between plasma IP-10/CXCL10 levels and the initial therapeutic response in patients receiving AB therapy. Methods: Forty-six patients receiving AB therapy were enrolled. Plasma IP-10/CXCL10 levels were measured at baseline, 3–7 days, 3 weeks, 6 weeks, and 8–12 weeks after the start of AB therapy. The initial therapeutic response was evaluated at 8–12 weeks. Results: The baseline IP-10/CXCL10 levels of partial response (PR) group was higher than that of stable disease (SD) or progressive disease (PD) group. Patients with the baseline IP-10/CXCL10 of 84 pg/mL or higher were likely to present PR than patients below (71 vs. 35%, p = 0.031), but prediction of PD using the baseline IP-10/CXCL10 levels was difficult. In contrast, IP-10/CXCL10 ratio of the PR group was lower than that of the SD/PD group at 3, 6, and 8–12 weeks. Patients with the 3, 6, and 8–12 weeks IP-10/CXCL10 ratio of 1.3, 0.4, and 0.4 or lower were likely to present PR than patients with ≥1.3, 0.4, and 0.4 (88, 35, 35 vs. 30, 3.8, 0%, p < 0.001, 0.011, 0.002). In other hand, the 3, 6, and 8–12 weeks IP-10/CXCL10 ratio for PD group was higher than that for non-PD group. Patients with the 3, 6, and 8–12 weeks IP-10/CXCL10 ratio of 1.3, 1.7, and 1.9 or higher were likely to present PD than patients below (85, 62, 57 vs. 32, 23, 14%, p = 0.002, 0.034, 0.009). Conclusion: High baseline IP-10/CXCL10 levels may be associated with better outcome, and high IP-10/CXCL10 ratio after 3–12 weeks may be associated with worse outcome in u-HCC patients receiving AB therapy.

Efficacy and safety of donafenib combined with transcatheter arterial chemoembolization (TACE) and anti-PD1 antibody for the treatment of unresectable hepatocellular carcinoma (uHCC): A retrospective study.

e16120 Background: For unresectable hepatocellular carcinoma (uHCC), the efficacy of TACE monotherapy is not satisfactory. It has recently been reported that molecular targeted drugs combined with anti-PD1 antibody and TACE exhibit improved anti-tumor efficacy compared with monotherapy. Donafenib is a new generation of multi-kinase inhibitor which is approved as the first-line treatment for uHCC. This study aimed to explore the efficacy and safety of the combination therapy of donafenib, anti-PD1 monoclonal antibody and TACE in patients with uHCC. Methods: This was a single-center retrospective study, and involved patients with uHCC who received donafenib (200 mg po bid) combined with TACE and anti-PD1 monoclonal antibody or donafenib (200 mg po bid) combined with TACE at Shanghai Eastern Hepatobiliary Surgery Hospital from September 2021 to September 2022. All patients had at least one measurable lesion defined by mRECIST criteria. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) data of patients were collected and analyzed. Results: A total of 34 patients with uHCC were included and had a median age of 56 years (32–81 years). Of these patients, 3 (9%) were classed as BCLC stage B, 31 (91%) were BCLC stage C. All 34 patients were complicated with HBV infection. First-line treatment was administered to 24 patients (71%), among which 21 patients received donafenib combined with TACE and anti-PD1 antibody. 3 patients were treated with donafenib combined with TACE. The remaining 10 patients (19%) received second-line treatment, among which 7 patients were treated with donafenib combined with TACE and anti-PD1 antibody. 3 patients received donafenib combined with TACE. There were 14 patients (41%) with baseline AFP ≥400 ng/mL. At data cut-off, the median follow-up time was 5 months [95% CI: 3.42-6.58]. The best overall response rate (BOR) was complete response in 5 patients (14.7%), partial response in 13 patients (38.2%), stable disease in 10 patients (29.4%), and progressive disease in 6 patients (17.6%). The ORR was 52.9% (95%CI: 36.7–68.6%) and DCR was 82.4% (95%CI: 66.5–91.7%). The median PFS and median OS were not reached, the one-year PFS rate was 61.6% (95%CI: 38–78.7%), and the one-year OS rate was 83.1% (95%CI: 56.1–95.2%). The ORR (58%) and DCR (87.5%) of patients receiving first-line treatment were better compared with those of patients receiving second-line treatment (40% and 70%, respectively). Treatment-related adverse events (TRAE) were reported by 30 patients (88.2%), of which 7 patients (20.6%) had grade 3 TRAE. No grade 4 or 5 TRAE was reported. Conclusions: Donafenib combined with TACE and anti-PD-1 antibody exhibited encouraging efficacy and favorable safety profile in patients with uHCC.

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

TPS4178 Background: Despite advances in treatment for unresectable hepatocellular carcinoma (HCC), long-term survival rates remain poor. The combination of bevacizumab (Bev) and atezolizumab (Atezo) is the preferred 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, 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 tumor microenvironment is intended to provide systemic antitumor activity and enhance therapeutic response to 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 and Bev as first- (1L) and second-line (2L) systemic therapies for unresectable and advanced HCC. 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 one 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 Eastern Cooperative Oncology Group performance status of 0−1. Key exclusion criteria include untreated esophageal and/or gastric varices with bleeding or at high risk for bleeding and macroscopic invasion of 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 1200 mg Atezo and 15 mg/kg Bev 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 overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Secondary endpoints are safety, ORR using HCC modified RECIST, duration of response, complete response rate, and progression-free survival. Clinical trial information: NCT05733598 .

Donafenib combined with anti-PD-1 antibodies plus transarterial therapy for initially unresectable hepatocellular carcinoma.

e16135 Background: Given its clear efficacy and high safety demonstrated in the phase 3 ZGDH3 study, donafenib has been recommended by the Chinese guidelines for the first-line treatment of unresectable hepatocellular carcinoma (uHCC). Recently, combination therapies have shown favorable results. However, triple therapy with donafenib, anti-PD-1 antibodies, and transarterial therapy has not yet been investigated. Thus, we aimed to investigate the efficacy and safety of triple therapy with donafenib, anti-PD-1 antibodies, and transarterial therapy in patients with uHCC. Methods: A single-center, retrospective study was performed based on the medical records of consecutive patients diagnosed with HCC who were not suitable for curative surgery or local ablation at Zhujiang Hospital of Southern Medical University from June 2021 to October 2022. Patients with ≥18 years, Child-Pugh score ≤7, ECOG PS ≤1, no prior systemic therapy, having at least one measurable lesion (per mRECIST) were enrolled. Patients were treated with donafenib 200 mg orally twice daily, anti-PD-1 antibodies intravenously every three weeks, and transarterial therapy until disease progression or unacceptable toxicity. Endpoints include objective response rate (ORR, the proportion of patients with partial or complete response according to mRECIST and RECIST v1.1), surgical conversion rate (the proportion of patients who successfully underwent resection), progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety. Results: A total of 27 patients were enrolled (median age 52 years [range, 29–74], 81% males, 85% with HBV infection, 41% with cirrhosis, 48% with AFP level ≥400 ng/mL, and 67% in BCLC C). All patients received donafenib and anti-PD-1 antibodies with hepatic arterial infusion chemotherapy (HAIC, n = 10), transarterial chemoembolization (TACE, n = 8), or both (n = 9). By the cutoff date of January 6, 2023, the median follow-up duration was 6.8 months (95% confidence interval [CI], 5.9–7.7), and 17 (63.0%) patients were still undergoing treatment. The ORR and DCR were 59.3% and 92.6% by mRECIST, and 18.5% and 88.9% by RECIST v1.1, respectively. The surgical conversion rate was 22.2%, and the median surgical conversion time was 3.4 months (range, 2.2–4.6). The median PFS was 8.3 months (95% CI, 6.8–9.8), and median OS was not reached. The 6-month PFS rate and 12-month OS rate were 74.7% and 72.9%, respectively. Grade 3 treatment-related adverse events (TRAEs) were observed in 5 patients (18.5%), the most common of which was increased total bilirubin (11.1%). No grade 4/5 TRAEs occurred. Conclusions: Donafenib combined with anti-PD-1 antibodies plus transarterial therapy shows promising efficacy and manageable toxicity in patients with initially uHCC. Clinical trial information: NCT05638438 .

Durvalumab + tremelimumab in biologically selected advanced/metastatic solid tumors.

2604 Background: Tremelimumab (T) in combination with Durvalumab (D) is approved by the FDA for the treatment of unresectable hepatocellular carcinoma and metastatic non–small cell lung cancer. We prospectively examined its clinical activity in a cohort of biologically-selected advanced/metastatic solid tumors from the MOST Plus clinical trial (NCT NCT02029001). Methods: Adult patients (pts) previously treated by at least one prior line but immunotherapy-naive were eligible if their tumor harbored TMB-H (&gt;10mut/Mb) and/or MSI/dMMR (by PCR and IHC tests), and/or PD1/PD-L1/CTLA4 amplification and/or POLD1 or POLE mutation. T was administered for up to 4 cycles (75mg, IV, Q4W) and D (1500mg, IV, Q4W) until disease progression, unacceptable toxicity or patient/investigator decision. Tumor response was assessed as per RECIST 1.1 and adverse events reported according to NCI-CTCAE v4.03. Results: 70 patients were enrolled (24 male, median age: 65 years [33-88], MSI n=56, TMB-H n=10, PDL1 and PDL2 ampl. n=1, POLE mut. n=1, MSH6 mut. n=1, MSH2 mut. n=1). The median number of prior lines of systemic therapy was 1 (range: 0-4). Main tumor types were colorectal (44%), endometrial (19%), and stomach (7%) carcinomas. As of October 2022, overall response (ORR) rate was 52.8% (21.4% CR, 31.4% PR). With a median follow-up of 37 months, median PFS and OS were 8.4 months [95% CI: 4.4- 22.1] and 37.2 months [95% CI: 10.4-NE], respectively. Median duration response of response was not reached. Overall, 24.3% of patients experienced at least one serious treatment-related (TR) adverse event. Two TR-deaths were reported (haemophagocytic lymphohistiocytosis and nephritis). ORR, median PFS and OS are reported. Conclusions: T+D is a highly efficient combination in biologically selected tumors leading to a high complete response rate. Enrolment is still ongoing, to further evaluate the utility of a maintenance treatment, i.e the optimal treatment duration. Clinical trial information: NCT02029001 . [Table: see text]

Safety and Efficacy of Drug-Eluting Bead Transarterial Chemoembolization Combined with Lenvatinib and Anti-PD-1 Antibodies for Unresectable Hepatocellular Carcinoma: A Retrospective Analysis.

Drug-eluting bead transarterial chemoembolization (DEB-TACE) has good efficacy in the treatment of unresectable hepatocellular carcinoma (uHCC), with a relatively high objective response rate (ORR) compared to conventional transarterial chemoembolization (cTACE). This study aimed to evaluate the safety and medium-term clinical efficacy of DEB-TACE combined with lenvatinib (LEN) plus PD-1 inhibitors as a triple therapy for the treatment of uHCC. Data of patients with uHCC who received triple therapy of DEB-TACE combined with LEN plus PD-1 inhibitors from January 2019 to June 2021 were analyzed retrospectively. The study endpoints were ORR, progression-free survival (PFS), and treatment-related adverse events based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Thirty-five patients were included in this study, with a median follow-up period of 15 months. The median cycle of DEB-TACE was 1, while that of all forms of TACE procedures per patient was 2. The median administration time of LEN was 7 months, and the median number of PD-1 inhibitor treatment was 4 cycles. The ORR based on mRECIST was 82.9%, disease control rate was 91.4%, and the median time to response was 7 weeks. Among these, the ORR of Barcelona Clinic Liver Cancer (BCLC) stage A reached 100%, while that of BCLC stages B and C reached 84.6% and 78.9%, respectively. The median PFS was 9 months; the mOS was not reached. Fourteen patients (40%) successfully underwent downstaging conversion and surgical resection, 32 patients (91.4%) experienced treatment-related adverse events, and no grade 5-related adverse reactions occurred. DEB-TACE combined with LEN and PD-1 inhibitors has a high ORR and surgical conversion rate in the treatment of uHCC tumors, and the toxicity and side effects were tolerable.

P-334 Lenvatinib plus checkpoint inhibitors (ICIs) versus sorafenib plus ICIs as first-line treatment for unresectable hepatocellular carcinoma with Child-Pugh B

P-334 Lenvatinib plus checkpoint inhibitors (ICIs) versus sorafenib plus ICIs as first-line treatment for unresectable hepatocellular carcinoma with Child-Pugh B

CO70 Matching Adjusted Indirect Comparison (MAIC) of Single Tremelimumab Regular Interval Durvalumab (STRIDE) Versus Atezolizumab with Bevacizumab (A+B) for the Treatment of Unresectable Hepatocellular Carcinoma (UHCC)

STRIDE and A+B demonstrated superiority vs sorafenib (S) for overall survival (OS), with median follow-up times of 33.2m and 15.6m, respectively. As there are no trials comparing these two regimens, this analysis estimated the comparative efficacy and safety of STRIDE vs A+B, based on the HIMALAYA and IMbrave 150 clinical trials.

SO-14 Randomized, phase 3 study of tislelizumab versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma (HCC): RATIONALE-301 age ≥65 years subgroup

SO-14 Randomized, phase 3 study of tislelizumab versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma (HCC): RATIONALE-301 age ≥65 years subgroup

Tislelizumab (TIS) versus sorafenib (SOR) in first-line (1L) treatment of unresectable hepatocellular carcinoma (HCC): The RATIONALE-301 European/North American (EU/NA) subgroup.

4082 Background: HCC is one of the most commonly diagnosed cancers globally. Most cases occur in Asia, although a number of patients (pts) are affected in Europe and North America. In the phase 3, open-label RATIONALE-301 trial (NCT03412773), TIS, a PD-1 inhibitor, showed non-inferior overall survival (OS) versus SOR (hazard ratio 0.85, 95% CI: 0.71, 1.02), and a favorable safety profile, in 1L treatment of pts with unresectable HCC. Here, efficacy and safety of TIS versus SOR in the RATIONALE-301 EU/NA subgroup were compared with the overall population (OP). Methods: Systemic therapy-naïve adults with histologically confirmed HCC were randomized (1:1) to receive TIS (200 mg IV Q3W) or SOR (400 mg orally BID) until disease progression, intolerable toxicity, or withdrawal. The primary endpoint was OS; secondary endpoints included objective response rate (ORR), progression-free survival (PFS), and duration of response (DoR) by blinded independent review committee per RECIST v1.1, and safety. Results: In the EU/NA subgroup (172/674 pts randomized), at data cutoff (July 11, 2022), median (m) OS follow-up was 37.9 months (mo) (TIS) vs 38.5 mo (SOR). At baseline, fewer pts in the EU/NA subgroup had Barcelona Clinic Liver Cancer (BCLC) Stage C disease (70% vs 78%) and extrahepatic spread (51% vs 62%), and more had a non-viral etiology (60% vs 24%) or underlying HCV infection (28% vs 13%) than in the OP, respectively. Distribution of other baseline characteristics was generally similar between the EU/NA subgroup and the OP. Efficacy data in the EU/NA subgroup were consistent with the OP. Numerically longer mOS and mDoR, higher ORR, and similar mPFS were observed with TIS versus SOR in the EU/NA subgroup. In the EU/NA safety population, incidence of ≥grade 3 treatment-emergent adverse events (TEAEs; 46% vs 66%), ≥grade 3 treatment-related TEAEs (TRAEs; 17% vs 50%), and TRAEs leading to discontinuation (9% vs 15%) was lower with TIS versus SOR, respectively, similar to the OP. Conclusions: In the RATIONALE-301 EU/NA subgroup, mOS of TIS was non-inferior versus SOR, consistent with the findings from the OP. Numerically longer mOS and mDoR, and a higher ORR was seen with TIS versus SOR in the EU/NA subgroup, which had a higher rate of pts with non-viral etiology and a slightly lower number of pts with advanced-stage disease (BCLC Stage C) compared with the OP. Clinical trial information: NCT03412773 . [Table: see text]

Comparing the effectiveness and safety of Sorafenib plus TACE with Apatinib plus TACE for treating patients with unresectable hepatocellular carcinoma: a multicentre propensity score matching study

ObjectiveLocal combined systemic therapy has been an important method for the treatment of unresectable hepatocellular carcinoma (HCC).The purpose of this study was to compare the effectiveness and safety of transarterial chemoembolization (TACE) plus Sorafenib versus TACE plus Apatinib for treating patients with unresectable HCC.MethodsThe clinical data of patients with unresectable HCC who were treated with TACE plus Sorafenib or TACE plus Apatinib at 5 Chinese medical centers between January 2016 and December 2020 were retrospectively analyzed. Propensity score matching (PSM) was applied to reduce the bias from confounding factors.ResultsA total of 380 patients were enrolled, of whom 129 cases were treated with TACE plus Sorafenib and 251 cases with TACE plus Apatinib. After the 1:1 PSM, 116 pairs of patients were involved in this study. The results showed that the PFS and OS in the TACE-Sorafenib group were significantly longer than those in the TACE-Apatinib group (PFS: 16.79 ± 6.45 vs. 14.76 ± 6.98 months, P = 0.049; OS: 20.66 ± 6.98 vs. 17.69 ± 6.72 months, P = 0.013). However, the ORR in the TACE-Apatinib group was markedly higher than that in the TACE-Sorafenib group (70.69% vs. 56.03%, P = 0.021). There were more patients with adverse events (AEs) in the TACE-Apatinib group than those in the TACE-Sorafenib group before dose adjustment (87 vs. 63, P = 0.001); however, the number of patients who suffered from AEs was not significantly different between the two groups after the dose adjustment (62 vs. 55, P = 0.148). No treatment-related death was found in the two groups. Subgroup analysis revealed that patients with unresectable HCC could better benefit from regular doses than reduced doses (Sorafenib, 22.59 vs. 18.02, P < 0.001; Apatinib, 19.75 vs. 16.86, P = 0.005).ConclusionTACE plus either Sorafenib or Apatinib could effectively treat patients with unresectable HCC, the safety of TACE plus Sorafenib was better. and the ORR of TACE plus Apatinib was higher.

A Novel Nomogram for Predicting the Overall Survival in Patients with Unresectable HCC after TACE plus Hepatic Arterial Infusion Chemotherapy

Background and aimTransarterial chemoembolization combined with hepatic arterial infusion chemotherapy (TACE-HAIC) has shown encouraging efficacy in the treatment of unresectable hepatocellular carcinoma (HCC). We aimed to develop a novel nomogram to predict overall survival (OS) of patients with unresectable HCC treated with TACE-HAIC. MethodsA total of 591 patients with unresectable HCC treated with TACE-HAIC between May 2009 and September 2020 were enrolled. These patients were randomly divided into training and validation cohorts. The independent prognostic factors were identified with Cox proportional hazards model. The model's discriminative ability and accuracy were validated using concordance index (C-index), calibration plots, the area under the time-dependent receiver operating characteristic curve (AUC) and decision curve analyses (DCAs). ResultsThe median OS was 15.6 months. A nomogram was established based on these factors, including tumor size, vein invasion, extrahepatic metastasis, tumor number, alpha fetoprotein (AFP), and albumin-bilirubin (ALBI), to predict OS for patients with unresectable HCC treated with TACE-HAIC. The C-index of the nomogram were 0.717 in the training cohort and 0.724 in validation cohort. The calibration plots demonstrated good agreement between the predicted outcomes and the actual observations. The AUC values were better than those of three conventional staging systems. The results of DCA indicated that the nomogram may have clinical usefulness. The patients in the low-risk group had a longer OS than those in intermediate-risk and high-risk groups (P<0.001). ConclusionA prognostic nomogram was developed and validated to assist clinicians in accurately predicting the OS of patients with unresectable HCC after TACE-HAIC.

Lenvatinib in the treatment of unresectable hepatocellular carcinoma: a systematic review of economic evaluations.

This aim of this study was to conduct a systematic review of economic evaluations comparing lenvatinib to other vascular endothelial growth factor (VEGF) inhibitors and other treatment options in the management of unresectable hepatocellular carcinoma (uHCC). A comprehensive literature search was conducted using highly sensitive search syntax. The titles and abstracts of all records were studied and screened to identify eligible economic evaluations. To enable comparison across different countries, the results of economic evaluations make it possible to compare, the costs and ICER of all studies were converted into 2022 US dollars, and a 3% annual increase for inflation was applied. The quality of the studies was assessed using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist. This study is conducted and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Lenvatinib was found to be cost-effective (ICER = dominant) compared to most drugs in the included studies, except in studies where it was compared with donafenib or when the price of sorafenib was significantly discounted (e.g., with a 90% discount, the value of ICER was + 104,669 USD). Lenvatinib was generally cost-effective in most studies, but not compared to donafenib or sorafenib (if the price sorafenib was significantly discounted).

Targeting NAD+ metabolism of hepatocellular carcinoma cells by lenvatinib promotes M2 macrophages reverse polarization, suppressing the HCC progression.

Lowered nicotinamide adenine dinucleotide (NAD+) levels in tumor cells drive tumor hyperprogression during immunotherapy, and its restoration activates immune cells. However, the effect of lenvatinib, a first-line treatment for unresectable hepatocellular carcinoma (HCC), on NAD+ metabolism in HCC cells, and the metabolite crosstalk between HCC and immune cells after targeting NAD+ metabolism of HCC cells remain unelucidated. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) and ultra-high-performance liquid chromatography multiple reaction monitoring-mass spectrometry (UHPLC-MRM-MS) were used to detect and validate differential metabolites. RNA sequencing was used to explore mRNA expression in macrophages and HCC cells. HCC mouse models were used to validate the effects of lenvatinib on immune cells and NAD+ metabolism. The macrophage properties were elucidated using cell proliferation, apoptosis, and co-culture assays. In silico structural analysis and interaction assays were used to determine whether lenvatinib targets tet methylcytosine dioxygenase 2 (TET2). Flow cytometry was performed to assess changes in immune cells. Lenvatinib targeted TET2 to synthesize and increase NAD+ levels, thereby inhibiting decomposition in HCC cells. NAD+ salvage increased lenvatinib-induced apoptosis of HCC cells. Lenvatinib also induced CD8+ T cells and M1 macrophages infiltration in vivo. And lenvatinib suppressed niacinamide, 5-Hydroxy-L-tryptophan and quinoline secretion of HCC cells, and increased hypoxanthine secretion, which contributed to proliferation, migration and polarization function of macrophages. Consequently, lenvatinib targeted NAD+ metabolism and elevated HCC-derived hypoxanthine to enhance the macrophages polarization from M2 to M1. Glycosaminoglycan binding disorder and positive regulation of cytosolic calcium ion concentration were characteristic features of the reverse polarization. Targeting HCC cells NAD+ metabolism by lenvatinib-TET2 pathway drives metabolite crosstalk, leading to M2 macrophages reverse polarization, thereby suppressing HCC progression. Collectively, these novel insights highlight the role of lenvatinib or its combination therapies as promising therapeutic alternatives for HCC patients with low NAD+ levels or high TET2 levels.