Vessels Encapsulating Tumor Clusters predict better outcomes in advanced hepatocellular carcinoma treated with atezolizumab-bevacizumab

Background & aims: Atezolizumab+bevacizumab and durvalumab+tremelimumab are the standard first-line therapies for advanced HCC. Histological variables routinely associated with outcomes remain poorly described. We aimed to assess the prognostic and predictive value of VETC in this setting. Methods: We retrospectively analyzed 208 patients in a discovery cohort with advanced HCC treated with atezolizumab+bevacizumab and available pre-treatment biopsies, and 163 patients in a validation cohort, including 99 treated with atezolizumab+bevacizumab and 64 with durvalumab+tremelimumab. In addition to baseline clinico-biological variables, we assessed histological features, including Vessels Encapsulating Tumor Clusters (VETC) phenotype, defined as complete (≥55% of tumor area), or incomplete (1-54% of tumor area). Prognostic impacts were evaluated using multivariable Cox models. Results: In the discovery cohort, the complete VETC phenotype (n=32) displayed the highest objective response rate in the cohort (66% vs 37% in non- or incomplete-VETC-HCC, p=0.002), according to mRECIST. The complete VETC phenotype was independently associated with better progression-free survival (PFS) (Hazard Ratio [HR] 0.42, 95%CI 0.26 - 0.69, p < 0.001) and overall survival (OS) (HR 0.46, 95%CI 0.26 - 0.82, p=0.008). In the validation cohort, complete VETC-HCC was associated with worse outcomes in patients treated with durvalumab+tremelimumab (PFS: HR 2.44, 95%CI 1.12, 5.29, p=0.024; OS: HR 3.90, 95%CI 1.66, 9.15, p=0.002). Patients with complete VETC HCC and treated with atezolizumab+bevacizumab had longer survival than patients with complete VETC HCC and treated with durvalumab+tremelimumab (PFS: HR 0.43, 95%CI 0.17, 1.06, p=0.07; OS: HR 0.19, 95%CI 0.07, 0.51, p=0.001). Conclusion: We identified complete VETC as a potential predictive marker of outcomes in patients with advanced HCC and treated with atezolizumab+bevacizumab or durvalumab+tremelimumab. Prospective validation of these findings is warranted. Impact and implications: Routinely assessable histological variables associated with response and survival are still lacking in patients with advanced HCC treated with atezolizumab+bevacizumab. In this study, we identified and validated, in a multicentric series of 371 pre-therapeutic biopsies, the complete VETC phenotype as a predictive factor for progression-free survival and overall survival in patients with HCC treated with atezolizumab+bevacizumab compared to those treated with durvalumab+tremelimumab. The VETC phenotype is easily assessable in routine practice on biopsy and could help select first-line therapy, although prospective validation of these results remains necessary.