Introduction

Lymphocytes inhibit the progression of hepatocellular carcinoma (HCC) through immune surveillance within an immunosuppressive microenvironment. Reduced lymphocyte counts, often associated with systemic inflammation, have been implicated in facilitating tumor progression. In contrast, elevated monocyte counts have been reported to be associated with microvascular invasion and poor prognosis in patients with HCC. Therefore, a high lymphocyte-to-monocyte ratio (LMR), calculated by dividing the lymphocyte count by the monocyte count, is considered a favorable prognostic indicator and is associated with improved clinical outcomes in patients with HCC.

Aims & Methods

We assessed the utility of the LMR in predicting the prognosis of patients with unresectable hepatocellular carcinoma who were treated with atezolizumab plus bevacizumab (Atezo/Bev). The study involved 941 patients who received Atezo/Bev treatment between September 2020 and February 2025. The median age was 74.0 years, and 754 were male. Performance status (PS) was distributed as follows: 741 patients with PS 0, 169 with PS 1, and 31 with PS ≥2. The liver background conditions were as follows: 149 patients with hepatitis B, 282 with hepatitis C, and 449 with non-hepatitis B or C (NBNC). Child-Pugh scores were distributed as follows: 522 patients with a score of 5, 254 with a score of 6, 67 with a score of 7, and 37 with a score of ≥8. The Barcelona Clinic Liver Cancer (BCLC) stages were as follows: 77 patients with stage ≤A, 317 with stage B, and 547 with stage ≥C. The median values of key biomarkers were as follows: LMR: 3.33, NLR: 2.63, AFP: 34.1 ng/mL. The median observation period was 14.3 months. NLR was included in Model 1, and LMR was incorporated in Model 2 of the multivariate analysis.

Results

The progression-free survival (PFS) was 6.8 months, and the overall survival (OS) was 23.6 months. The optimal cutoff for LMR, determined via time-dependent receiver operating characteristic (ROC) analysis based on median OS, was 3.6. The objective response rate (ORR) and disease control rate (DCR) were 27.3% and 76.5%, respectively. In the multivariate analysis of PFS, Model 1 identified the following factors as significant: BMI (HR: 0.98), Child-Pugh score ≥7 (HR: 1.34), BCLC stage C or higher (HR: 1.23), Log AFP (HR: 1.16), second or later treatment line (HR: 1.19). In Model 2, LMR was included as a significant factor (HR: 0.94). For OS, the following factors were identified as significant: age (HR: 1.01), Child-Pugh score ≥7 (HR: 2.09), BCLC stage C or higher (HR: 1.24), Log AFP (HR: 1.28), second or later treatment line (HR: 1.24), and NLR (HR: 1.03). The integrated discrimination improvement (IDI) for NLR and LMR at PFS (at 3 and 6 months) was 0.012 (95% CI: 0.012). The net reclassification improvement (NRI) was 0.016 (95% CI: 0.006-0.030, p<0.001) at 3 months, 0.023 (95% CI: 0.006-0.030, p<0.001) at 6 months, and 0.023 (95% CI: 0.004-0.024, p<0.001) at 12 months. The IDI for NLR and LMR at OS (12 and 24 months) was 0.027 (95% CI: 0.011-0.049, p=0.002) and 0.034 (95% CI: 0.012-0.064, p<0.001), with LMR demonstrating superior performance. The NRI for OS at 12 and 24 months was 0.036 (95% CI: 0.016-0.062, p<0.001) and 0.053 (95% CI: 0.020-0.091, p<0.001), respectively, both favoring LMR. In the time-dependent ROC analysis, the area under the curve (AUROC) was higher for LMR compared to NLR throughout the study period, with the exception of PFS at 3 months and OS at 18 months.

Conclusion

The LMR serves as a valuable biomarker for predicting prognosis in patients receiving Atezo/Bev.

Disclosure

Toshifumi Tada: lecture fees from AbbVie, AstraZeneca, Eisai, and Chugai
Atsushi Hiraoka: lecture fees from Eisai, Bayer, Eli Lilly, and Otsuka
Hidenori Toyoda: lecture fees from AbbVie, Eisai, Gilead, Terumo, and Bayer

Introduction

The combination of Atezolizumab plus Bevacizumab (atezobeva) has changed the treatment landscape of advanced hepatocellular carcinoma (HCC), but its efficacy and safety in patients with impaired liver function or portal hypertension is still debated.

Aims & Methods

In this multicenter, real-life, study we compared 247 patients with unresectable HCC treated with atezobeva, matched to 494 patients treated with tyrosine kinase inhibitors (TKIs). We evaluated the impact of liver function and decompensation on treatment outcomes.

Results

Patients in the atezobeva group showed longer median overall survival (OS; 18·30 vs 10·20 months, p<0·0001), longer time to progression (TTP; 13·60 vs 10·10 months, p=0·0002) and increased progression-free survival (PFS; 10·50 VS 6·10 months, p<0·0001) compared with the TKIs group. Although survival was better in Child Pugh A patients than in Child Pugh B patients (20·20 vs 9·83 months, p=0·0008), no clear differences in TTP and overall treatment safety were observed· Liver decompensation occurred in 63 (25·51%) patients, specifically 41 (27·89%) Child Pugh A and 22 (51·16%) Child Pugh B and was associated with worse survival (10·50 vs 20·20 months; p=0·006). Among decompensated patients, 26 patients (41·26%) were able to resume atezobeva after decompensation, achieving an OS comparable to those who never decompensated (20·87 vs 20·2 months; p=0·77), and significantly better than those who permanently stopped treatment (8·07 months; p=0·02). Treatment interruption following decompensation was an independent predictor of survival (HR 2·04, 95% CI 1·25-3·33, p=0·004), while ALBI score 2-3 (HR 2·21, 95%CI 1·07-4·55; p=0·03), Child Pugh class B (HR 1·81, 95% CI 1·03-3·18; p=0·04), portal hypertension (HR 2·54, 95%CI 1·37-4·72; p=0·003) and sAEs (HR 1·71, 95%CI 1·04-2·82; p=0·04) emerged as predictors of decompensation. Time to decompensation was similar for patients with ALBI 2, regardless of Child Pugh class, and the probability of recovery from decompensation was similar for Child A and B patients.

Conclusion

In this real-life multicentric study atezobeva was effective in both Child Pugh A and B patients. Child Pugh B patients despite their higher risk of decompensation have an equal chance of recovery. The possibility to resume treatment after an episode of decompensation highlights the necessity of integrated hepato-oncological management, optimizing the therapeutic efficacy of atezobeva.

References

-Finn R.S. et al. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med 2020.
-Cabibbo G, et al. Optimizing systemic therapy for advanced hepatocellular carcinoma: the key role of liver function. Dig Liver Dis 2022.
-D’Alessio A, et al. Preliminary evidence of safety and tolerability of atezolizumab plus bevacizumab in patients with hepatocellular carcinoma and Child-Pugh A and B cirrhosis: A real-world study. Hepatology 2022.
-Pinato DJ et al. Immunotherapy in hepatocellular cancer patients with mild to severe liver dysfunction: adjunctive role of the ALBI grade. Cancers Basel 2020.
-Kudo M, et al. Albumin-Bilirubin Grade Analyses of Atezolizumab plus Bevacizumab versus Sorafenib in Patients with Unresectable Hepatocellular Carcinoma: A Post Hoc Analysis of the Phase III IMbrave150 Study. Liver Cancer 2023.
-Tanaka T, et al. Therapeutic efficacy of atezolizumab plus bevacizumab treatment for unresectable hepatocellular carcinoma in patients with Child-Pugh class A or B liver function in real-world clinical practice. Hepatol Res 2022.
-Vitale A, et al. Personalised management of patients with hepatocellular carcinoma: a multiparametric therapeutic hierarchy concept. Lancet Oncol 2023.
-Thabut D, et al Treatment of portal hypertension in patients with HCC in the era of Baveno VII. J Hepatol 2023.

Disclosure

​None

Introduction

Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related mortality worldwide, with limited therapeutic options available for unresectable cases. In recent years, immune checkpoint inhibitors (ICIs) have revolutionized the treatment landscape. Among them, the combination of durvalumab (anti-PD-L1) and tremelimumab (anti-CTLA-4), collectively referred to as Dur/Tre, has demonstrated significant survival benefits in patients with advanced HCC. However, robust prognostic biomarkers specific to patients receiving Dur/Tre therapy have yet to be established. The neutrophil-to-lymphocyte ratio (NLR), a systemic marker of inflammation, has been correlated with prognosis in various malignancies, including HCC [1, 2].

Aims & Methods

This study aimed to assess the prognostic significance of baseline NLR in patients with unresectable HCC treated with Dur/Tre. This multicenter retrospective cohort study included 182 patients with unresectable HCC who received Dur/Tre therapy between May 2022 and June 2024. Eligibility criteria included the availability of baseline NLR data and complete clinical records. The treatment regimen comprised a single 300 mg dose of tremelimumab on day 1, followed by 1500 mg of durvalumab administered every four weeks. Primary endpoints were progression-free survival (PFS) and overall survival (OS), assessed using the Kaplan-Meier method and Cox proportional hazards modeling. Baseline NLR values were calculated, and the optimal cutoff for OS prediction was determined using hazard ratio (HR) spline curve analysis.

Results

The median age of patients was 74 years, and 82.9% were male. The median baseline NLR was 3.13. Dur/Tre was administered as first-line therapy in 29.7% of patients and as second-line or later therapy in 70.3%. The median PFS was 3.5 months (95% confidence interval [CI]: 2.7–4.4 months), while the median OS was not reached (95% CI: 12.1 months–not reached). Multivariate analysis identified administration of Dur/Tre after second-line treatment as an independent predictor of shorter PFS (HR: 1.819; p = 0.003). Notably, an NLR ≥2.56 independently predicted poorer OS (HR: 1.919; p = 0.039). Median OS was not reached in the low-NLR group (<2.56), whereas it was 12.1 months in the high- NLR group (≥2.56) (p = 0.016). A Sankey diagram revealed that patients with higher NLR were more likely to receive best supportive care (BSC) rather than subsequent anticancer therapies post-Dur/Tre (p = 0.046). Spline curve analysis identified an optimal NLR threshold range of 2.3–3.0 for OS prediction.

Conclusion

This large, real-world, multicenter study demonstrated that baseline NLR serves as a significant and independent prognostic biomarker for overall survival in patients with unresectable HCC undergoing Dur/Tre therapy. Higher baseline NLR values (≥2.56) were associated with reduced survival and a lower likelihood of receiving subsequent anticancer treatment, whereas patients with lower NLR values were more likely to continue active therapeutic interventions. These findings suggest that NLR may function not only as a prognostic indicator but also as a practical tool for therapeutic decision-making and patient stratification in clinical settings. Further prospective studies with extended follow-up are warranted to validate these findings and refine NLR-based stratification strategies to optimize immunotherapy outcomes in HCC.

References

1. Tada T, Kumada T, Hiraoka A, et al. Neutrophil-to-lymphocyte ratio is associated with survival in patients with unresectable hepatocellular carcinoma treated with Lenvatinib. Liver Int. 2020; 40: 968-976.
2. Tada T, Kumada T, Hiraoka A, et al. Neutrophil-lymphocyte ratio predicts early outcomes in patients with unresectable hepatocellular carcinoma treated with atezolizumab plus bevacizumab: a multicenter analysis. Eur J Gastroenterol Hepatol. 2022; 34: 698-706.

Disclosure

Toshifumi Tada: lecture fees from AbbVie, AstraZeneca, Eisai, and Chugai
Atsushi Hiraoka: lecture fees from Eisai, Bayer, Eli Lilly, and Otsuka
Hidenori Toyoda: lecture fees from AbbVie, Eisai, Gilead, Terumo, and Bayer

Introduction

An important issue for unresectable advanced stage hepatocellular carcinoma (uHCC) patients with Child-Pugh class B liver cirrhosis (CP-B), is lack of safe treatment options that show therapeutic efficacy, thus it is considered to be an unmet need. Atezolizumab plus bevacizumab (At/Bv) and durvalumab plus tremelimumab (Dur/Tre) have each been used as first-line systemic immunotherapy for uHCC.

Aims & Methods

The present study aimed to elucidate clinical outcomes of uHCC patients with CP-B treated with those combination treatments. The records of 169 uHCC patients with CP-B in Japan, treated with At/Bv or Dur/Tre as first-line systemic therapy from 2020 to 2024 at participating institutions were examined (median age: 73 years, males: 143, Child-Pugh score 7:8:9 = 121:43:5, BCLC stage B:C = 65:104, At/Bv:Dur/Tre = 131:38). Each regimen was analyzed for therapeutic efficacy and safety, and the results compared, in a retrospective manner.

Results

Using RECIST, ver. 1.1, the objective response rate (ORR) was shown to be 25.9% in the At/Bv group, and 18.4% in the Dur/Tre group (p=0.08). Disease control rate (DCR) was significantly higher in the At/Bv group (64.9% vs. 39.5%, p=0.01). There were no significant differences between the groups for progression-free survival (PFS) [At/Bv vs. Dur/Tre=5.3 vs. 3.5 months (95% CI: 3.9–6.5 and 2.3–7.2, respectively), p=0.90], overall survival (OS) [10.5 vs. 12.5 months (95% CI: 9.1–13.3 and 7.9–NA, respectively), p=0.58], or post-progression survival (PPS) [4.9 vs. 7.5 months (95% CI: 3.7–7.5 and 2.2–NA, respectively), p=0.60]. The rate of incidence of immune-related adverse events (irAEs) of any grade was 11.5% in the At/Bv group and 23.7% in the Dur/Tre group (p=0.07), while irAEs of grade 3 or higher were noted in 3.1% and 15.8%, respectively (p=0.02) significantly greater in the Dur/Tre group).

Conclusion

The incidence rate of irAEs in each group was similar to that observed in clinical trials previously performed for these regimens. uHCC patients with CP-B, who received Dur/Tre had a greater rate of incidence of high-grade irAEs, while the At/Bv group had a better DCR, though there were no significant differences for PFS, OS, or PPS between the groups. Neither treatment was found to sufficiently improve the prognosis of uHCC patients with CP-B. Development of safe and effective treatment options for patients affected by uHCC, that can be administered even to those with CP-B remains necessary.

Disclosure

Atsushi Hiraoka: lecture fee Chugai, AstraZeneca, and Lilly.