Aim of the study is to evaluate the efficacy of up-front atezolizumab/ bevacizumab (Atezo/Bev) followed by on-demand selective transarterial chemoembolization (sdTACE) and of initial synchronous treatment with TACE and Atezo/Bev in the treatment of unresectable HCC patients.

Key Inclusion Criteria

1. Patient's signed informed consent
2. Age ≥18 years at time of signing Informed Consent Form
3. Ability to comply with the study protocol, according to investigator's judgement
4. Life expectancy of at least 12 weeks
5. HCC with histologically confirmed diagnosis
6. Disease that is not amenable to curative surgical and/or local ablation but eligible for TACE
7. ECOG Performance Status of 0 or 1
8. Child-Pugh class A or B7
9. Adequate hematologic and end-organ function
10. Negative HIV test at screening

Key Exclusion Criteria

1. Diffuse HCC or presence of vascular invasion or extrahepatic spread or more than 7 lesions or at least one lesion >= 7 cm

2. Clinically relevant ascites

3. Uncontrolled pleural effusion or pericardial effusion

4. History or presence of hepatic encephalopathy

5. Co-infection of HBV and HCV

6. Patients on a liver transplantation list.

7. Prior systemic therapy for HCC

8. Prior treatment with TACE or selective internal radiation treatment (SIRT)

9. Any condition representing a contraindication to TACE

10. Major gastrointestinal bleeding within 4 weeks prior to randomization, untreated or incompletely treated varices with bleeding or high-risk for bleeding.

11. Active or history of autoimmune disease or immune deficiency

12. Prior allogeneic stem cell or solid organ transplantation

13. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan

14. Active tuberculosis

15. Severe infection requiring antibiotics within 4 weeks prior to randomization

16. Significant cardiovascular disease

17. History of congenital long QT syndrome or corrected QT interval >500 ms at screening ECG

18. Inadequately controlled arterial hypertension or prior history of hypertensive crisis or hypertensive encephalopathy

19. Significant vascular disease including aortic aneurysm requiring surgical repair or peripheral arterial thrombosis with 6 months prior to randomization

20. History of abdominal or tracheoesophageal fistula or gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to randomization.

21. History or clinical signs of gastrointestinal obstruction or requirement for routine parenteral hydration, parenteral nutrition, or tube feeding. Evidence of abdominal free air that is not explained by paracentesis or recent surgical procedure

22. History of intra-abdominal inflammatory process within 6 months prior to randomization, including but not limited to peptic ulcer disease, diverticulitis, or colitis

23. Evidence of bleeding diathesis or significant coagulopathy

24. Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications.

25. Uncontrolled tumor-related pain. Patients requiring pain medication must be on a stable regimen at enrollment.

26. Severe, non healing or dehisced wound, active ulcer, or untreated bone fracture

27. History of malignancy other than HCC, with the exception of patients who have been disease-free for at least five years before enrollment or patients with adequately treated and completely resected basal cell or squamous cell skin cancer, in situ cervical, breast or prostate cancer, stage I uterine cancer

28. Current or recent (within 10 days of randomization) use of acetylsalicyclic acid or treatment with dipyramidole, ticlopidine, clopidogrel, and cilostazol

29. Current or recent (within 10 days prior to randomization) use of full dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic purpose.

30. Chronic daily treatment with a nonsteroidal anti-inflammatory drug (NSAID). Occasional use of NSAIDs for the symptomatic relief of medical conditions such as headache or fever is allowed.

31. Treatment with a live, attenuated vaccine within 4 weeks prior to randomization, or anticipation of need for such a vaccine during atezolizumab treatment or within 5 months after the last dose of atezolizumab

32. Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, and antiPD-L1 therapeutic antibodies

33. Hypersensitivity to atezolizumab or bevacizumab or any of the excipients, known hypersensitivity to Chinese hamster ovary cell products, known hypersensitivity to human or humanized antibodies

34. Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin 2 [IL-2]) within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to randomization

35. Treatment with systemic immunosuppressive medication within 2 weeks prior to randomization, or anticipation of need for systemic immunosuppressive medication during study treatment, with the following exceptions:

    Patients who received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible.

    Inhaled corticosteroids for chronic obstructive pulmonary disease or bronchial asthma, supplemental mineralocorticosteroids or low-dose corticosteroids for adrenalcortical insufficiency are allowed.

36. Major surgical procedure other than for diagnosis, open biopsy, or significant traumatic injury within 28 days prior to randomization, or abdominal surgery, abdominal interventions or significant abdominal traumatic injury within 60 days prior to randomization or anticipation of need for major surgical procedure during the course of the study or non-recovery from side effects of any such procedure

37. Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 3 days prior to the first dose of bevacizumab

38. Pregnant or breastfeeding females

39. Participation in a clinical trial or experimental drug treatment within 28 days prior to inclusion in the clinical trial or within a period of 5 half-lives of the substances administered in a clinical trial or during an experimental drug treatment prior to inclusion in the clinical trial, depending on which period is longest, or simultaneous participation in another clinical trial while taking part in this clinical trial.

40. Patient committed to an institution by virtue of an order issued either by the judicial or the administrative authorities

41. Patient possibly dependent from the investigator including the spouse, children and close relatives of any investigator