Efficacy of liver transplantation after response to atezolizumab-bevacizumab downstaging of intermediate and advanced hepatocellular carcinoma (ImmunoXXL)

Background & aims: Liver transplantation (LT) is a curative treatment in early and intermediate hepatocellular carcinoma (HCC) after downstaging with locoregional therapies (LRT). Tumor response to immune check-point inhibitors may extend LT eligibility to intermediate and advanced stages. Methods: In this prospective phase II study, intermediate and advanced HCCs beyond extended transplant criteria, not amenable to further locoregional treatments and downstaged with atezolizumab-bevacizumab (Atezo-Bev) underwent LT. Primary endpoint was recurrence-free survival (RFS) with safety and efficacy as additional registered outcomes. Spectral quantitative pathology and immune signatures on tumor tissue and in peripheral blood were longitudinally studied. Results: 16 HCC patients presenting beyond expanded transplant criteria [median size: 6.5 cm (IQR: 3-8), median AFP 283 (IQR: 6-1080), portal vein thrombosis: 50%] were downstaged to LT after a median of 4.7 months (IQR: 2.4-7.6). Previous LRTs were employed in 15 (94%) patients. Washout period from last Atezo-Bev to transplant was 57.5 (IQR: 29-87) days. Median follow-up was 16 (95%CI: 4-22) months. Pre-transplant immune-related adverse events occurred in 3 (19%) patients while post-transplant acute rejection in 4 (25%). Post-LT 90-day morbidity and mortality were 62.5% (95%CI: 35-85%) and 6.3% (95%CI: 0.2-30%) respectively. Explant pathology revealed 10 complete and 6 partial responses. Responding patients harboured a tumour microenvironment with features suggestive of immune activation/extinguishment, correlated with duration of Atezo-Bev treatment and length of pre-LT washout. One (6.2%) HCC post-LT recurrence occurred during follow-up. Recurrence-free and post-transplant overall survival were 90% and 94% after 2 years, respectively. Conclusions: LT after Atezo-Bev is characterized by competitive RFS estimates in intermediate and advanced HCC presenting beyond transplant indications. Acute rejection seems increased but remains clinically manageable. LT should be considered after HCC response to immunotherapy.