The prognosis of liver transplanted (LT) patients with recurrence of hepatocellular carcinoma (HCC), especially those with progression after locoregional treatment or advanced HCC, remains poor. Current treatment modalities involve tyrosine kinase inhibitors (TKIs) characterized by a low response rate and often poor tolerability. Encouraging findings from the Imbrave 150 study, demonstrating increased survival rates coupled with favorable treatment tolerance, prompt the investigators to consider the potential of offering the combination of treatment with Atezolizumab-Bevacizumab (Atezo-Beva) to patients with LT. No data regarding the safety and efficacy of this new combination are available for patients with LT as they were not included in Imbrave 150. Immunosuppression after LT is low when compared to essentially all other organ recipients, liver recipients are considered with lower immunological risk. However, the use of ICIs has been associated with a risk of hepatic rejection in LT patients. In this study, in order to prevent acute cellular rejection (ACR) occurrence, we propose to adopt a standardized immunosuppressive regimen closed to the one used immediately after LT but with lower therapeutic goals for tacrolimus and everolimus to allow immunotherapy treatment to be effective. The better tolerance of liver grafts will probably lead to less risk of rejection with Atezo-Beva than in other organ transplants.

Open-label multicentric single-arm two-stage phase 2 trial. Population: Adult LT patients with advanced HCC recurrence with indication to systemic treatment Primary objective: To study the safety (ACR on histology) at 6 months of the first-line Atezo-Beva combination in LT patients with recurrent HCC in association with a standardized immunosuppressive treatment to prevent the risk of liver graft rejection.

Primary endpoint: Rate of Acute cellular rejection (ACR) (defined by a Histological Banff score ≥ 5) at 6 months (confirmed by an external expert center).

Secondary objective:

To study the safety (ACR on histology) at 24 months and at the end of Atezo-Beva treatment in LT patients with recurrent HCC in association with a standardized immunosuppressive treatment to prevent the risk of liver graft rejection.

• To assess the efficacy and tolerance of first-line Atezo-Beva combination in LT patients with advanced HCC in association with a standardized immunosuppressive treatment to prevent the risk of ACR based on:
• the Progression Free Survival (PFS)
• the Overall survival (OS)
• the objective response rate (ORR) (complete and partial response)
• the duration of response
• the quality of life of the patients under Atezo-Beva treatment
• To compare the efficacy (OS and PFS) of LT patients treated by Atezo- Beva treatment to an historical retrospective cohort of LT patients already available treated by TKI as first line (external arm comparison)
• To assess the adverse events related to Atezo-Beva treatment in LT patients with recurrent advanced HCC.
• To assess the evolution of the level of donor specific antibodies (DSA) during Atezo-Beva treatment and its association with ACR, PFS and OS.

Translational research/ancillary studies:

• To assess the association before the first injection between the risk of ACR, PFS, OS and side effects and
• the "Immunome" imaging on tumor sample and non-tumoral liver sample to quantify and regionalize immune populations on pathology (Multispectral Imaging, Mantra)
• the Leukocyte DNA analysis to identify constitutional genetic variants
• To assess the association before the first injection or just before the second injection and at 3 months between the risk of ACR, PFS, OS and side effects and
• the "immunomonitoring" on blood sample (frequency and/or the phenotype of circulating immune cells)
• the presence of tumors cells (liquid biopsies)
• the presence of circulating tumor DNA and the type of mutations
• the presence of circulating proteins
• the profile of circulating exosomes

Inclusion Criteria:

• All patients over 18 and under 90 years old:

• who underwent LT more than 6 months ago (to prevent the higher risk of ACR which exists within the first months after LT and to deal with populations with a lowered immunosuppressive regimen long after LT)

• with HCC recurrence diagnosis according to the EASL diagnostic criteria (33)

• with advanced HCC not accessible to surgery and locoregional treatment

• with at least one measurable untreated lesion

• With a proposal for Atezo-Beva in first line treatment made in a multidisciplinary meeting

• Adequate hematologic and end-organ function, defined by the following laboratory test results, obtained within 14 days prior to initiation of study treatment, unless otherwise specified:

  • ANC ≥ 1.5 x 109/L (1500/µL) without granulocyte colony-stimulating factor support
  • Lymphocyte count ≥ 0.5 x 109/L (500/µL)
  • Platelet count ≥ 75 x 109/L (75,000/µL) without transfusion
  • Hemoglobin ≥ 90 g/L (9 g/dL). Patients may be transfused to meet this criterion.
  • AST, ALT ≤ 5 x upper limit of normal (ULN)
  • Serum bilirubin ≤ 3x ULN
  • creatinine clearance≥40 mL/min (calculated using the Cockcroft-Gault formula)
  • For patients not receiving therapeutic anticoagulation: INR or aPTT ≤ 2x ULN
  • Urine dipstick for proteinuria < 2+ (within 7 days prior to initiation of study treatment). Patients discovered to have ≥ 2+ proteinuria on dipstick urinalysis at baseline should undergo a 24-hour urine collection and must demonstrate <1 g of protein in 24 hours

• ECOG Performance Status of 0 or 1

• For women of childbearing potential and men: agreement to remain abstinent or use effective contraception during treatment and at least :

  • 5 months after the end of the treatment with atezolizumab,
  • 6 months after the end of the treatment with bevacizumab

• Child-Pugh class A

Exclusion Criteria:

• History of ACR within 3 months before starting Atezo-Beva treatment
• Banff score for ACR ≥ 3 on liver biopsy performed before the initiation of the treatment
• Pregnant or breastfeeding woman
• Patient not affiliated to a beneficiary or entitled social security scheme or to the PUMA
• Patient not having signed consent
• History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT-scan
• History of malignancy other than HCC within 5 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death
• Untreated or incompletely treated esophageal and/or gastric varices with bleeding or high-risk for bleeding
• A prior bleeding event due to esophageal and/or gastric varices within 6 months prior to initiation of study treatment.
• Inadequately controlled arterial hypertension (defined as systolic blood pressure (BP) ≥ 160 mmHg and/or diastolic blood pressure > 100 mmHg), based on an average of ≥ 3 BP readings on ≥ 2 sessions Anti-hypertensive therapy to achieve these parameters is allowable.
• Prior history of hypertensive crisis or hypertensive encephalopathy
• History of intestinal obstruction and/or clinical signs or symptoms of GI obstruction including sub-occlusive disease related to the underlying disease or requirement for routine parenteral hydration
• Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture
• Metastatic disease that involves major airways or blood vessels, or centrally located mediastinal tumor masses
• Hypersensitivity to the active substance or to any of the excipients of the SmPC of bevacizumab and the SmPC of atezolizumab
• Hypersensitivity to Chinese Hamster Ovary (CHO) cell products or other recombinant human or humanised antibodies
• Prior arterial thromboembolic reactions including cerebrovascular accidents, transient ischaemic attacks and myocardial infarctions;
• Significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina
• In case of proteinuria > 1g in 24 hours
• History of leptomeningeal disease
• Active tuberculosis
• Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia