Therapy For Unresectable Hepatocellular Carcinoma Research Articles

Envafolimab plus lenvatinib and transcatheter arterial chemoembolization for unresectable hepatocellular carcinoma: a prospective, single-arm, phase II study

Evidences regarding the feasibility of transcatheter arterial chemoembolization (TACE)-based therapy for unresectable hepatocellular carcinoma (uHCC) remains limited. This study aimed to investigate the efficacy and safety of TACE combined with envafolimab and lenvatinib for uHCC. Eligible patients with uHCC received envafolimab and lenvatinib after TACE until disease progression, conversion to surgery, intolerable toxicities, or death. The primary endpoint was the objective response rate (ORR) assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Between March 2022 and July 2022, 38 patients were included for safety analysis, and 36 patients were included for efficacy analysis. As of the data cutoff (13 December 2023), the median follow-up was 16.9 months. The ORR was 50%, and disease control rate (DCR) was 83.3% per RECIST 1.1 (ORR and DCR of both 83.3% per modified RECIST (mRECIST)). The median progression-free survival (PFS) was 7.58 months. Of 36 patients, 17 patients were converted to resectable HCC with a surgical conversion rate of 47.2%, and 16 patients underwent surgery with R0 resection rate of 100%, pathologic complete response (pCR) rate of 31.3%. Overall incidences of treatment-related adverse events (TRAEs) of any grade was 97.4%. Grade ≥ 3 TRAEs were observed in 52.6% patients. No treatment-related deaths occurred. Image mass cytometry (IMC) analysis revealed that combined treatment improved the immune status of the tumor microenvironment, and resident macrophages had the potential to predict efficacy of this treatment. Envafolimab plus lenvatinib and TACE yielded promising survival outcomes and conversion efficiency with a tolerable safety profile. Trial registration Clinical trials: NCT05213221.

Gut microbiota as a prognostic biomarker for unresectable hepatocellular carcinoma treated with anti-PD-1 therapy

ObjectiveTo investigate the relationship between the gut microbiome and the response to anti-PD-1-based combination therapy in unresectable hepatocellular carcinoma (HCC). We aimed to identify potential non-invasive biomarkers and new strategies to modulate immunotherapy in HCC.MethodsIn this study, fresh stool samples and clinical data were collected from unresectable HCC patients treated with anti-PD-1-based combination therapy at the Cancer Hospital of the Chinese Academy of Medical Sciences between January 2020 and December 2021. The patients were divided into two groups based on their response to treatment: the treatment responder group (R group) and the treatment non-responder group (NR group). The composition and diversity of the gut microbiome were bioinformatically analyzed by using the Whole Genome Shotgun strategy, including taxonomic composition analysis, Alpha diversity analysis, Beta diversity analysis, and differentially enriched bacterial taxa analysis. Differentially enriched bacterial taxa between R and NR groups were identified based on the magnitude of the linear discriminant analysis effect size (LEfSe) and analyzed for their impact on the survival of the patient.ResultsA total of 45 eligible patients with unresectable HCC treated with anti-PD-1-based combination therapy participated in this study. The gut microbiological composition and Alpha diversity of patients were not statistically different, but there was a statistically significant difference in Beta diversity between the R and NR groups. (PERMANOVA tests, P = 0.006). We further identified 56 enriched bacterial taxa in the R group and 44 enriched bacterial taxa in the NR group based on the LEfSe analysis (LDA >2.66, P< 0.05). Patients with a high abundance of Collinsella genus, Ruminococcus_AM4211, and Ruminococcus_AF25_28AC had a longer median PFS and median OS compared to those with low abundance (P < 0.05). On the contrary, the median PFS and OS of patients with a high abundance of Bacteroides_AF20_13LB and Veillonella_atypica were significantly shorter than those of patients with low abundance (P < 0.05). The multivariate analysis showed that the abundance of Bacteroides_AF20_13LB and Ruminococcus_ AF25_28AC was independent related factors for PFS, and the abundance of Bacteroides_AF20_13LB was an independent related factor of OS.ConclusionThe enrichment of specific gut microbiota affected clinical efficacy and survival benefits in HCC treated with anti-PD-1 therapy and may be a promising non-invasive gut microbial biomarker and a new strategy for modulating immunotherapy in HCC.

Is atezolizumab plus bevacizumab as first-line therapy for unresectable hepatocellular carcinoma superior to lenvatinib? a systematic review and meta‑analysis.

This meta-analysis was dedicated to evaluating the effectiveness and safety of Atezolizumab plus Bevacizumab (Atez/Bev) and Lenvatinib (LEN) as first-line systematic therapy for unresectable hepatocellular carcinoma (u-HCC). The prospective protocol for this study was registered with the PROSPERO (Registration number: CRD42022356874). Literature searches were conducted in PubMed, EMBASE database Cochrane Library, and Web Science to determine all clinical controlled studies that reported Atez/Bev and LEN for treating u-HCC. We. evaluated as primary end-point overall survival (OS) and progression-free survival (PFS), as well as other outcomes such as tumor response and adverse events (AEs).Quality assessment and data extraction of studies were conducted independently by three reviewers. Mean difference (MD) and odds ratio (OR) with 95% confidence interval (CI) were calculated using a fixed-effects or random-effects model. The meta-analysis was performed with RevMan 5.3 software. 12 retrospective cohort studies (RCSs) involving a total of 4948 patients were finally included. The results showed that compared with LEN, Atez/Bev can improve the patient's PFS (HR = 0.80, 95% CI: 0.72 ~ 0.88; p < 0.0001) and reduce the rate of overall AEs (OR = 0.46 95% CI: 0.38 ~ 0.55, p < 0.00001) and grade ≥ 3 AEs (OR = 0.43; 95% CI: 0.36 ~ 0.51, p < 0.00001), while there is no difference between OS and treatment responses rate (objective response rate, disease control rate, complete response, partial response, progressive disease, and stable disease) between two groups. In addition, the subgroup analysis shows that Atez/Bev can promote the OS of patients with viral hepatitis. (HR = 0.79, 95% CI: 0.67 ~ 0.95; p = 0.01), while LEN has an advantage in improving OS in patients with Child-Pugh grade B liver function (HR = 1.98, 95% CI: 1.50 ~ 2.63; p < 0.00001). Current evidence shows that compared with LEN, Atez/Bev has more advantages in PFS and safety in treating u-HCC and can improve the OS of patients with viral. LEN has advantages in improving the OS of patients with grade B liver function. However, more multicenter randomized controlled experiments are needed in the future to verify our results.

Initial treatment efficacy and safety of durvalumab plus tremelimumab combination therapy in unresectable hepatocellular carcinoma in clinical practice.

We aimed to evaluate the efficacy and safety of durvalumab plus tremelimumab (Dur + Tre) combination therapy in patients with unresectable hepatocellular carcinoma (uHCC) in clinical practice. We retrospectively evaluated 37 patients with uHCC from our institutions between April 2023 and January 2024. Patients were divided into first- and later-line groups for analysis of antitumor efficacy, adverse events (AEs), and transition rate to second-line treatment according to the Response Evaluation Criteria in Solid Tumors (RECIST). The disease control rate (DCR) for the first-line group was 80.9%, which was significantly higher than that for the later-line group (50%). The incidence of immune-related AEs (irAEs) was 24.3%, with grade 3 or higher irAEs including increased transaminase (8.1%), diarrhea (8.1%), and adrenal insufficiency (2.7%). The rates of drug withdrawal and discontinuation owing to AEs were 23.8% and 19%, respectively, in the first-line treatment and 31.2% and 12.5%, respectively, in the later-line treatment, with no significant difference. Analysis of changes in liver reserve using the albumin-bilirubin (ALBI) score showed no obvious loss of liver reserve for up to 12 weeks. The transition rate from first- to second-line therapy after progressive disease (PD) was as high as 94.7%. The efficacy and safety of Dur + Tre in clinical practice were comparable to those reported in a recent phase III trial. The first-line Dur + Tre therapy had a higher DCR than that of the later lines, and the transition rate to second-line therapy was considerably high, suggesting that Dur + Tre therapy would be more beneficial in first-line treatment.

Comparing watch-and-wait vs. resection in radiologic complete response after conversion therapy for unresectable hepatocellular carcinoma: correspondence

Comparing watch-and-wait vs. resection in radiologic complete response after conversion therapy for unresectable hepatocellular carcinoma: correspondence

Economic evaluation of camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma in the United States and China.

Camrelizumab combined with rivoceranib has been proven effective for treating unresectable hepatocellular carcinoma (uHCC). However, their higher prices than sorafenib could impose a substantial economic burden on patients. This study aimed to evaluate the relative cost-effectiveness of the combination of camrelizumab and rivoceranib versus sorafenib as first-line therapy for patients with uHCC from the perspective of the US and Chinese payers. Using data from the CARES-310 trial, a partitioned survival model (PSM) was developed, considering the perspectives of the US and Chinese payers. The model employed a 15-year time horizon and a biweekly cycle. Direct medical costs and utility data were collected from previous studies and open-access databases. Primary outcomes included quality-adjusted life years (QALYs) and the incremental cost-effectiveness ratio (ICER). Price simulations, sensitivity analyses, and subgroup analyses were conducted. The ICER for the US and China was $122,388.62/QALY and $30,410.56/QALY, respectively, falling below the willingness-to-pay (WTP) thresholds of $150,000/QALY for the US and $35,898.87/QALY for China. Price simulations indicated the cost-effectiveness of camrelizumab plus rivoceranib when the price of camrelizumab (200mg) remained below $6275.19 in the US and $558.09 in China. The primary determinant of cost-effectiveness in both regions was the cost of camrelizumab. The combination of camrelizumab and rivoceranib is a cost-effective first-line therapy for uHCC in both the US and China. Lowering their prices could significantly influence their cost-effectiveness and accessibility to patients. These findings will guide clinicians in treating uHCC and help decision-makers formulate value-based drug pricing strategies.

Efficacy and Safety of Durvalumab/Tremelimumab in Unresectable Hepatocellular Carcinoma as Immune Checkpoint Inhibitor Rechallenge Following Atezolizumab/Bevacizumab Treatment.

While guidelines recommend immune checkpoint inhibitor (ICI) rechallenge as second-line therapy for unresectable hepatocellular carcinoma (HCC), data supporting this remain limited, particularly regarding a standard regimen for first- and second-line treatments. Tremelimumab/durvalumab was recently approved but data on ICI rechallenge are lacking. The purpose of this study was to evaluate the early efficacy and safety of tremelimumab/durvalumab for HCC as an ICI rechallenge following initial ICI therapy with atezolizumab/bevacizumab. This multicenter retrospective study included patients with HCC who underwent treatment with tremelimumab/durvalumab, with relevant available clinical information. We evaluated the safety and efficacy of tremelimumab/durvalumab as ICI rechallenge following initial treatment with atezolizumab/bevacizumab. We analyzed the outcomes in patients who underwent tremelimumab/durvalumab as an ICI rechallenge and those who received tremelimumab/durvalumab as their initial ICI therapy RESULT: A total of 45 patients treated with tremelimumab/durvalumab were included, with 55.6% (25/45) undergoing ICI rechallenge. The objective-response and disease-control rates in patients who underwent ICI rechallenge were 14.3% (3/21) and 47.6% (10/21), respectively, similar to those in patients initially treated with tremelimumab/durvalumab. All patients (n = 3) who experienced the best response to progressive disease (PD) with initial atezolizumab/bevacizumab experienced PD during ICI rechallenge. The incidence rates of adverse events were similar between patient groups treated with tremelimumab/durvalumab as ICI rechallenge and initial ICI. Among patients experiencing immune-related adverse events (irAEs) with atezolizumab/bevacizumab, 75% (3/4) encountered similar irAEs during ICI rechallenge. Early safety and efficacy profiles of durvalumab/tremelimumab as ICI rechallenge are satisfactory.

Second-line Treatment Strategy in Unresectable Hepatocellular Carcinoma After First-line Atezolizumab Plus Bevacizumab.

Atezolizumab plus beva-cizumab (AteBev) are an integral part of first-line therapy for unresectable hepatocellular carcinoma (uHCC), whereas no second-line regimen has been developed for these patients. This study evaluated the efficacy of second-line therapy for uHCC following AteBev treatment. Sixty uHCC patients who were administered AteBev therapy were included in the study. Dynamic computed tomography was conducted after 6, 9, and 12 weeks, and blood tests were performed at baseline and after three weeks. After six weeks of AteBev therapy, 19 patients experienced partial response (PR), 12 had stable disease (SD), and 29 exhibited progressive disease (PD), with an overall response rate (ORR) of 31.7%. Of the 21 patients treated with lenvatinib as second-line treatment, one dropped out, nine experienced a compete response (CR) or PR, and 11 had SD or PD, resulting in an ORR of 45.0%. Serum levels of fibroblast growth factors (FGF)-19 increased substantially following lenvatinib therapy in the CR+PR group, although the levels decreased significantly in the SD+PD group. Soluble FGF-R4 levels did not differ significantly between the CR+PR group and the SD+PD group when assessed before and after lenvatinib treatment. Lenvatinib is useful as second-line treatment after Ate/Bev for uHCC patients who do not response to Ate/Bev treatment. Changes in serum FGF-19 levels after three weeks of AteBev therapy may serve as a biomarker for selecting lenvatinib as second-line therapy.

Atezolizumab- and bevacizumab -induced encephalitis in a patient with advanced hepatocellular carcinoma: a case report and literature review

Treatment with atezolizumab and bevacizumab is the first-line therapy for unresectable hepatocellular carcinoma. Although immune checkpoint inhibitors are novel and effective treatments, they can induce immune-related adverse events. However, neurological immune-related adverse events have rarely been reported. We report the case of a man in his 40s with hepatocellular carcinoma who developed life-threatening encephalitis after atezolizumab plus bevacizumab was administered. The patient presented with fever, headache, altered mentality, and general epileptic seizures, ten days after administration. Cerebrospinal fluid analysis showed elevated white blood cells and elevated protein levels, but revealed no infection or malignancy. Brain magnetic resonance imaging showed diffuse leptomeningeal enhancement in both the cerebrum and cerebellum. As immune checkpoint inhibitor-induced encephalitis was strongly suspected, steroid pulse therapy was initiated and neurological symptoms quickly improved. The patient was discharged after 66 days of hospitalization, and administration of sorafenib and radiotherapy was started for the hepatocellular carcinoma on an outpatient basis. This case demonstrates the importance of recognizing neurological immune-related adverse events following atezolizumab and bevacizumab treatment for early intervention. We discuss this case in comparison to available literature and previous two cases of Atezolizumab- and bevacizumab- induced encephalitis in hepatocellular carcinoma.

Dynamic Changes of Neutrophil-to-Lymphocyte Ratio on Predicting Response of Immune Checkpoint Inhibitors Plus Targeted Therapies for Unresectable Hepatocellular Carcinoma.

Multiple regimens of immune checkpoint inhibitors (ICIs) plus targeted therapies are commonly prescribed as first-line treatments for unresectable hepatocellular carcinoma (uHCC). Here, we aimed to investigate the correlation between dynamic changes of neutrophil-to-lymphocyte ratio (NLR) and tumor response to the combination of ICIs and targeted therapies for uHCC. Sixty-one patients who received ICIs plus targeted therapies for uHCC were enrolled in this retrospective study. The NLR before and at 3-6 weeks after treatments were assessed to calculate the dynamic NLR changes (ΔNLR). Multivariate logistic regression and Cox regression models were used to explore the relationship between dynamic NLR changes and tumor response or progression-free survival (PFS), respectively. Furthermore, we assessed the predictive effect of alpha-fetoprotein (AFP) changes in combination with dynamic NLR changes compared to AFP changes alone. The NLR at 3-6 weeks and ΔNLR after treatments significantly increased in patients who underwent progressive disease (PD), while the baseline NLR showed no significant difference between different tumor responses. Increased NLR and AFP after treatments were both independent predictors of PD (For NLR increase: OR, 2.28; 95% CI, 1.47-3.88, P < 0.001; For AFP increase: OR, 1.46; 95% CI, 1.03-2.17, P = 0.043), and correlated with worse PFS (for NLR increase: HR, 4.08; 95% CI, 1.99-8.36, P < 0.001; for AFP increase: HR, 2.10; 95% CI, 1.04-4.24, P = 0.039). The receiver operating characteristic (ROC) curve and net reclassification index (NRI) showed that the combination of dynamic NLR and AFP changes was better than AFP changes alone on predicting PD (AUC: 0.83 vs 0.68, P = 0.034; NRI: 0.340, P = 0.048) and PFS (AUC: 0.80 vs 0.70, P = 0.166; NRI: 0.431, P = 0.042). Dynamic changes of NLR might be an effective predictor of the therapeutic response to ICIs plus targeted therapies for uHCC.

Pathological complete response after conversion therapy in unresectable hepatocellular carcinoma: a retrospective study

BackgroundHepatocellular carcinoma is a highly lethal tumor worldwide, and China has a correspondingly high incidence and mortality rate. For patients with unresectable hepatocellular carcinoma, the prognosis is often poor. The objective of this retrospective study was to investigate the effects of conversion therapies on these patients.MethodsThe study included patients between the ages of 18 and 75 who were initially diagnosed with unresectable hepatocellular carcinoma and received conversion therapy. After completing surgery, the patients underwent pathological diagnosis, which showed complete necrosis. The study was conducted retrospectively at the First Affiliated Hospital, Zhejiang University School of Medicine, from January 2019 to December 2021. The main objectives of the study were to evaluate the overall survival and recurrence-free survival.ResultsA total of 60 patients who met the inclusion criteria were enrolled. The median age of the patients was 56.6 ± 9.5 years, and 85% of them were male. The one-year overall survival rate (OS) was 98.3%, and the three-year OS was 95.6%. The one-year recurrence-free survival rate (RFS) was 81.1%, and the three-year RFS was 71.4%. In subgroup analysis, there was no statistically significant difference in RFS between patients with BCLC stages 0-A and BCLC stages B-C (p = 0.296). Additionally, there was no statistically significant difference in RFS between patients who received postoperative new adjuvant therapy and those who did not (p = 0.324).ConclusionsConversion therapy followed by surgical resection could be a promising treatment for patients with initially unresectable hepatocellular carcinoma, and the prognosis is good with a pathological complete response.

Interleukin-7 Risk Allele, Lymphocyte Counts, and Autoantibodies for Prediction of Risk of Immune-Related Adverse Events in Patients Receiving Atezolizumab plus Bevacizumab Therapy for Unresectable Hepatocellular Carcinoma.

Atezolizumab plus bevacizumab (AB) therapy was the effective immune checkpoint inhibitor (ICI) for unresectable hepatocellular carcinoma (u-HCC). However, immune-related adverse events (irAEs) are common in patients receiving ICI therapies. Our research aimed to explore the risk factors for irAE development, with attention to interleukin-7 (IL-7) risk alleles, lymphocyte counts, and autoantibodies. Seventy-six patients receiving AB therapy for u-HCC were recruited. Single nucleotide polymorphism genotyping was done for the analysis of rs16906115 polymorphism near IL-7-expressing genes using 20 μL of stored buffy coat at baseline. The association between IL-7 risk alleles, lymphocyte counts, autoantibodies, and irAE development was investigated. irAEs were found in 14 (18%) patients. The incidence of irAEs did not differ significantly between the groups showing IL-7 AG/AA and the GG group (p = 0.72). The incidence in the group with a lymphocyte count of 1,130/µL or more at baseline was higher than in that with a value below 1,130/µL (p = 0.0093). The group showing IL-7 AG/AA or lymphocyte count &gt;1,130/μL had a higher irAE prevalence rate than the others (p = 0.019). IL-7 AG/AA or lymphocyte count &gt;1,130/μL and positivity for autoantibodies at baseline were the prognostic factors for irAE development. irAE incidence could be stratified using a combination of IL-7 AG/AA or lymphocyte counts ≥1,130/µL and positive autoantibodies (p = 0.016). Patients with IL-7 risk alleles, high lymphocyte counts, and autoantibodies at baseline may require careful monitoring for irAE development.

Machine learning-based decision support model for selecting intra-arterial therapies for unresectable hepatocellular carcinoma: A national real-world evidence-based study.

Intra-arterial therapies(IATs) are promising options for unresectable hepatocellular carcinoma(HCC). Stratifying the prognostic risk before administering IAT is important for clinical decision-making and for designing future clinical trials. To develop and validate a machine learning(ML)-based decision support model(MLDSM) for recommending IAT modalities for unresectable HCC. Between October 2014 and October 2022, a total of 2,959 patients with HCC who underwent initial IATs were enroled retrospectively from 13 tertiary hospitals. These patients were divided into the training cohort (n = 1700), validation cohort (n = 428), and test cohort (n = 200). Thirty-two clinical variables were input, and five supervised ML algorithms, including eXtreme Gradient Boosting (XGBoost), Categorical Gradient Boosting (CatBoost), Gradient Boosting Decision Tree (GBDT), Light Gradient Boosting Machine (LGBM) and Random Forest (RF), were compared using the areas under the receiver operating characteristic curve (AUC) with the DeLong test. A total of 1856 patients were assigned to the IAT alone Group(I-A), and 1103 patients were assigned to the IAT combination Group(I-C). The 12-month death rates were 31.9% (352/1103) in the I-A group and 50.4% (936/1856) in the I-C group. For the test cohort, in the I-C group, the CatBoost model achieved the best discrimination when 30 variables were input, with an AUC of 0.776 (95% confidence intervals [CI], 0.833-0.868). In the I-A group, the LGBM model achieved the best discrimination when 24 variables were input, with an AUC of 0.776 (95% CI, 0.833-0.868). According to the decision trees, BCLC grade, local therapy, and diameter as top three variables were used to guide clinical decisions between IAT modalities. The MLDSM can accurately stratify prognostic risk for HCC patients who received IATs, thus helping physicians to make decisions about IAT and providing guidance for surveillance strategies in clinical practice.

Clinical significance of circulating biomarkers of immune-checkpoint molecules with atezolizumab plus bevacizumab therapy in unresectable hepatocellular carcinoma.

The aims of this study were to identify clinically significant biomarkers of a response to atezolizumab plus bevacizumab (ATZ + BV) therapy and to develop target strategies against unresectable hepatocellular carcinoma (u-HCC). We first investigated the potential of circulating tumor DNA (ctDNA) to serve as a biomarker for predicting the therapeutic outcome in 24 u-HCC patients treated with ATZ + BV therapy. Next, we analyzed levels of immune-related cytokines in blood samples from 134 u-HCC patients who received ATZ + BV. For this, serum immune-related molecules or cancer-immune cycle-related molecules that have been reported in HCC patient sera, namely CD274, LAG-3, CCL2, 4, 5, CXCL1, 9, 10, 12, 13, CX3CL1, CCR5, IFNγ and IL-6, 8 were measured using enzyme-linked immunosorbent assay. More than 1% of variant read frequency (VRF) mutations were found in TP53, APC, PIK3CA and VHL, although with no correlation with treatment response. Among the 15 cytokines evaluated, CXCL9 and LAG-3 levels were significantly different between patients with objective response (OR), stable disease (SD), and progressive disease (PD) following ATZ + BV treatment. Receiver-operating characteristic curve analyses of CXCL9 (cut-off value: 419.1pg/ml) and LAG-3 (cut-off value: 3736.3pg/ml) indicated areas of 0.779 and 0.697, respectively, for differentiating PD from non-PD and OR from non-OR. In multivariate analysis of progression-free survival (PFS) and overall survival (OS), high serum CXCL9 (hazard ratio (HR) and 95% confidence interval (CI): 0.412 (0.251-0.677) (p = 0.0005) for PFS and 0.252 (0.125-0.508) (p = 0.0001) for OS), and low serum LAG-3 (HR and 95% CI 0.419 (0.249-0.705) (p = 0.0011) for PFS and 0.294 (0.140-0.617) (p = 0.0012) for OS) were independent positive predictive factors. Although, as far as we examined, no ctDNA mutations in blood were found to be related to ATZ + BV treatment efficacy, serum CXCL9 and LAG-3 levels, which are related to the cancer-immune cycle, were associated with treatment efficacy and could be predictive markers of the efficacy of ATZ + BV treatment in HCC patients.

Anti-PD-1/L1 antibody plus anti-VEGF antibody vs. plus VEGFR-targeted TKI as first-line therapy for unresectable hepatocellular carcinoma: a network meta-analysis.

This article is based on our previous research, which was presented at the 2023 ASCO Annual Meeting I and published in Journal of Clinical Oncology as Conference Abstract (JCO. 2023;41:e16148. doi: 10.1200/JCO.2023.41.16_suppl.e16148). Both anti-programmed death 1/ligand-1 (PD-1/L1) antibody + anti-vascular endothelial growth factor (VEGF) antibody (A + A) and anti-PD-1/L1 antibody + VEGF receptor (VEGFR)-targeted tyrosine kinase inhibitor (A + T) are effective first-line therapies for unresectable hepatocellular carcinoma. However, there lacks evidence from head-to-head comparisons between these two treatments. We conducted a network meta-analysis on the efficacy and safety of them. After a rigorous literature research, 6 phase III trials were identified for the final analysis, including IMbrave150, ORIENT-32, COSMIC-312, CARES-310, LEAP-002, and REFLECT. The experiments were classified into three groups: A + A, A + T, and intermediate reference group. The primary endpoint was overall survival (OS), and secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and incidence of treatment-related adverse events (TRAEs). Hazard ratio (HR) with 95% confidence intervals (CI) for OS and PFS, odds ratio (OR) for ORR, and relative risk (RR) for all grade and grade ≥3 TRAEs were calculated. Under Bayesian framework, the meta-analysis was conducted using sorafenib as intermediate reference. With the rank probability of 96%, A + A showed the greatest reduction in the risk of death, without significant difference from A + T (HR: 0.82, 95% CI: 0.65-1.04). A + T showed the greatest effect in prolonging PFS and improving ORR with the rank probability of 77%, but there were no statistical differences with A + A. A + A was safer than A + T in terms of all grade of TRAEs (RR: 0.91, 95% CI: 0.82-1.00) and particularly in those grade ≥3 (RR: 0.65, 95% CI: 0.54-0.77). A + A had the greatest probability of delivering the longest OS, while A + T was correlated with larger PFS benefits at the cost of a lower safety rate.

Safety/efficacy of atezolizumab + bevacizumab during anti-platelet/anticoagulation therapy in unresectable hepatocellular carcinoma.

This study aimed to determine the safety and efficacy of atezolizumab + bevacizumab therapy in hepatocellular carcinoma patients receiving anti-platelet agents or anticoagulants. Patients were divided into those using (IM out) and those not using (IM in) anti-platelet agents or anticoagulants, who violated the exclusion criteria of the IMbrave150 trial, and were retrospectively examined. The study included 185 patients (IM in: 157; IM out: 28). For first-line treatment, progression-free survival was 184 days for IM in and 266 days for IM out (p = .136). Overall survival was 603 days for IM in and not reached for IM out (p = .265), with no significant between-group difference. Similarly, there were no significant between-group differences in progression-free survival or overall survival for later-line treatment. Haemorrhagic adverse events of ≥grade 3 were observed in 11 IM in patients and 3 IM out patients. No significant factors associated with haemorrhagic adverse events of ≥grade 3 were identified in the multivariate analysis including IM out classification, whose p value was .547. Regarding thrombotic/embolic adverse events in the IM out group, one case of exacerbation of portal vein thrombosis was observed. No deaths were directly attributable to bleeding events or exacerbations of thrombosis. Atezolizumab + bevacizumab therapy shows similar safety and efficacy in patients receiving and those not receiving anti-platelet agents or anticoagulants; therefore, it can be considered for patients with hepatocellular carcinoma receiving anti-platelet agents or anticoagulants.

Cure can be Achieved by Conversion to Microwave Ablation following Atezolizumab-Bevacizumab Therapy in Unresectable Hepatocellular Carcinoma.

Atezolizumab/bevacizumab is the recommended first-line systemic therapy for unresectable hepatocellular carcinoma (uHCC) and may facilitate curative conversion through resection and locoregional therapies. However, there have been very few reports on curative conversion using microwave ablation (MWA). This study aimed to determine the curative conversion rate with MWA using atezolizumab-bevacizumab as the first-line treatment in patients with uHCC, and to compare the characteristics and survival of patients with and without curative conversion. Consecutive patients with uHCC who were started on atezolizumab-bevacizumab from May 2021 and December 2023 in a single tertiary center were included. Objective response (ORR) and disease control rate (DCR) were based on the RECIST 1.1 and mRECIST criteria. Twenty consecutive patients with uHCC (60% advanced-stage) were included, 90% exceeding the up-to-7 criteria. The ORR and DCR were 35% and 60%, and 35% and 55% using RECIST and mRECIST, respectively. Five (25%) patients underwent successful curative conversion with MWA (4 advanced and 1 intermediate stage) despite a median HCC size of 6.1 (range: 2.4-7.3) cm. Two of these patients were tumor and drug-free 132-133 weeks from the 1st atezolizumab-bevacizumab dose. Patients who underwent curative conversion had significantly longer survival than those who did not. (p=0.024) Other factors associated with survival were male sex, Child-Pugh class A, and an objective response. Despite the relatively large tumor size, successful curative conversion with MWA was achieved with first-line atezolizumab-bevacizumab in uHCC. However, data from prospective multicenter trials are required to determine whether this strategy is universally applicable.

Transarterial chemoembolization (TACE) combined with donafenib as first-line therapy for unresectable hepatocellular carcinoma (uHCC): A real-world clinical study.

e16145 Background: To evaluate the efficacy and safety of TACE combined with Donafenib, which is as a new tyrosine kinase inhibitors therapy recommended by the China liver cancer staging (CNLC) system for the treatment of unresectable hepatocellular carcinoma (uHCC). Methods: We conducted a single-center, retrospective study on patients diagnosed with uHCC treated by TACE plus Donafenib as the first-line therapy between May 2021 and September 2023 at The First Affiliated Hospital of Sun Yat-sen University. The primary outcomes evaluated in this study were progression-free survival (PFS) and overall survival (OS). Local response, one-year survival rate, safety and tolerability were the secondary outcomes. Results: All of 48 eligible patients by August, 2023, with the median age of 59 years. The clinical characteristics were as follows: BCLC stage A:2 (4.2%), B:16 (33.3%), and C:30 (62.5%); Child-Pugh class A:33 (68.8%) and B:15 (31.2%); ECOG PS 0: 27 (56.2%) and 1: 21 (43.7%). In this study, 10 (20.8%) patients had huge intrahepatic lesions, 15 (31.2%) subjects exhibited extrahepatic metastases at multiple sites, 19 (42.2%) patients presented with portal vein tumor thrombus, and 4 patients were diffuse-type HCC.107 TACE sessions were performed. Three patients had liver transplantation as frequent therapy, and histopathological examination of tissue from these subjects revealed complete necrotic foci. The median PFS was 12.8 months (95% CI: 8.66–NA) , mOS was not reached and the one-year OS rate was 87.5% (95% CI: 77%-97%) in the survival results. The tumor objective response rate was 58.3% with 14.5% complete response and 43.7% partial response based on mRECIST assessment. The disease control rate of the study group was 81.3%. The most common treatment-related adverse events (TRAEs) observed were elevated aspartate aminotransferase (AST) levels (75.0%), increase in bilirubin level (72.9%), elevated alanine aminotransferase (ALT) levels (54.2%), hand-foot syndrome (53.1%), diarrhea (29.1%), rashes (22.9%), hair loss (18.4%) and hypertension (12.5%). Twenty-three (46.9%) patients presented with grade 3 or 4 TRAEs including elevated AST levels (22.4%), elevated ALT levels (16.3%), increase in bilirubin level (4%), diarrhea (4%) and hypertension (2%). No Grade 5 TRAEs were observed. Conclusions: The combination of TACE and Donafenib presented good efficacy and tolerability, which could be potentially used as the first-line treatment of Chinese uHCC patients.

Real-world study of anlotinib monotherapy and combination therapy for unresectable hepatocellular carcinoma.

e16146 Background: Unresectable hepatocellular carcinoma (uHCC) is an aggressive tumor with poor prognosis. Anlotinib is a novel small-molecule tyrosine kinase inhibitor (TKI) that selectively targets VEGFR, FGFR, PDGFR, and c-kit receptors. Clinical trials have confirmed the efficacy and safety of anlotinib monotherapy or anlotinib-based combination therapy for uHCC. However, many patients in clinical practice fail to meet the criteria for these trials. Therefore, this study aimed to investigate the efficacy and safety of anlotinib, as monotherapy or in combination therapy, for uHCC in clinical practice in China. Methods: This multicenter, real-world study enrolled patients with uHCC who had received anlotinib-based therapy, and completed at least one post-treatment efficacy assessment between July 2020 to February 2023. Patients who did not undergo imaging after one cycle of treatment, were lost to follow-up before completing one cycle of treatment, or required systemic chemotherapy or radiotherapy for the primary lesion were excluded from the study. The efficacy assessments were performed based on the RECIST version 1.1. OS, PFS, TTP, DCR and ORR for patients with anlotinib monotherapy (n = 12) and anlotinib-based combination therapy (n = 60) were evaluated. The main statistical analysis was conducted using the Kaplan–Meier method and log-rank test. Subgroup comparisons were performed based on different combinations of anlotinib therapy and the number of treatment lines in patients with uHCC. Occurrence of adverse events (AEs) to evaluate the safety profiles of anlotinib monotherapy or anlotinib-based combination therapy was collected. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire HCC-18 (EORTC QLQ-HCC18) was used to evaluate health-related quality of life (HRQOL). Results: For the anlotinib monotherapy group, the OS, PFS, TTP, DCR and ORR were 14.2 months, 6.9 months, 7.9 months, 16.7%, and 50.0%, respectively. For the anlotinib-based combination therapy group, these values were 15.8 months, 8.6 months, 10.2 months, 25.0%, and 65.0%, respectively. There was no significant difference in OS, PFS, and TTP between the two groups. PFS were significantly decreased in the non-first-line treatment group compared to the first-line treatment group. The incidence of drug-related AEs of any grade was 93.1%, with the most common grade ≥3 treatment-related AEs being lymphopenia and elevated transaminases. The time to deterioration was 14.0 months (95%CI: 8.3–19.8) and 12.2 months (95%CI: 9.8–14.7) in the monotherapy and combination therapy groups. Conclusions: Anlotinib demonstrated satisfactory efficacy and safety as a single agent and in combination with other therapies in the treatment of uHCC, with potential benefit on health-related quality of life.

Camrelizumab plus rivoceranib vs sorafenib as first-line therapy for unresectable hepatocellular carcinoma (uHCC): Final overall survival analysis of the phase 3 CARES-310 study.

4110 Background: The phase 3 CARES-310 trial is the first to demonstrate significant progression-free survival (PFS) and overall survival (OS) benefits with immunotherapy plus an anti-angiogenic tyrosine kinase inhibitor (TKI) over standard TKI as first-line treatment for uHCC. In the primary analysis of PFS (data cut-off [DCO], May. 10, 2021) and interim analysis of OS (DCO, Feb. 8, 2022), significant improvements were observed with camrelizumab (C; anti-PD-1 antibody) + rivoceranib (R; VEGFR2-TKI) vs. sorafenib (S). Here, we report updated data at the final analysis (FA), after an additional follow-up of ~16 mo. Methods: In this international, randomized, open-label, phase 3 trial, 543 patients with uHCC who had not previously received systemic treatment were randomized 1:1 to receive either C (200 mg, iv, q2w) + R (250 mg, po, qd) or S (400 mg, po, bid). As of Jun.14, 2023, 351 (65%) deaths occurred, and a protocol-specified FA was performed. Results: 272 patients were allocated to C+R and 271 to S. At DCO of FA, median follow-up was 22.1 mo in C+R group and 14.9 mo in S group. After end of study treatment, 36% of patients in C+R group and 42% in S group received subsequent targeted therapy; 17% and 36% received immunotherapy, respectively. Median OS was significantly prolonged with C+R vs . S (23.8 mo [95% CI 20.6-27.2] vs. 15.2 mo [95% CI 13.2-18.5]; hazard ratio (HR) 0.64 [95% CI 0.52-0.79]; 1-sided p &lt;0.0001). OS rate with C+R vs.S was 49.0% vs. 36.2% at 24 mo, and 37.7% vs. 24.8% at 36 mo. OS benefits with C+R was generally consistent across subgroups, regardless of geographical region, race, and aetiology. Benefits in PFS, objective response rate (ORR) and duration of response (DoR) with C+R were also sustained after prolonged follow-up (Table). Safety data aligned with the interim OS analysis, with no new signals noted. Conclusions: At the protocol-specified FA, C+R continued to show clinically meaningful survival improvement compared with S, with manageable safety. The extended follow-up further confirmed the favorable benefit-to-risk profile of C+R, supporting it as a new first-line treatment option for uHCC. Clinical trial information: NCT03764293 . [Table: see text]