Vessels encapsulating tumor clusters predict better outcomes in advanced hepatocellular carcinoma treated with...

Atezolizumab + bevacizumab and durvalumab + tremelimumab are the standard first-line therapies for advanced hepatocellular carcinoma (HCC). Histological variables routinely associated with outcomes remain poorly described. We aimed to assess the prognostic and predictive value of the vessels encapsulating tumor clusters (VETC) phenotype in this setting.

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 the VETC phenotype, defined as complete (≥55% of tumor area), or incomplete (1-54% of tumor area). Prognostic impacts were evaluated using multivariable Cox models.

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 the modified RECIST. 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).

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.

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 PFS and OS in patients with HCC treated with atezolizumab + bevacizumab compared with 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.