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Introduction: Atezolizumab plus bevacizumab (Atez/Bev) was the first immune checkpoint inhibitor regimen approved in 2020 for unresectable hepatocellular carcinoma (uHCC), followed by durvalumab plus tremelimumab (Dur/Tre) in 2023. There is very little data available comparing the efficacy and safety of Atez/Bev with those of Dur/Tre. This study aimed to clarify the therapeutic outcomes and safety of Atez/Bev and Dur/Tre. Methods: We retrospectively analyzed patients with uHCC (BCLC-B/C and Child-Pugh class A) treated with Atez/Bev (n = 302) or Dur/Tre (n = 129) as first-line systemic therapy across multiple institutions between 2023 and 2025. A retrospective comparison of the treatment outcomes and safety of Atez/Bev and Dur/Tre was conducted. Results: The objective response rate and disease control rate were comparable between the Atez/Bev and Dur/Tre groups (31.8%/71.9% vs. 28.7%/63.6%, p = 0.570/p = 0.110, respectively). Median progression-free survival (PFS) was longer with Atez/Bev (9.1 vs. 5.0 months, p = 0.002), while OS was comparable (25.6 vs. 22.1 months, p = 0.172). Similar results were shown after adjusting with inverse probability weighting (IPW). Grade 5 immune-related adverse events occurred in 0.3% (n = 1, interstitial pneumonia) of the patients receiving Atez/Bev and 0.8% (n = 1, colitis) of those receiving Dur/Tre. In the Cox hazard analysis adjusted with IPW, Dur/Tre demonstrated a favorable trend in OS (hazard ratio [HR] <0.75) in patients with elevated alpha-fetoprotein (AFP) (≥100 ng/mL) (HR 0.72, interaction p = 0.006) or double positive elevation of tumor marker (AFP and des-gamma-carboxy prothrombin [≥100 mAU/mL]) (HR 0.66, interaction p = 0.005). Conclusion: Although Atez/Bev was associated with a longer PFS, OS did not differ significantly between Atez/Bev and Dur/Tre. This dissociation between PFS and OS may reflect differences in disease biology, treatment sequencing, and post-progression management rather than intrinsic superiority of either regimen. These findings highlight the importance of individualized treatment selection and careful consideration of tumor characteristics and hepatic reserve when choosing first-line immunotherapy for uHCC.
BACKGROUND AND AIMS:This multicenter retrospective study in Japan aimed to investigate the prognostic significance of lymphocyte-to-monocyte ratio (LMR) in patients with unresectable hepatocellular carcinoma (HCC) treated with durvalumab plus tremelimumab (Dur/Tre). METHODS:A total of 377 patients with HCC and treated with Dur/Tre across 30 institutions in Japan were included in this multicenter study. Time-dependent receiver operating characteristic (ROC) analysis was performed to determine the optimal LMR cut-off value. Hazard ratio (HR) spline curve analysis was used to identify the optimal LMR range for predicting progression-free survival (PFS) and overall survival (OS). RESULTS:Time-dependent ROC analysis identified an optimal LMR cut-off value of 2.52 for predicting median OS. Multivariate analysis demonstrated that an LMR of ≥ 2.52 was independently associated with superior PFS (HR: 0.777) and OS (HR: 0.657). The median PFS was 2.6 months in patients with an LMR of < 2.52, compared with 3.5 months in those with an LMR of ≥ 2.52 (p = 0.022). The median OS was 12.8 months in patients with an LMR of < 2.52, compared with 23.4 months in those with an LMR of ≥ 2.52 (p < 0.001). The disease control rate was significantly higher in the high LMR group (p = 0.032). The HR spline curve analysis revealed that an LMR range of approximately 1.8-2.6 represents an optimal cut-off for predicting both PFS and OS. CONCLUSIONS:LMR is a readily accessible prognostic biomarker for both PFS and OS in patients with unresectable HCC treated with Dur/Tre, and may serve as a practical tool for risk stratification in clinical practice.
AIM:We aimed to determine the associations between the pretreatment Advanced Lung Cancer Inflammation Index (ALI) and survival outcomes in patients with unresectable hepatocellular carcinoma (u-HCC) who received atezolizumab plus bevacizumab (Atez/Bev). METHODS:This retrospective study analyzed 563 patients with u-HCC who were treated with Atez/Bev (Sept 2020-Dec 2024). The ALI was calculated according to Body Mass Index × serum albumin level/neutrophil-to-lymphocyte ratio. Associations between ALI and overall survival (OS) and progression-free survival (PFS) were evaluated by Cox proportional hazards regression analysis. RESULTS:An ALI cutoff value of 27.04, determined by receiver operating characteristic curve analysis, was used to classify patients into low- and high-ALI groups. High-ALI patients had longer median OS (26.1 vs. 13.7 months, p < 0.001) and PFS (9.3 vs. 5.2 months, p < 0.001), and a higher disease control rate (82.5% vs. 69.1%, p < 0.001) compared to low-ALI patients. Multivariate Cox regression analysis confirmed that a high ALI value was a significant prognostic marker for OS (hazard ratio [HR] 0.69, 95% confidence interval [CI] 0.54-0.88, p = 0.003) and PFS (HR: 0.75, 95% CI: 0.61-0.92, p = 0.006). Subgroup analyses showed that the trend toward improved outcomes was consistent for high ALI values in all clinically relevant subgroups. CONCLUSIONS:A high pretreatment ALI value was associated with improved survival and disease control in u-HCC patients receiving Atez/Bev, underscoring its potential utility as a prognostic marker for clinical management and further studies.
BACKGROUND & AIMS:Metabolic dysfunction-associated steatotic liver disease (MASLD) is a complex, multifactorial condition. To achieve truly personalized therapy for MASLD, it will be essential to stratify patients based on clinical and biochemical data by identifying subgroups with distinct disease mechanisms and prognostic trajectories. METHODS:This study conducted unbiased clustering analysis of 349 patients with MASLD based on clinical variables. Multi-omics analyses that included spatial transcriptomics, single-cell RNA sequencing (scRNA-seq), and immunohistochemistry were subsequently applied to characterize the biological features of high-risk subgroups. RESULTS:Among the four identified MASLD subgroups, one cluster showed a higher 5-year cumulative incidence of liver-related events (LREs) (24.0%; 95% CI 14.8%-37.4%), with excess risk persisting after adjustment for advanced fibrosis. This high-risk subgroup was characterized by an immune-driven disease phenotype with excessive immunoglobulin A (IgA) expression. Multivariable analysis identified elevated IgA (≥318 mg/dl) as an independent predictor of LREs (hazard ratio = 3.17, 95% CI 1.27-7.91; p = 0.01), a finding validated in an independent vibration-controlled transient elastography cohort (n = 287) as well as an external multicenter validation cohort (n = 272). Spatial transcriptomics and scRNA-seq analyses demonstrated portal enrichment of IgA-expressing B-lineage cells, with IGHA1-high regions showing activation of pathways related to B-cell receptor signaling, extracellular matrix remodeling, and vascular remodeling. Intestinal immunohistochemistry and circulating EndoCAb IgG levels supported a link between increased gut permeability and coordinated systemic and intrahepatic IgA-associated immune activation. CONCLUSION:A data-driven clustering strategy identified a novel MASLD subtype characterized by enhanced IgA-mediated immune activation along the gut-liver axis as a key determinant of disease progression. This IgA-based stratification improves risk assessment and enables mechanism-based therapeutic targeting in patients with high-risk MASLD. IMPACT AND IMPLICATIONS:This study identified a high-risk MASLD subgroup characterized by elevated IgA levels and increased incidence of liver-related events, independent of fibrosis severity. These findings highlight the relevance of immune dysregulation, particularly IgA-associated responses, in MASLD progression.
ABSTRACT Durvalumab plus tremelimumab (Dur/Tre) is the first‐line treatment for unresectable hepatocellular carcinoma (uHCC). Immune‐mediated adverse events (imAEs) are common; however, the impact of specific imAE types on treatment persistence and outcomes remains unclear. This study evaluated the clinical features and prognostic implications of common imAEs during Dur/Tre therapy. This multicenter retrospective analysis included 351 patients with uHCC treated with Dur/Tre (January 2023 and February 2025), of whom 69 developed imAEs and had a follow up period of > 1 month. Baseline characteristics, period to onset and severity of imAEs, corticosteroid use, treatment continuation and subsequent therapies, progression‐free survival (PFS) and overall survival (OS) were analyzed according to imAE types. Among 69 patients, 34 developed colitis, 19 developed hepatitis and 16 developed endocrine disorders. The median age was 72 years, with 13% classified as Child‐Pugh B. The median period to imAE onset was 0.75 months (interquartile range, 0.38–1.25). Steroids at a dose equivalent to > 20 mg of prednisolone were administered to 46 patients (66.7%). Two‐thirds of the patients continued Dur/Tre despite imAE onset. Colitis occurred the earliest (median 0.54 months) and had the highest steroid requirement (82.4%), frequently resulting in treatment interruption. Endocrine disorders showed the highest continuation rate (75%). Although not statistically significant in PFS (median 11.2 months: 95% CI, 1.96–not achieved (NA), p = 0.450) and OS (95% CI, NA–NA, p = 0.134), compared with colitis (PFS; 4.3 months, OS; not reached) and hepatitis (PFS; 3.4 months, OS: 14.6 months). These findings should be interpreted cautiously given the small sample size. Subsequent systemic or locoregional therapies, including tyrosine kinase inhibitors, atezolizumab plus bevacizumab and interventional therapies, were administered to more than 65% of the patients. In Dur/Tre therapy, imAE impact varied by type; endocrine disorders are linked to better treatment continuation and prognosis, whereas colitis and hepatitis often lead to treatment interruption. Trial Registration: Takasaki General Medical Center (IRB No. TGMC2024–03)
