Background and Aims: Durvalumab plus tremelimumab (Dur/Tre) therapy is expected to have good therapeutic efficacy for patients with unresectable hepatocellular carcinoma (u‐HCC). We previously reported that the neutrophil‐to‐lymphocyte ratio (NLR) during atezolizumab plus bevacizumab therapy in u‐HCC patients was a useful marker for predicting the therapeutic response. Therefore, we investigated whether the NLR during Dur/Tre therapy could predict treatment outcomes in patients with u‐HCC.Design: The present study included 64 u‐HCC patients treated with Dur/Tre and evaluated for their initial response by dynamic computed tomography or magnetic resonance imaging at least once until December 2024. Alpha‐fetoprotein (AFP) and des‐gamma‐carboxyprothrombin (DCP) ratios were defined as follows: the pretreatment levels of AFP and DCP were set to 1, and the AFP and DCP ratios to pretreatment were calculated at the start of the second course of Dur/Tre therapy.Results: Of the 64 HCC patients, 34 patients (53%) achieved a disease control rate (non‐PD) at the initial evaluation. The NLR at the start of the second course (NLR‐2c) tended to be lower in patients with non‐PD than progressive disease (p = 0.133), and the optimal cutoff value was 5.75. Patients with NLR‐2c ≥ 5.75 had a shorter progression‐free survival (PFS) than those with NLR‐2c < 5.75 (median: 1.7 vs. 5.5 months, p = 0.002). Multivariate analysis showed that NLR‐2c ≥ 5.75 (HR 4.66; p < 0.001) and AFP ratio ≥ 0.933 (HR 4.32; p = 0.004) were significantly associated with poor PFS.Conclusions: The NLR‐2c value is useful for predicting PFS in u‐HCC patients treated with Dur/Tre therapy.

Advanced hepatocellular carcinoma (HCC) remains a highly lethal malignancy, although several systemic therapeutic options are available, including sorafenib (SFN), which has been one of the standard treatment agents for almost a decade. As early prediction of response to SFN remains challenging, biomarkers that enable early prediction using a clinically feasible method are needed. Here, we report that the serum secretory form of clusterin (sCLU) protein and its related predictive index are potential beneficial biomarkers for early prediction of SFN response. Using high‐throughput screening and subsequent multivariate analysis in the derivation cohort, we found that changes in the concentrations of CLU, vascular cell adhesion molecule‐1 (VCAM1), and α‐fetoprotein were significantly associated with response to SFN. Furthermore, we confirmed that an increase in CLU serum level 1 month after treatment initiation was significantly associated with shorter progression‐free survival. In addition, “NR‐index,” which comprises these proteins, was evaluated as a tool for accurately predicting the efficacy of SFN and confirmed in the validation cohort. We also established SFN‐resistant HepG2 cells (HepG2‐SR) and found that sCLU significantly increased in HepG2‐SR cells compared with normal HepG2 cells, and confirmed that HepG2‐SR cells treated with SFN were resistant to apoptosis. The mechanism underlying activation of sCLU expression in acquired SFN resistance involves aberrant signaling and expression of Akt, mammalian target of rapamycin (mTOR), and a nutrient‐related transcription factor, sterol regulatory element binding protein 1c (SREBP‐1c). Furthermore, the PI3K and mTOR inhibitor BEZ235 markedly decreased sCLU expression in HepG2‐SR cells. Conclusion: These results suggest that measurement of sCLU serum levels and the sCLU‐related NR‐index are promising clinical tools for the early prediction of SFN response in HCC. Additionally, sCLU‐overexpressing HCC might be susceptible to mTOR inhibition.

We retrospectively evaluated the impact of therapeutic modifications of atezolizumab (Atezo) plus bevacizumab (Bev) therapy (Atezo/Bev), including the interruption or discontinuation of both Atezo and Bev, and the reduction or discontinuation of Bev, on the outcome of patients with unresectable hepatocellular carcinoma (uHCC) (median observation period: 9.40 months). One hundred uHCC from five hospitals were included. Therapeutic modifications without discontinuation of both Atezo and Bev (n = 46) were associated with favorable overall survival (median not reached; hazard ratio (HR): 0.23) and time to progression (median: 10.00 months; HR: 0.23) with no therapeutic modification defined as the reference. In contrast, the discontinuation of both Atezo and Bev without other therapeutic modifications (n = 20) was associated with unfavorable overall survival (median: 9.63 months; HR: 2.72) and time to progression (median: 2.53 months; HR: 2.78). Patients with modified albumin–bilirubin grade 2b liver function (n = 43) or immune-related adverse events (irAEs) (n = 31) discontinued both Atezo and Bev without other therapeutic modifications more frequently (30.2% and 35.5%, respectively) than those with modified albumin–bilirubin grade 1 (10.2%) and without irAEs (13.0%). Patients with objective response (n = 48) experienced irAEs more frequently (n = 21) than those without (n = 10) (p = 0.027). Avoiding the discontinuation of both Atezo and Bev without other therapeutic modifications may be the optimal management of uHCC.