Low-Baseline PD1+ Granulocytes Predict Responses to Atezolizumab–Bevacizumab in Hepatocellular Carcinoma

Simple Summary Immune check point inhibitors (ICPIs) are one of the treatment options for advanced hepatocellular carcinoma (HCC). No biomarker is currently available to upfront select patients to be addressed to one or another drug. We have tested a prospective series of patients with advanced HCC treated with atezolizumab-bevacizumab combination with the aim of identifying biomarkers of response by using a simple cytofluorimetric test on peripheral blood. Due to the relevant role of granulocyte in the immune response, here we have focused on granulocyte immunophenotype by investigating PD1 and PD-L1 expression on their surface by using a simple cytofluorimetric test on peripheral blood. A low baseline PD1+ granulocyte percentage identified patients likely to benefit from atezolizumab-bevacizumab. Our findings warrant to validate this cheap and immediate cytofluorimetric test in larger cohorts, to verify whether the individual accuracy could be informative for the clinical practice. Introduction: Immune check point inhibitors have recently entered the armamentarium of advanced hepatocellular carcinoma (HCC) treatment. Among them, the combination of atezolizumab plus bevacizumab has pushed it a step forward; however, a number of patients still present primary non-responses without any biomarker to predict responses to different options. Here, we aimed to identify a putative baseline biomarker to predict the response to atezolizumab-bevacizumab, by investigating whether baseline PD1+ and PD-L1+ peripheral granulocyte percentages might offer a non-invasive, cheap, and easily feasible assay. Methods: A prospective Italian cohort of 34 patients treated by atezolizumab-bevacizumab was tested to assay the baseline percentage of peripheral granulocytes and their PD1 and PD-L1 expression. The neutrophil to lymphocyte ratio (NLR) was also considered, and all data were compared with the clinical course of patients. Results: A low-baseline PD1+ peripheral granulocyte percentage turned out to predict responder patients (mean +/- SD of PD1+ granulocyte percentage in responders versus non-responders: 9.9 +/- 9.1 vs. 29.2 +/- 17.6; student's t-test, p < 0.01). In line, patients identified by a low PD1+ granulocyte percentage displayed a longer TTP (log-rank test, p < 0.0001). A lower granulocyte percentage on total white blood cells, irrespective of PD1 or PD-L1 expression, is also associated with responses to atezolizumab-bevacizumab (log-rank test, p < 0.05). No predictive value was observed for either the PD-L1+ granulocyte percentage or NLR. Conclusions: A low-baseline PD1+ peripheral granulocyte percentage is associated with responses to atezolizumab-bevacizumab treatment in advanced HCC. These findings encourage evaluating this minimally invasive, cheap, and easy test in further independent cohorts and outlining the relevance of innate immunity in the response to immune-checkpoint inhibitors

Real-Life Clinical Data of Lenvatinib versus Sorafenib for Unresectable Hepatocellular Carcinoma in Italy

Background: Lenvatinib has been approved in Italy since October 2019 as a first-line therapy for advanced hepatocellular carcinoma (HCC) and to date data on effectiveness and safety of lenvatinib are not available in our region. To fill this gap, we performed a multicentric analysis of the real-world treatment outcomes with the propensity score matching in a cohort of Italian patients with unresectable HCC who were treated with either sorafenib or lenvatinib. Aims and Methods: To evaluate the effectiveness of sorafenib and lenvatinib as primary treatment of advanced HCC in clinical practice we performed a multicentric analysis of the treatment outcomes of 288 such patients recruited in 11 centers in Italy. A propensity score was used to mitigate confounding due to referral biases in the assessment of mortality and progression-free survival. Results: Over a follow-up period of 11 months the Cox regression model showed 48% reduction of death risk for patients treated with lenvatinib (95% CI: 0.34-0.81; p = 0.0034), compared with those treated with sorafenib. The median PFS was 9.0 and 4.9 months for lenvatinib and sorafenib arm, respectively. Patients treated with lenvatinib showed a higher percentage of response rate (29.4% vs 2.8%; p < 0.00001) compared with patients treated with sorafenib. Sorafenib was shown to be correlated with more HFSR, diarrhea and fatigue, while lenvatinib with more hypertension and fatigue. Conclusion: Our study highlighted for the first time the efficacy and safety of lenvatinib in an Italian cohort of patients