Search Results (96)

Background: Atezolizumab plus bevacizumab (A + B) and durvalumab plus tremelimumab (D + T) are approved first-line systemic therapy options for advanced hepatocellular carcinoma (HCC), with no head-to-head comparison. In this propensity-matched analysis, we compared the survival of patients with advanced HCC who received either A + B or D + T therapy. Methods: Patients with advanced HCC who received A + B or D + T treatment in the first-line setting were identified using the TriNetX platform, a health research network that provides access to electronic health record data from 112 healthcare organizations. Propensity-score-matched (PSM) analysis was conducted, and the median overall survival (OS) was estimated using the Kaplan–Meier method. Results: We identified 2819 patients with HCC who were treated with A + B or D + T: 2031 patients received A + B and 788 received D + T. Compared to patients in the A + B cohort, those who received D + T were more likely to be older (median age: 68.4 vs. 66.9 years), have lower platelet counts (186.8 vs. 201.3), higher prevalence of hypoalbuminemia with levels < 2.7 g/dL (35.2% vs. 28.4%), higher prevalence of bilirubin levels between 2.0 and 2.9 mg/dL (28.8% vs. 23.8%), and decreased INR with levels between 0.0 and 1.6 (92.1% vs. 86.3%). After PSM, 1536 patients were included in the survival analyses, with all variables adequately matched. There was no significant difference in the median OS between those receiving A + B or D + T [16.3 vs. 22.5 months, hazard ratio (HR) 0.89, 95% confidence interval (CI) 0.76–1.0]. Higher rates of immune-mediated colitis were noted in the D + T group. Conclusions: Similar survival rates were observed among patients with advanced HCC who received A + B and D + T in the first-line setting. Our study suggests that both A + B and D + T are valid treatment options, and that therapy can be tailored based on comorbidities, adverse effects, and patient preferences. Full article

Background: Carbon-ion radiotherapy (CIRT) is an effective local treatment for hepatocellular carcinoma (HCC); however, evidence on systemic immunotherapy after CIRT and the role of CIRT following immunotherapy remains limited. This study aimed to assess clinical outcomes and sequencing of CIRT and systemic immunotherapy in real-world practice. Methods: We retrospectively analyzed 41 patients with HCC who received CIRT and systemic immunotherapy (atezolizumab plus bevacizumab or durvalumab plus tremelimumab). Patients were categorized into three groups: (i) systemic immunotherapy for recurrent HCC after CIRT (n = 20), (ii) curative-intent CIRT after systemic immunotherapy (n = 10), and (iii) CIRT for residual or insufficiently responding lesions (≤3 lesions) after systemic immunotherapy (n = 11). Results: In group (i), 14 of 20 patients achieved complete or partial responses. These responders had low tumor burden (within the up-to-7 criteria) and preserved liver function (modified albumin–bilirubin grade 1/2a) at treatment initiation and demonstrated significantly longer progression-free and overall survival than those with stable or progressive disease. In group (ii), 4 of 10 patients achieved a clinical complete response and became drug-free; notably, all had solitary intrahepatic tumors at immunotherapy initiation. In group (iii), the rate of transition to clinical complete response was low, and disease control remained limited. Conclusions: Systemic immunotherapy demonstrated high effectiveness in recurrent HCC following CIRT, particularly in patients with low tumor burden and preserved liver function. Moreover, curative-intent CIRT after immunotherapy may benefit patients with solitary intrahepatic tumors but appears limited in those with insufficient response to immunotherapy, including residual oligolesions. Full article

Background/Objectives: The efficacy of lenvatinib after different first-line immune checkpoint inhibitor (ICI)-based regimens for hepatocellular carcinoma (HCC) remains unclear. Materials and Methods: In this retrospective single-center study, we analyzed 56 patients with unresectable HCC who received lenvatinib as second-line therapy after atezolizumab plus bevacizumab (Atz/Bev; n = 41) or durvalumab plus tremelimumab (Dur/Tre; n = 15). Antitumor response was evaluated using RECIST v1.1 and modified RECIST (mRECIST). Results: Patients in the Dur/Tre group demonstrated significantly lower disease control rates (46.7% vs. 82.9%, p = 0.014) and shorter progression-free survival (PFS) (median, 56 vs. 210 days; p = 0.015) during prior ICI therapy, indicating more refractory disease. Despite this, lenvatinib demonstrated clinically meaningful antitumor activity after both Atz/Bev and Dur/Tre. Objective response rates were 12.2% vs. 26.7% by RECIST v1.1 and 41.5% vs. 60.0% by mRECIST in the Atz/Bev and Dur/Tre groups, respectively. Similar findings were observed in the Child–Pugh class A subgroup, in which mRECIST response rates were numerically higher in the Dur/Tre group. PFS and overall survival (OS) after lenvatinib initiation were comparable between groups. Objective responses were observed even in patients with progressive disease during prior ICI therapy. Multivariate analysis identified ECOG performance status and mALBI grade, but not prior ICI regimen or antitumor response, as independent prognostic factors for OS. Conclusions: Lenvatinib demonstrated clinically meaningful efficacy after both Atz/Bev and Dur/Tre, and no significant association was observed between prior ICI response and subsequent lenvatinib efficacy. These findings suggest that resistance to immunotherapy does not necessarily confer resistance to lenvatinib in patients with unresectable HCC. The observed differences in response patterns according to prior treatment exposure warrant further investigation and may have implications for treatment sequencing in the current ICI era. However, these findings should be considered hypothesis-generating and require validation in larger multicenter studies. Full article

Background/Objectives: The integration of locoregional and systemic therapies represents a promising strategy in hepatocellular carcinoma (HCC). Yttrium-90 (Y-90) radioembolization provides durable local tumor control, while immune checkpoint inhibitors (ICIs) improve systemic disease outcomes. This review evaluates the biological rationale, clinical evidence, and emerging role of combination Y-90 radioembolization and immunotherapy in HCC. Methods: A semi-systematic (PRISMA-informed) literature review of PubMed/MEDLINE through September 2025 was conducted, including clinical trials, retrospective and prospective studies, and translational investigations evaluating Y-90 radioembolization, immunotherapy, and their combination. Results: Preclinical and translational studies demonstrate that Y-90 radioembolization induces immunogenic cell death, enhances antigen presentation, and activates immune pathways including interferon signaling and STING-mediated responses, supporting a mechanistic basis for potential synergy with ICIs. Early clinical studies, including phase I/II trials, report objective response rates ranging from approximately 30% to 41.5% and median overall survival up to 20.9 months in selected populations. Treatment-related grade ≥ 3 adverse events range from 10% to 25%, comparable to monotherapy approaches. However, outcomes vary across heterogeneous patient populations, and cross-trial comparisons remain limited. Ongoing prospective trials are evaluating combination strategies incorporating contemporary first-line regimens, including atezolizumab plus bevacizumab and the STRIDE regimen. Conclusions: Combination Y-90 radioembolization and immunotherapy demonstrates a strong biological rationale and encouraging early clinical signals, with acceptable safety profiles. However, current evidence remains preliminary and derived from non-randomized studies. Ongoing randomized trials are required to define optimal patient selection, treatment timing, and sequencing, and to establish whether combination therapy provides meaningful benefit over current standards of care. Full article

Background/Objectives: Although thermal ablation is an established curative treatment for early-stage hepatocellular carcinoma (HCC), local tumor progression (LTP) after ablation remains a clinically important issue. In advanced-stage HCC treated with immunotherapy, ablation is increasingly performed concurrently with atezolizumab plus bevacizumab (atezo/bev). However, evidence regarding its clinical outcome is limited. This study aimed to evaluate the association between concurrent atezo/bev and LTP after ablation. Methods: This retrospective study included 467 ablated tumors from 376 treatment courses. Tumors were classified into two groups according to atezo/bev administration status. The cumulative incidence of LTP was compared between the two groups. Factors associated with LTP and ablation-related complications were also assessed. Results: Twenty-five tumors were ablated during atezo/bev treatment in 17 treatment courses (ablation + atezo/bev group), whereas 442 tumors were ablated without concurrent atezo/bev in 359 treatment courses (ablation-alone group). The cumulative incidence of LTP was significantly lower in the ablation + atezo/bev group than in the ablation-alone group (p = 0.031). In the multivariable analysis, ongoing atezo/bev treatment was independently associated with a reduced risk of LTP (hazard ratio, 0.124; p = 0.015). No significant differences in ablation procedure-related complications were observed between the two groups. Conclusions: Thermal ablation during atezo/bev treatment was associated with a reduced risk of LTP without an apparent increase in procedure-related complications. These findings suggest that concurrent administration of atezo/bev may be associated with improved local tumor control after ablation, supporting the feasibility of ablation as part of multidisciplinary treatment strategies for advanced-stage HCC. Full article

Background: Responses to atezolizumab plus bevacizumab (Atezo+Bev) in hepatocellular carcinoma (HCC) are heterogeneous, and response determinants remain unclear. We investigated whether spatial proximity between PD-L1(+) tumor-associated macrophages (TAMs) and CD8(+) T cells represents an immune niche associated with Atezo+Bev responsiveness. Methods: Multiplex immunohistochemistry was performed on biopsies from patients treated with Atezo+Bev (n = 23) or lenvatinib (n = 20). An interaction variable was defined via nearest-neighbor analysis as CD8(+) T cells within 25 µm of PD-L1(+) TAMs, normalized to cell counts. Associations with tumor shrinkage and progression-free survival (PFS) were examined. CD8(+) T cell phenotypes were evaluated via GZMB and TIM3. Transcriptomic profiling of resected HCCs (n = 8) was conducted using next-generation sequencing and gene set enrichment analysis (GSEA). Results: In a patient with responsive and non-responsive lesions, the responsive lesion showed closer PD-L1(+) TAM-CD8(+) T cell proximity. In cohort analyses, the interaction variable was associated with tumor shrinkage and prolonged PFS in the Atezo+Bev group, whereas PD-L1(+) TAM or CD8(+) T cell density alone was not predictive. This association was absent in the lenvatinib cohort. High-interaction tumors showed increased GZMB(+) and TIM3(+) CD8(+) T cells. Transcriptomic analysis revealed the upregulation of inflammatory, cytotoxic, chemotactic, and immunoregulatory genes, with enrichment of the chemokine, IFN-gamma, and IL-10 signaling pathways. Conclusions: Spatial proximity between PD-L1(+) TAMs and CD8(+) T cells defines an immune niche characterized by coexisting immune activation and regulatory programs and is strongly associated with Atezo+Bev responsiveness in HCC. Quantification of this spatial interaction may serve as a biopsy-based biomarker for immunotherapy stratification. Full article

Recent findings suggest that the gut microbiota modulates antitumor immunity and influences the efficacy of immune checkpoint inhibitors, yet no established consensus has been reached. This study examined the association between gut microbiota composition before initiation of atezolizumab plus bevacizumab combination therapy (Atez/Bev) and treatment response in patients with advanced hepatocellular carcinoma (HCC). Twenty-nine patients with advanced HCC from whom stool samples were collected before Atez/Bev treatment were enrolled. A comparative analysis was performed between the responder and non-responder groups to identify the genera associated with treatment response and progression-free survival (PFS). A total of 90 genera were identified. ROC analysis was performed for the responder and non-responder groups using the relative abundance of each genus. The prevalence of Faecalibacterium was significantly correlated with the responder group. Furthermore, multivariate analysis incorporating clinical prognostic factors also showed a statistically significant correlation between the prevalence of Faecalibacterium and the responder group. Analysis of the association with PFS revealed significantly prolonged PFS in the Acidaminococcus-high, Megamonas-high, Lachnoclostridium-low, and Flavonifractor-low groups. Multivariate analysis for PFS also confirmed significant correlations with the prevalence of Acidaminococcus and Megamonas. Our results suggest that gut microbiota may be associated with the efficacy of Atez/Bev treatment for advanced HCC. Full article

Background/Objectives: Atezolizumab plus bevacizumab (Atez/Bev) is a standard treatment for unresectable hepatocellular carcinoma (HCC), but its anti-tumor efficacy remains limited. Combining intrahepatic locoregional treatment (IHLRT) with Atez/Bev has been explored as a strategy to overcome this limitation. This study aimed to clarify the significance of IHLRT in Atez/Bev treatment for unresectable HCC. Methods: Eighty consecutive patients with unresectable HCC treated with Atez/Bev were retrospectively analyzed. IHLRT was performed in patients with residual viable hepatic lesions amenable to locoregional treatment during Atez/Bev therapy. Anti-tumor response was evaluated by RECIST; and progression-free survival (PFS), overall survival (OS), potential biomarkers, and contributing factors to OS were also assessed. Results: IHLRT was selectively performed in 20 patients based on individual clinical conditions. Pretreatment characteristics were comparable between patients who did and did not receive IHLRT. Both best and initial tumor responses were superior in the IHLRT group, and PFS was significantly longer (16.2 vs. 8.4 months, p = 0.019), with comparable rates of severe treatment-related adverse events. On multivariate analysis, hepatic reserve function, objective response, neutrophil-to-lymphocyte ratio (NLR) and IHLRT were independent predictors of OS (HR: 2.17, 3.13, 0.58, and 1.62; p = 0.02, <0.01, 0.03 and 0.03, respectively). Although high NLR was a negative predictive factor, IHLRT appeared to mitigate the negative prognostic impact of an elevated NLR. Conclusions: On-demand, selective IHLRT during Atez/Bev treatment is well tolerated and provides superior and more durable tumor control, particularly in patients achieving an initial objective response. Full article

Background: Atezolizumab plus bevacizumab (ATZ/BEV) is widely used as first-line therapy for advanced hepatocellular carcinoma (HCC); however, optimal subsequent treatment after ATZ/BEV failure remains unclear. Methods: Between October 2020 and August 2024, 165 patients with unresectable HCC treated with first-line ATZ/BEV were retrospectively analyzed. After excluding patients with insufficient follow-up, outcomes were compared between those who received lenvatinib (LEN) as second-line therapy (n = 49) and those who did not (n = 95). Results: Median overall survival (OS) was significantly longer in the LEN group than in the non-LEN group (20.9 vs. 8.47 months, p < 0.01). LEN administration was independently associated with improved OS (hazard ratio 0.48), and this benefit remained significant after inverse probability weighting adjustment (adjusted hazard ratio 0.50). Among LEN-treated patients, a lower albumin–bilirubin score before ATZ/BEV and a total LEN dose ≥ 400 mg were independent prognostic factors. Conclusions: Lenvatinib as second-line therapy after ATZ/BEV was associated with improved survival in unresectable HCC. Preservation of liver function and the ability to maintain adequate lenvatinib exposure were associated with favorable outcomes, likely reflecting baseline prognosis and treatment feasibility rather than lenvatinib-specific predictive factors. Full article

Background/Objectives: Atezolizumab plus bevacizumab (Atz+Bev) is widely used for advanced hepatocellular carcinoma (HCC), yet predictors of post-progression survival (PPS), a clinically meaningful endpoint reflecting the feasibility of treatment sequencing, remain unclear. We aimed to identify determinants of PPS and factors associated with successful transition to subsequent therapy after progressive disease (PD) on Atz+Bev. Methods: We retrospectively analyzed 132 patients with HCC who initiated Atz+Bev with Child–Pugh A and Eastern Cooperative Oncology Group performance status (ECOG PS) 0/1. PPS was defined as survival from radiological PD to death; tumor response was assessed by RECIST v1.1. Results: Among 132 patients treated with Atz+Bev, median progression-free and overall survival were 9.2 and 21.2 months. PD occurred in 97 patients, with a median PPS of 9.2 months. At PD, 76 patients (78.4%) maintained both Child–Pugh A and ECOG PS 0/1; 93.4% of these patients transitioned to subsequent therapy, compared with 38.0% of patients who did not maintain Child–Pugh A and ECOG PS 0/1. The median PPS values were 14.7 and 2.0 months, respectively (p < 0.0001). In this PD cohort, disease control achieved with subsequent therapy after radiological PD was associated with longer PPS (16.1 vs. 5.0 mosnths; p = 0.0002). ECOG PS 0, Child–Pugh A, absence of portal vein invasion, and AFP < 400 ng/mL at PD independently predicted prolonged PPS. A baseline Child–Pugh score of 5 independently predicted preservation of Child–Pugh A and ECOG PS 0/1 at PD. Conclusions: Initiating Atz+Bev under optimal liver function (Child–Pugh 5) and preserving hepatic reserve and performance status through progression are critical for enabling subsequent therapy and achieving longer PPS. Full article

Background/Objectives: Management of hepatocellular carcinoma (HCC) with macrovascular invasion (MVI) varies between systemic immunotherapy and locoregional approaches. We compared atezolizumab plus bevacizumab (Atezo–Bev) with locoregional therapy in treatment-naïve patients. Methods: We conducted a retrospective cohort study of patients with image- or biopsy-proven HCC and MVI, Child–Pugh A/B, and ECOG 0–1 who received first-line Atezo–Bev or locoregional therapy (transarterial chemoembolization [TACE] with or without external-beam radiotherapy [RT]). Inverse probability of treatment weighting (IPTW) minimized baseline imbalances. Primary outcomes were overall survival (OS) and progression-free survival (PFS). Modified RECIST assessed radiologic response, and major adverse events were classified using Society of Interventional Radiology criteria. Results: We analyzed 475 patients (Atezo–Bev, n = 191; locoregional therapy, n = 284). Baseline characteristics were similar, and IPTW achieved covariate balance. Median OS was 9.3 months with Atezo–Bev and 10.8 months with locoregional therapy; after IPTW, OS remained comparable (hazard ratio [HR] 0.95; 95% CI 0.76–1.19; p = 0.635). Median PFS was 6.0 versus 4.1 months, favoring Atezo–Bev; this persisted after IPTW (HR 0.64; 95% CI 0.52–0.79; p < 0.001). Objective response rates were similar (45% vs. 48%; p = 0.49). Major adverse events occurred in 11% of patients in both groups. Subgroup analyses showed no OS differences and a consistent PFS advantage with Atezo–Bev. Conclusions: In HCC with MVI, first-line Atezo–Bev achieved longer PFS than locoregional therapy, with comparable OS and safety, supporting Atezo–Bev as a valid and effective first-line option for disease control while locoregional modalities remain relevant within multidisciplinary care. Full article

Recent advances in systemic therapies have improved clinical outcomes for patients with unresectable hepatocellular carcinoma (uHCC), as shown in randomized phase 3 clinical trials. Given the availability of alternative systemic regimens, an early imaging biomarker of treatment efficacy is crucial to avoid delays in deciding whether to continue the current regimen or switch to another therapy. We report two cases of uHCC that demonstrated patchy pooling of contrast material within the tumor on early follow-up contrast-enhanced computed tomography after the initiation of atezolizumab combined with bevacizumab (AB therapy), an imaging feature consistent with the vascular lake-like phenomenon. In both cases, this imaging feature appeared at the first response assessment after several cycles, and each patient achieved a partial response as the best overall response per Response Evaluation Criteria in Solid Tumors version 1.1. Subsequently, each patient underwent or was considered for conversion therapy. The vascular lake-like phenomenon may represent an early imaging biomarker of treatment efficacy following AB therapy. Full article

Background/Objectives: Immune checkpoint inhibitor (ICI)-based combinations are the standard first-line therapy for unresectable hepatocellular carcinoma (HCC). A major challenge is the early identification of patients with primary progression (1st-PD) and those who experience early progression despite initial disease control (2nd-PD). This study evaluated whether very early treatment changes in alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP) could serve as predictors of treatment response during atezolizumab plus bevacizumab (Atz + Bev) therapy. Methods: A total of 147 patients treated with Atz + Bev were retrospectively analyzed. Serum tumor markers were measured approximately every 3 weeks, and radiologic responses were assessed using the Response Evaluation Criteria in Solid Tumors version 1.1 at week 6 (first evaluation) and again at a median of 14.8 weeks (second evaluation). Results: At the first evaluation, 32 patients achieved a partial response, 81 showed stable disease, and 25 had progression. In the week 3 landmark analysis, early increases in AFP (ratio ≥ 1.4) or DCP (ratio ≥ 1.0) identified patients who would experience primary radiologic progression, with a clear separation in landmark progression-free survival (PFS) (3.4 vs. 13.1 months; p < 0.001). Among the 109 patients with disease control at week 6, 92 maintained control and 17 progressed at the second evaluation. In the week 9 landmark cohort, modest rises in AFP (ratio ≥ 1.1) or DCP (ratio ≥ 1.5) identified individuals at risk for early secondary progression, again showing marked differences in landmark PFS (3.8 vs. 14.0 months; p < 0.001). Conclusions: The dynamic monitoring of AFP and DCP provides a simple framework for biomarker-based responder selection and adaptive treatment optimization during Atz + Bev therapy. Clinically actionable thresholds at weeks 3 and 9 may support timely treatment switching and the integration of locoregional strategies, enabling personalized, biomarker-guided management to improve outcomes in unresectable HCC. Full article

Background: Atezolizumab plus bevacizumab (Atezo + Bev) is the standard of care for treatment-naïve patients with unresectable hepatocellular carcinoma (uHCC). Proteinuria is a treatment-emergent adverse event that often leads to Bev interruption. However, the relationship between Bev-related proteinuria and renal dysfunction is unclear. We retrospectively investigated the impact of proteinuria after starting Atezo + Bev on renal function in patients with uHCC. Methods: We performed a single-arm retrospective study of patients with uHCC treated with Atezo + Bev between 25 September 2020 and 31 May 2022, at Kindai University Hospital, Japan. The impact of proteinuria on renal function during Atezo + Bev treatment was analyzed in terms of the correlation between changes in urine protein creatinine ratio (UPCR) and estimated glomerular filtration rate (eGFR) relative to baseline. Results: We analyzed data from 100 patients (median age 74 years; range 41–89; 75% male). During Atezo + Bev treatment, the median (interquartile range) maximum increase from baseline in UPCR was 0.39 (0.08 to 2.05) and the median maximum decline from baseline in eGFR was −7.5 (−20.5 to −3.0) mL/min/1.73 m². The Pearson and Spearman correlation coefficients (95% confidence intervals) between these variables were −0.16 (−0.34 to 0.04) and −0.13 (−0.32 to 0.07), respectively. Conclusions: We found no correlation between the changes in UPCR and eGFR during Atezo + Bev treatment. Bev interruption criteria are based on the degree of proteinuria; however, our results suggest that proteinuria does not necessarily impair renal function. Physicians should consider the risk–benefit profile when deciding whether to discontinue Bev in patients who develop proteinuria during Atezo + Bev treatment. Full article

Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality. Atezolizumab plus bevacizumab (Atezo/Bev) has emerged as a first-line therapy for unresectable HCC (uHCC), improving overall and progression-free survival (OS, overall survival and PFS, progression-free survival) in IMbrave150. This study evaluates the real-world efficacy and safety of Atezo/Bev in uHCC. Methods: A retrospective analysis was performed on 87 patients (median age 68 years) treated with Atezo/Bev at Houston Methodist Hospital between January 2020 and June 2023. Demographics, treatment patterns, radiological response, OS, PFS, and toxicities were reviewed. Atezo/Bev was administered per FDA guidelines (atezolizumab 1200 mg plus bevacizumab 15 mg/kg every 3 weeks). Results: Of 87 patients, 78% were male, 71% White, and 70% had BCLC stage C disease. Most (60%) had Child–Pugh class A liver function, and 62% had viral hepatitis. Median OS was 15.1 months (95% CI: 10.57–25.97) and PFS was 9.1 months (95% CI: 7.4–21.07). Objective response rate was 31.3% (CR 7.2%, PR 25%, SD 52%, PD 16%). OS was longer in CP A versus CP B patients (21.2 vs. 5.2 months, p < 0.001) and in those receiving post-Atezo/Bev locoregional therapy (21.2 vs. 10.4 months, p = 0.043). Discontinuation due to toxicity occurred in 14%, mainly gastrointestinal bleeding and fatigue. Conclusions: Atezo/Bev demonstrated favorable real-world efficacy and manageable toxicity in uHCC, particularly in patients with preserved liver function or multimodal therapy. Full article