Impact of body mass index on the prognosis of unresectable HCC patients receiving first-line Lenvatinib or atezolizumab plus bevacizumab.

INTRODUCTION: Overweight is a negative prognostic factor in the general population in the long term. However, the role of body mass index (BMI) in the short-mid term in advanced tumours is unclear. The present analysis investigates the role of BMI weight classes in a large sample of patients affected by HCC and receiving atezolizumab plus bevacizumab or lenvatinib as first-line treatment. METHODS AND MATERIAL: The cohort included consecutive patients affected by BCLC-c and BCLC-B HCC patients from a multicenter international study group who received atezolizumab plus bevacizumab or lenvatinib as first-line therapy. Population was stratified according to the BMI in under-, over- and normal-weight according to the conventional thresholds. The primary objective of the study was to evaluate the prognostic and predictive impact of BMI in patients affected by advanced or intermediate HCC. Survival curves were estimated using the product-limit method of Kaplan-Meier. The role of stratification factors was analysed with log-rank tests. RESULTS: 1292 consecutive patients with HCC were analysed. 466 (36%) patients were treated with lenvatinib and 826 (64%) patients were treated with atezolizumab plus bevacizumab. In the atezolizumab plus bevacizumab arm, 510 (62%) patients were normal-weight, 52 (6%) underweight and 264 (32%) overweight. At the univariate analysis for OS, underweight patients had significantly shorter OS compared to normal-weight patients, whereas no differences were found between normal-weight versus overweight. Multivariate analysis confirmed that underweight patients had significantly shorter OS compared to normal-weight patients (HR: 1.7; 95% CI: 1.0-2.8; p = .0323). In the lenvatinib arm, 26 patients (5.6%) were categorized as underweight, 256 (54.9%) as normal-weight, and 184 (39.5%) as overweight. At the univariate analysis for OS, no significant differences were found between normal-weight versus underweight and between normal-weight versus overweight, which was confirmed at multivariate analysis. CONCLUSION: Our analysis highlighted a prognostic role of BMI in a cohort of patients with advanced HCC who received atezolizumab plus bevacizumab, while no prognostic role for low BMI was apparent in patients who received lenvatinib.

Safety and Efficacy of Lenvatinib in Very Old Patients with Unresectable Hepatocellular Carcinoma.

BACKGROUND: Data concerning the use of lenvatinib in very old patients (≥ 80 years) are limited, although the incidence of hepatocellular carcinoma (HCC) in this patient population is constantly increasing. OBJECTIVE: This analysis aimed to evaluate the efficacy and safety of lenvatinib in a large cohort of very old patients (≥ 80 years) with unresectable HCC. PATIENTS AND METHODS: The study was conducted on a cohort of 1325 patients from 46 centers in four Western and Eastern countries (Italy, Germany, Japan, and the Republic of Korea) who were undergoing first-line treatment with lenvatinib between July 2010 and February 2022. Patients were stratified according to age as very old (≥ 80 years) and not very old (< 80 years). RESULTS: The median overall survival (OS) was 15.7 months for patients < 80 years old and 18.4 months for patients ≥ 80 years old [hazard ratio (HR) = 1.02, 95% confidence interval (CI) 0.84-1.25, p = 0.8281]. Median progression free survival (PFS) was 6.3 months for patients < 80 years old and 6.5 months for patients ≥ 80 years old (HR = 1.07, 95% CI 0.91-1.25, p = 0.3954). No differences between the two study groups were found in terms of disease control rate (DCR; 80.8% versus 78.8%; p = 0.44) and response rate (RR; 38.2% versus 37.9%; p = 0.88). Patients < 80 years old experienced significantly more hand-foot skin reaction (HFSR) grade ≥ 2 and decreased appetite grade ≥ 2. Conversely, patients ≥ 80 years old experienced significantly more fatigue grade ≥ 2. In the very old group, parameters associated with prognosis were AFP, albumin-bilirubin (ALBI) grade, Barcelona Clinic Liver Cancer (BCLC), and Child-Pugh score. BCLC stage was the only independent predictor of overall survival (OS; HR = 1.59, 95% CI 1.11-2.29, p = 0.01115). CONCLUSIONS: Our study highlights the same efficacy and safety of lenvatinib between very old and not very old patients.

α-FAtE: A new predictive score of response to atezolizumab plus bevacizumab for unresectable hepatocellular carcinoma.

Atezolizumab plus bevacizumab (AB) and lenvatinib can be alternatively used as first-line systemic treatment of unresectable hepatocellular carcinoma (HCC). However, no direct comparison of the two regimens has been performed in randomized clinical trials, making the identification of baseline differential predictors of response of major relevance to tailor the best therapeutic option to each patient. Baseline clinical and laboratory characteristics of real-world AB-treated HCC patients were analyzed in uni- and multivariate analyses to find potential prognostic factors of overall survival (OS). Significant variables were incorporated in a composite score (α-FAtE) and it was tested for specificity and sensitivity in receiver operating characteristic (ROC) curve and in multivariate analysis for OS. The score was applied in uni- and multivariate analyses for OS of a comparable lenvatinib-treated HCC population. Finally, comparison between treatments was performed in patients with low and high α-FAtE scores and predictivity estimated by interaction analysis. Time-to-progression (TTP) was a secondary endpoint. OS of AB-treated HCC patients was statistically longer in those with α-fetoprotein <400 ng/mL (HR 0.62, p = .0407), alkaline phosphatase (ALP) <125 IU/L (HR 0.52, p = .0189) and eosinophil count ≥70/µL (HR 0.46, p = .0013). The α-FAtE score was generated by the sum of single points attributed to each variable among the above reported. In ROC curve analysis, superior sensitivity and specificity were achieved by the score compared to individual variables (AUC 0.794, p < .02). Patients with high score had longer OS (HR 0.44, p = .0009) and TTP (HR 0.34, p < .0001) compared to low score if treated with AB, but not with lenvatinib. Overall, AB was superior to lenvatinib in high score patients (HR 0.55, p = .0043) and inferior in low score ones (HR 1.75, p = .0227). At interaction test, low α-FAtE score resulted as negative predictive factor of response to AB (p = .0004). In conclusion, α-FAtE is a novel prognostic and predictive score of response to first-line AB for HCC patients that, if validated in prospective studies, could drive therapeutic choice between lenvatinib and AB.

Sequential therapies after atezolizumab plus bevacizumab or lenvatinib first-line treatments in hepatocellular carcinoma patients.

INTRODUCTION: The aim of this retrospective proof-of-concept study was to compare different second-line treatments for patients with hepatocellular carcinoma and progressive disease (PD) after first-line lenvatinib or atezolizumab plus bevacizumab. MATERIALS AND METHODS: A total of 1381 patients had PD at first-line therapy. 917 patients received lenvatinib as first-line treatment, and 464 patients atezolizumab plus bevacizumab as first-line. RESULTS: 49.6% of PD patients received a second-line therapy without any statistical difference in overall survival (OS) between lenvatinib (20.6months) and atezolizumab plus bevacizumab first-line (15.7months; p = 0.12; hazard ratio [HR]= 0.80). After lenvatinib first-line, there wasn't any statistical difference between second-line therapy subgroups (p = 0.27; sorafenib HR: 1; immunotherapy HR: 0.69; other therapies HR: 0.85). Patients who underwent trans-arterial chemo-embolization (TACE) had a significative longer OS than patients who received sorafenib (24.7 versus 15.8months, p < 0.01; HR=0.64). After atezolizumab plus bevacizumab first-line, there was a statistical difference between second-line therapy subgroups (p < 0.01; sorafenib HR: 1; lenvatinib HR: 0.50; cabozantinib HR: 1.29; other therapies HR: 0.54). Patients who received lenvatinib (17.0months) and those who underwent TACE (15.9months) had a significative longer OS than patients treated with sorafenib (14.2months; respectively, p = 0.01; HR=0.45, and p < 0.05; HR=0.46). CONCLUSION: Approximately half of patients receiving first-line lenvatinib or atezolizumab plus bevacizumab access second-line treatment. Our data suggest that in patients progressed to atezolizumab plus bevacizumab, the systemic therapy able to achieve the longest survival is lenvatinib, while in patients progressed to lenvatinib, the systemic therapy able to achieve the longest survival is immunotherapy.

Real-World Data for Atezolizumab Plus Bevacizumab in Unresectable Hepatocellular Carcinoma: How Does Adherence to the IMbrave150 Trial Inclusion Criteria Impact Prognosis?

BACKGROUND: Atezolizumab plus bevacizumab has recently been approved as a new first-line standard of care for patients with unresectable hepatocellular carcinoma (HCC). OBJECTIVE: We performed a real-world study to evaluate the impact of the IMbrave150 trial inclusion criteria on the safety and efficacy of treatment outside of clinical trials. METHODS: We analyzed patients treated with atezolizumab plus bevacizumab for unresectable HCC from four different countries. No specific inclusion and exclusion criteria were applied, except for the absence of previous systemic therapies for HCC. The entire population was split into two groups according to concordance with the inclusion criteria as reported in the IMbrave150 trial in 'IMbrave150-in' and 'IMbrave150-out' patients, and safety and efficacy in the two groups of patients were evaluated. RESULTS: Overall, 766 patients were included in the analysis: 561/766 (73%) in the 'IMbrave150-in' group and 205/766 (27%) in the 'IMbrave150-out' group. Median overall survival (OS) and median progression-free survival (PFS) were 16.3 versus 14.3 months (hazard ratio [HR] 0.48, 95% confidence interval [CI] 0.35-0.65; p < 0.0001] and 8.3 versus 6.0 months (HR 0.79, 95% CI 0.63-0.99; p = 0.0431) in 'IMbrave150-in' and 'IMbrave150-out' patients, respectively. Multivariate analysis confirmed that patients included in the 'IMbrave150-in' group had significantly longer OS compared with patients included in the 'IMbrave150-out' group (HR 0.76, 95% CI 0.47-0.97; p = 0.0195). In 'IMbrave150-in' patients, the albumin-bilirubin (ALBI) grade was not associated with OS, whereas in 'IMbrave150-out' patients, those with ALBI grade 1 reported a significant benefit in terms of OS compared with those with ALBI grade 2 (16.7 vs. 5.9 months; HR 4.40, 95% CI 2.40-8.08; p > 0.0001). No statistically significant differences were reported in the 'IMbrave150-in' and 'IMbrave150-out' groups in terms of safety profile. CONCLUSION: Adherence to the IMbrave150 trial inclusion criteria favorably impacts the prognosis of patients receiving atezolizumab plus bevacizumab. Among patients who did not meet the IMbrave150 inclusion criteria, those with ALBI grade 1 could benefit from the treatment.

Survival outcomes from atezolizumab plus bevacizumab versus Lenvatinib in Child Pugh B unresectable hepatocellular carcinoma patients.

INTRODUCTION: The best first-line treatment for patients with advanced hepatocellular carcinoma (HCC) and Child-Pugh (CP) class B remains unknown. The aim of the present study was to perform a real-world analysis on a large sample of patients with unresectable HCC with CP B treated with atezolizumab plus bevacizumab Vs Lenvatinib. METHODS: The study population included patients affected by advanced (BCLC-C) or intermediate (BCLC-B) HCC patients not suitable for locoregional therapies from both the Western and Eastern world (Italy, Germany, Republic of Korea and Japan), who received atezolizumab plus bevacizumab or Lenvatinib as first-line treatment. All the study population presented a CP class of B. The primary endpoint of the study was the overall survival (OS) of CP B patients treated with Lenvatinib compared to atezolizumab plus bevacizumab. Survival curves were estimated using the product-limit method of Kaplan-Meier. The role of stratification factors was analyzed with log-rank tests. Finally, an interaction test was performed for the main baseline clinical characteristics. RESULTS: 217 CP B HCC patients were enrolled in the study: 65 (30%) received atezolizumab plus bevacizumab, and 152 (70%) received lenvatinib. The mOS for patients receiving Lenvatinib was 13.8 months (95% CI: 11.6-16.0), compared to 8.2 months (95% CI 6.3-10.2) for patients receiving atezolizumab plus bevacizumab as first-line treatment (atezolizumab plus bevacizumab Vs Lenvatinib: HR 1.9, 95% CI 1.2-3.0, p = 0.0050). No statistically significant differences were highlighted in terms of mPFS. The multivariate analysis confirmed that patients receiving Lenvatinib as first-line treatment have a significantly longer OS compared to patients receiving atezolizumab plus bevacizumab (HR 2.01; 95% CI 1.29-3.25, p = 0.0023). By evaluating the cohort of patients who received atezolizumab plus bevacizumab, we found that Child B patients with ECOG PS 0, or BCLC B stage or ALBI grade 1 were those who had benefited from the treatment thus showing survival outcomes no significantly different compared to those receiving Lenvatinib. CONCLUSION: The present study suggests for the first time a major benefit from Lenvatinib compared to atezolizumab plus bevacizumab in a large cohort of patients with CP B class HCC.

Role of the Prognostic Nutritional Index in Predicting Survival in Advanced Hepatocellular Carcinoma Treated with Atezolizumab Plus Bevacizumab.

INTRODUCTION: The prognostic nutritional index (PNI) is a multiparametric score introduced by Onodera based on the blood levels of lymphocytes and albumin in patients with gastrointestinal neoplasms. Regarding hepatocellular carcinoma (HCC), its prognostic role has been shown in patients treated with sorafenib and lenvatinib. The aim of this real-world study was to investigate the association between clinical outcomes and PNI in patients being treated with atezolizumab plus bevacizumab. METHODS: The overall cohort of this multicentric study included 871 consecutive HCC patients from 5 countries treated with atezolizumab plus bevacizumab in first-line therapy. The PNI was calculated as follows: 10 × serum albumin concentration (g/dL) + 0.005 × peripheral lymphocyte count (number/mm3). RESULTS: Data regarding lymphocyte counts and albumin levels were available for 773 patients; therefore, these patients were included in the final analysis. The cut-off point of the PNI was determined to be 41 by receiver operating characteristic analysis. 268 patients (34.7%) were categorized as the PNI-low group, while the remaining 505 (65.3%) patients as the PNI-high group. At the univariate analysis, high PNI was associated with longer overall survival (OS) (22.5 vs. 10.1 months, HR 0.34, p <0.01) and progression-free survival (PFS) (8.7 vs. 5.8 months, HR 0.63, p <0.01) compared to patients with low PNI. At the multivariate analysis, high versus low PNI resulted as an independent prognostic factor for OS (HR 0.49, p <0.01) and PFS (HR 0.82, p = 0.01). There was no difference in objective response rate between the two groups (high 26.1% vs. low 19.8%, p = 0.09), while disease control rate was significantly higher in the PNI-high group (76.8% vs. 66.4%, p = 0.01). CONCLUSION: PNI is an independent prognostic factor for OS and PFS in HCC patients on first-line treatment with atezolizumab plus bevacizumab.

Atezolizumab plus bevacizumab versus lenvatinib for unresectable hepatocellular carcinoma: a large real-life worldwide population.

BACKGROUND AND AIMS: Atezolizumab plus bevacizumab and lenvatinib have not been compared in a randomised controlled trial. We conducted a retrospective multi-centre study to compare the clinical efficacy and safety of lenvatinib and atezolizumab with bevacizumab as a first-line treatment for patients with unresectable HCC in the real-world scenario. METHODS: Clinical features of lenvatinib and atezolizumab plus bevacizumab patients were balanced through inverse probability of treatment weighting (IPTW) methodology, which weights patients' characteristics and measured outcomes of each patient in both treatment arms. Overall survival (OS) was the primary end-point. RESULTS: The analysis included 1341 patients who received lenvatinib, and 864 patients who received atezolizumab plus bevacizumab. After IPTW adjustment, atezolizumab plus bevacizumab did not show a survival advantage over lenvatinib HR 0.97 (p = 0.739). OS was prolonged by atezolizumab plus bevacizumab over lenvatinib in viral patients (HR: 0.76; p = 0.024). Conversely, OS was prolonged by lenvatinib in patients with non-alcoholic steatohepatitis/non-alcoholic fatty liver disease (HR: 1.88; p = 0.014). In the IPTW-adjusted population, atezolizumab plus bevacizumab provided better safety profile for most of the recorded adverse events. CONCLUSION: Our study did not identify any meaningful difference in OS between atezolizumab plus bevacizumab and lenvatinib. Although some hints are provided suggesting that patients with non-alcoholic steatohepatitis/non-alcoholic fatty liver disease might benefit more from lenvatinib therapy and patients with viral aetiology more from atezolizumab plus bevacizumab.

Clinical outcomes with atezolizumab plus bevacizumab or lenvatinib in patients with hepatocellular carcinoma: a multicenter real-world study.

PURPOSE: The purpose of this study is to compare response rates of lenvatinib and atezolizumab plus bevacizumab, in first-line real-world setting. METHODS: Overall cohort included Western and Eastern hepatocellular carcinoma (HCC) patient populations from 46 centres in 4 countries (Italy, Germany, Japan, and Republic of Korea). RESULTS: 1312 patients were treated with lenvatinib, and 823 patients were treated with atezolizumab plus bevacizumab. Objective response rate (ORR) was 38.6% for patients receiving lenvatinib, and 27.3% for patients receiving atezolizumab plus bevacizumab (p < 0.01; odds ratio 0.60). For patients who achieved complete response (CR), overall survival (OS) was not reached in both arms, but the result from univariate Cox regression model showed 62% reduction of death risk for patients treated with atezolizumab plus bevacizumab (p = 0.05). In all multivariate analyses, treatment arm was not found to be an independent factor conditioning OS. Comparing ORR achieved in the two arms, there was a statistically significant difference in favor of lenvatinib compared to atezolizumab plus bevacizumab in all subgroups except for Eastern patients, Child-Pugh B patients, presence of portal vein thrombosis, α-feto-protein ≥ 400 ng/mL, presence of extrahepatic disease, albumin-bilirubin (ALBI) grade 2, and no previous locoregional procedures. CONCLUSION: Lenvatinib achieves higher ORR in all patient subgroups. Patients who achieve CR with atezolizumab plus bevacizumab can achieve OS so far never recorded in HCC patients. This study did not highlight any factors that could identify patient subgroups capable of obtaining CR.