Safety of Atezolizumab-Bevacizumab in Liver Transplanted Patients With Advanced Hepatocellular Carcinoma

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 whichexists within the first months after LT and to deal with populations with a loweredimmunosuppressive 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 multidisciplinarymeeting

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

• ANC ≥ 1.5 x 109/L (1500/µL) without granulocyte colony-stimulating factorsupport

• 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 thiscriterion.

• 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 studytreatment). Patients discovered to have ≥ 2+ proteinuria on dipstick urinalysisat baseline should undergo a 24-hour urine collection and must demonstrate <1 gof protein in 24 hours

• ECOG Performance Status of 0 or 1

• For women of childbearing potential and men: agreement to remain abstinent or useeffective 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 thetreatment

• Pregnant or breastfeeding woman

• Patient not affiliated to a beneficiary or entitled social security scheme or to thePUMA

• Patient not having signed consent

• History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-inducedpneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis onscreening chest CT-scan

• History of malignancy other than HCC within 5 years prior to screening, with theexception of malignancies with a negligible risk of metastasis or death

• Untreated or incompletely treated esophageal and/or gastric varices with bleeding orhigh-risk for bleeding

• A prior bleeding event due to esophageal and/or gastric varices within 6 monthsprior to initiation of study treatment.

• Inadequately controlled arterial hypertension (defined as systolic blood pressure ≥ 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 theseparameters is allowable.

• Prior history of hypertensive crisis or hypertensive encephalopathy

• History of intestinal obstruction and/or clinical signs or symptoms of GIobstruction including sub-occlusive disease related to the underlying disease orrequirement 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 centrallylocated mediastinal tumor masses

• Hypersensitivity to the active substance or to any of the excipients of the SmPC ofbevacizumab and the SmPC of atezolizumab

• Hypersensitivity to Chinese Hamster Ovary (CHO) cell products or other recombinanthuman 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 orgreater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstableangina

• 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, orsevere pneumonia