The ImmunoXXL Study

This study is aimed at confirming data of efficacy and safety of liver transplantation (LT) in patients with hepatocellular carcinoma (HCC) beyond current transplant criteria who demonstrate a sustained partial or complete radiological response to the atezolizumab and bevacizumab combination treatment, prescribed after completion of loco-regional therapies or as a first line systemic treatment.

The aim of the study is to demonstrate that liver transplantation, after effective HCC downstaging with atezolizumab and bevacizumab combination, may confer a survival benefit over atezolizumab and bevacizumab maintained treatment alone and that this strategy (tested in a consecutive non-randomized cohort) is not undermined by added risks.

Liver transplantation (LT) is an accepted treatment for hepatocellular carcinoma (HCC). For patients with intermediate-advanced stage hepatocellular carcinoma (HCC) otherwise not eligible to curative treatments, tumor downstaging to LT is now an accepted strategy, as transplantation after a successful downstaging with loco-regional treatments confers a significant benefit in survival and recurrence/progression free survival compared to non-transplant strategies. Immune checkpoint inhibitors (ICIs) efficacy has been proven both as an adjuvant treatment in surgically treated HCCs and as a first line systemic therapy for advanced stage patients; in both cases with more than tolerable safety profiles. Therefore there is interest in using immunotherapy as a downstaging treatment prior to curative liver transplantation (LT).

This observational prospective single-arm study enrols patients on the transplant list after the achievement of a sustained radiological partial response (PR) or complete response (CR) on treatment with atezolizumab (flat dose of 1200 mg) and bevacizumab (15 mg/Kg) given intravenously every three weeks for a non otherwise treatable intermediate-advanced HCC.

Radiological response has to be sustained (for at least 3 months) and accompanied by a level of alpha fetoprotein (AFP) ≤ 100 UI/ml, if levels \> 100 UI/ml at baseline or by decrease of the level of AFP parallel to the modified response evaluation criteria in solid tumors (mRECIST), if baseline levels ≤ 100 UI/ml.

Radiological and biochemical responses need to satisfy a ≥60% post-transplant survival at 5 years according to the Metroticket 2.0 calculator (www.hcc-olt-metroticket.org).

While on the liver transplant waiting list, treatment with atezolizumab and bevacizumab will be stopped. Treatment may be restored, according to clinical judgement:

* if waiting time on transplant list \> 2 months
* if radiological and/or AFP progression within transplant criteria (predicted 5 year survival according to Metroticket 2.0 calculator ≥60%).
* if radiological and/or AFP progression beyond transplant criteria (predicted 5 year survival according to Metroticket 2.0 calculator \< 60%); patients will be delisted (drop out) and treated according to clinical judgement and local standards.

Priority on the waiting list will follow local standards for candidates with HCC at risk of progression. Both donation after brain death (DBD) and after cardiac death (DCD) will be accepted for organ procurement.

Participants will also undergo a comprehensive blood immunomonitoring in order to explore the effect of liver transplantation and of related immunosuppressive regimens on the anti-tumoral immunomediated environment induced by the combination of atezolizumab and bevacizumab.

Eligibility Criteria:
Inclusion Criteria:

* age ≥ 18 and \< 75 years
* signed Informed Consent Form
* hepatocellular carcinoma (HCC) previously diagnosed by histology/cytology or clinically by the American Association for the Study of Liver Disease (AASLD) criteria in cirrhotic patients. Patients without cirrhosis require compulsory histological confirmation of diagnosis.
* hepatocellular carcinoma (HCC) at diagnosis beyond "AFP-adjusted up-to-seven criteria" not amenable to loco-regional treatments and with sustained (at least 3 months) complete o partial response according to mRECIST after systemic treatment with atezolizumab and bevacizumab
* no major contraindications (cardiological, pulmonary, mental and social) to transplantation.

Exclusion Criteria:

* presence of extra-hepatic spread (EHS) defined as organ involvement other than the liver and hilar lymphnodes with short axis \> 2 cm
* presence of tumoral portal vein thrombosis invading the main portal trunk for more than 1 cm in cranio-caudal extension (measured at coronal reconstructions scans at contrast enhanced CT/MRI).