Hisashi Kosaka

Aim The lymphocyte-to-monocyte ratio (LMR) has emerged as a potential immune-related biomarker; however, its prognostic significance in patients with unresectable hepatocellular carcinoma (HCC) treated with atezolizumab plus bevacizumab (Atezo/Bev) remains unclear. To investigate the prognostic significance of the LMR in patients with unresectable HCC treated with Atezo/Bev. Methods This multicentre study included 941 patients with unresectable HCC treated with Atezo/Bev therapy at 30 institutions in Japan. The optimal LMR cutoff value was determined using time-dependent receiver operating characteristic (ROC) analysis. Multivariate survival analyses were performed for progression-free survival (PFS) and overall survival (OS). The prognostic utility of the LMR was compared with that of the neutrophil-to-lymphocyte ratio (NLR) using integrated discrimination improvement and net reclassification improvement. Results Time-dependent ROC analysis identified an optimal LMR cutoff value of 3.6 based on median OS. The median PFS was 5.6 months in patients with an LMR < 3.6 and 8.9 months in those with an LMR ≥ 3.6 (P<0.01). The disease control rate was significantly higher in the high LMR group (P<0.01). Multivariate analysis identified the LMR as an independent factor associated with prolonged PFS (hazard ratio [HR], 0.94; 95% confidence interval [CI], 0.90–0.98; P<0.01) and OS (HR, 0.90; 95% CI, 0.85–0.96; P<0.01). Compared with NLR, LMR demonstrated a significantly greater improvement in prognostic predictive performance for both PFS and OS (P<0.01). Conclusions The LMR is a simple and clinically useful prognostic biomarker for predicting both PFS and OS in patients with unresectable HCC treated with Atezo/Bev therapy.

Background and Aims: For unresectable hepatocellular carcinoma (HCC), atezolizumab plus bevacizumab (Atez/Bev) and durvalumab plus tremelimumab (Dur/Tre) are widely used first‐line immunotherapies; however, biomarkers to guide regimen selection before treatment initiation remain undefined. We investigated whether baseline des‐γ‐carboxy prothrombin (DCP) modifies objective response rate (ORR) according to treatment regimen. Methods: We analysed 1464 patients with unresectable HCC treated with first‐line systemic therapy between 2020 and 2025 across multiple centers. Patients were divided into training and validation cohorts. Restricted cubic spline‐based interaction models were used to evaluate the association between baseline DCP and ORR according to treatment regimen. The predicted absolute difference in ORR (ΔORR) between regimens was examined across continuous DCP values, with a prespecified 10% threshold considered clinically meaningful. Robustness was assessed using leave‐one‐center‐out and repeated random‐split sensitivity analyses. Results: Overall ORR did not differ significantly between Atez/Bev and Dur/Tre. However, a significant interaction between baseline DCP and treatment regimen was observed in both cohorts. Atez/Bev showed a relatively stable ORR across DCP concentrations, whereas Dur/Tre showed a DCP‐dependent increase in ORR. At low DCP levels, Atez/Bev was favoured; with increasing DCP levels, the relative benefit shifted toward Dur/Tre. Sensitivity analyses confirmed a consistent DCP‐dependent transition pattern, although the DCP level at which ΔORR exceeded 10% varied across analyses, supporting a transition zone rather than a fixed cutoff. Conclusions: Baseline DCP may modify the relative treatment benefit between Atez/Bev and Dur/Tre in unresectable HCC. Rather than defining a rigid cutoff, DCP appears to delineate a continuum in which higher levels increasingly favour Dur/Tre, providing a practical framework for individualized immunotherapy selection.

Background and Aim: Atezolizumab plus bevacizumab (Atez/Bev) and durvalumab plus tremelimumab (Dur/Tre) are widely used first‐line immune checkpoint inhibitor (ICI)‐based regimens for unresectable hepatocellular carcinoma (uHCC). However, reliable biomarkers to inform treatment choice remain limited. This study evaluated whether the simplified BALAD‐based score (BALAD‐S) is associated with differential treatment outcomes. Materials and Methods: This multicenter retrospective study included 752 Japanese patients with uHCC who received first‐line Atez/Bev ( n = 645) or Dur/Tre ( n = 107) between October 2020 and March 2026. BALAD‐S was calculated using bilirubin, albumin, AFP, AFP‐L3, and des‐γ‐carboxy prothrombin, and patients were stratified into BALAD‐S low (≤ 2) and high (≥ 3) groups. Treatment response, progression‐free survival (PFS), and overall survival (OS) were evaluated. Results: In the BALAD‐S low group, Atez/Bev showed longer PFS than Dur/Tre (10.5 vs. 4.3 months; p < 0.001), with longer OS also observed (28.3 vs. 19.4 months; p = 0.049). In the BALAD‐S high group, PFS did not differ significantly (7.0 vs. 5.3 months with Dur/Tre and Atez/Bev, respectively, p = 0.210), whereas OS was longer with Dur/Tre than with Atez/Bev (27.3 vs. 16.4 months; p = 0.022). Treatment effects differed by BALAD‐S category (HR for Dur/Tre vs. Atez/Bev: 1.50 in BALAD‐S low and 0.55 in BALAD‐S high; p for interaction = 0.005). In patients treated from 2023 onward, similar treatment‐effect heterogeneity was observed (HR 1.61 in BALAD‐S low and 0.59 in BALAD‐S high; p for interaction = 0.007). Conclusion: Outcomes with Atez/Bev and Dur/Tre differed according to BALAD‐S score. BALAD‐S may help identify patients with differential outcomes between first‐line ICI‐based regimens and represents a candidate stratification marker requiring validation.

Background: This study evaluated the association between cumulative chemotherapy exposure and overall survival (OS) in patients with advanced biliary tract cancer (BTC) and explored baseline factors associated with prolonged treatment continuation. Methods: Patients with advanced BTC receiving systemic chemotherapy were stratified by cumulative chemotherapy exposure (p < 0.001). Multivariable logistic regression identified metastatic disease as an independent factor associated with a lower likelihood of receiving ≥8 cycles (OR 0.34, 95% CI 0.12–0.97, p = 0.044). In landmark-adjusted multivariable analysis (n = 66), receiving ≥8 chemotherapy cycles remained independently associated with longer OS (HR 0.46, 95% CI 0.22–0.96, p = 0.039). Restricted cubic spline analysis demonstrated progressive hazard reduction with increasing chemotherapy exposure, although the magnitude of reduction attenuated beyond approximately 8 cycles. Conclusion: Greater cumulative chemotherapy exposure was associated with prolonged OS in advanced BTC, with attenuation of the survival benefit beyond approximately 8 cycles. Sustained treatment exposure may partly reflect preserved physiological reserve and ability to maintain systemic therapy in real-world clinical practice.

Background and Aim: This study evaluated clinical outcomes in patients with hepatocellular carcinoma (HCC) treated with durvalumab plus tremelimumab (Dur/Tre) in routine practice, stratified by whether they fulfilled the eligibility criteria of the phase 3 HIMALAYA trial. Methods: A total of 412 patients with unresectable HCC receiving Dur/Tre at 30 Japanese institutions were enrolled. Of these, 92 fulfilled the HIMALAYA trial eligibility criteria (HIMALAYA group) and 320 did not (non‐HIMALAYA group). Results: Median progression‐free survival (PFS) was 5.4 months in the HIMALAYA group and 3.0 months in the non‐HIMALAYA group ( p = 0.012). Multivariable analysis identified body mass index ≥ 25 kg/m ² (hazard ratio [HR], 0.780; 95% confidence interval [CI], 0.612–0.993; p = 0.044) and portal vein invasion (HR, 1.509; 95% CI, 1.049–2.170; p = 0.027) as independent predictors of PFS. Median overall survival (OS) was 19.4 months in the HIMALAYA group versus 15.4 months in the non‐HIMALAYA group ( p = 0.014). Multivariable analysis showed Eastern Cooperative Oncology Group performance status ≥ 1 (HR, 1.878; 95% CI, 1.253–2.814; p = 0.002) and albumin–bilirubin grade ≥ 2 (HR, 2.032; 95% CI, 1.319–3.318; p = 0.001) as independent determinants of OS. Any‐grade endocrine dysfunction occurred in 13 (14.1%) and 21 (6.6%) patients ( p = 0.030), with grade ≥ 3 events in 5 (5.4%) and 2 (0.6%), respectively ( p = 0.007). Subgroup analysis suggested that non‐HIMALAYA patients with ALBI grade 1 may have OS comparable to the HIMALAYA group. Conclusions: Patients fulfilling the HIMALAYA trial eligibility criteria and those who did not but had preserved hepatic function demonstrated favorable survival outcomes with Dur/Tre.

Aim: Atezolizumab plus bevacizumab (Atez/Bev) in unresectable hepatocellular carcinoma (uHCC) is a standard first‐line therapy, but bleeding‐related adverse events (BL‐AEs) remain clinically concerning, particularly in real‐world patients with advanced tumors, portal hypertension, or undergoing antithrombotic therapy (ATT). We aimed to evaluate whether ATT increases bleeding risk, identify pretreatment factors associated with BL‐AEs, and assess the impact of bleeding on progression‐free survival (PFS) and overall survival (OS) in patients with uHCC treated with Atez/Bev. Methods: This multicenter retrospective study included 981 patients with uHCC treated with Atez/Bev. BL‐AEs were identified by clinical assessment, imaging, or endoscopy. Predictors of BL‐AEs were analyzed using logistic regression. Survival outcomes were compared by Kaplan–Meier method, with inverse probability weighting (IPW) applied to adjust for baseline imbalances. Results: BL‐AEs occurred in 102 patients (10.4%) and led to treatment discontinuation in 2.7% patients. Independent predictors of BL‐AEs included advanced tumor burden components, such as Vp ≥ 3 portal vein invasion and extrahepatic metastasis. Neither ATT nor portal hypertension–related factors were associated with bleeding risk. PFS did not differ between groups, whereas OS was significantly shorter in the BL group before IPW adjustment than after IPW adjustment. Conclusions: During Atez/Bev therapy, BL‐AEs were primarily associated with advanced tumor burden rather than with ATT or baseline portal hypertension–related factors. Although BL‐AEs were associated with poorer OS, this should be interpreted cautiously, as bleeding may reflect aggressive tumor biology rather than a direct mortality cause. Careful monitoring for bleeding complications may be required in patients with advanced tumor burden receiving Atez/Bev.

Background: Durvalumab plus gemcitabine–cisplatin (GCD) has become a standard first-line therapy for advanced biliary tract cancer (BTC) following the TOPAZ-1 trial. However, whether the survival benefit observed in trial-eligible patients can be generalized to broader real-world populations remains uncertain. We evaluated the impact of TOPAZ-1 eligibility on the effectiveness of GCD in routine clinical practice. Methods: In this multicenter retrospective cohort study, 610 patients with unresectable or recurrent BTC treated with first-line GCD ( n = 268) or gemcitabine–cisplatin (GC) ( n = 342) at 19 Japanese institutions were analyzed. Patients were classified according to TOPAZ-1 eligibility criteria. Overall survival (OS) was compared between treatment groups in the entire cohort and stratified by eligibility status. Multivariable Cox models were constructed separately for eligible and ineligible patients. Results: Among 610 patients, 324 (53.1%) met TOPAZ-1 eligibility criteria. In the overall cohort, GCD was associated with longer OS than GC (median, 13.7 vs 11.3 months; p = 0.009). Among eligible patients, GCD significantly improved OS compared with GC (18.0 vs 13.1 months; p = 0.004), whereas no significant difference was observed among ineligible patients (10.8 vs 10.0 months; p = 0.675). However, the interaction between treatment and TOPAZ-1 eligibility was not statistically significant ( p for interaction = 0.162). Conclusions: In this real-world cohort, the survival benefit of GCD appeared to be primarily observed in patients meeting TOPAZ-1 eligibility criteria. Trial-based eligibility may influence the magnitude of benefit from immunochemotherapy in advanced BTC, underscoring the importance of patient selection in routine practice.

Background & Aims: Systemic therapy is the standard care for patients with hepatocellular carcinoma (HCC) and extrahepatic metastases. However, the relative prognostic importance of the intrahepatic tumor burden versus the extent of extrahepatic disease in the era of immune checkpoint inhibitor‐based therapy remains unclear. This study aimed to clarify the prognostic impact of intrahepatic tumor burden in patients with metastatic HCC treated with atezolizumab plus bevacizumab (Atez/Bev). Methods: We conducted a multicenter retrospective study of patients with HCC and extrahepatic metastases who received first‐line Atez/Bev therapy. The intrahepatic tumor burden was assessed using established radiologic parameters, including tumor size, number, and vascular invasion, and the patients were stratified according to the intrahepatic disease severity. Overall survival (OS) was defined as the primary endpoint. Survival analyses were carried out using the Kaplan–Meier method and Cox proportional hazards models. Results: Overall, 306 patients were included in the study. During a median follow‐up of 13.5 months, the OS differed markedly according to the intrahepatic tumor burden and macrovascular invasion. The median OS was 17.8 months in the mild MVI group, 12.2 months in the severe MVI group, 29.8 months in the UT7 in group, and 15.2 months in the UT7 out group ( p < 0.001). In multivariate analysis, the intrahepatic tumor burden remained an independent predictor of OS, whereas the extent and number of extrahepatic metastatic sites were not significantly associated with prognosis. Conclusions: In metastatic HCC treated with atezolizumab plus bevacizumab, intrahepatic tumor burden was associated with overall survival and may be useful for risk stratification and treatment optimization.

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.

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)