The purpose of this research is to compare progression free survival between two available systemic therapies - immunotherapy and tyrosine kinase inhibitors - after Therasphere® (yttrium-90) treatment in adult patients with advanced hepatocellular carcinoma. The immunotherapy consists of a standard-of-care treatment with Atezolizumab and Bevacizumab. Treatment with tyrosine kinase inhibitors consists of standard-of-care Lenvatinib or Cabozantinib.

PRIMARY OBJECTIVES:

I. To compare Progression Free Survival (PFS) in patients with advanced HCC who receive Y90 followed by immunotherapy (atezolizumab + bevacizumab, Arm A) or Y90 followed by TKI treatment ( lenvatinib or cabozantinib, Arm B). For ARM B, [patients will receive Lenvatinib. If they have prior history of treatment with Lenvatinib, then can be given Cabozantinib]..

SECONDARY OBJECTIVES:

I. To compare the Time to Progression (TTP) in patients with advanced HCC who receive Immunotherapy combination compared to TKI following Y90.

II. To compare the Objective Response Rate (ORR) as assessed by RECIST v1.1 in patients with advanced HCC who receive immunotherapy combination and those who receive TKI treatment after Y90.

III. To compare the Duration of Response (DOR) in patients with advanced HCC who receive immunotherapy combination and those who receive TKI treatment after Y90.

IV. To compare the Clinical Benefit Rates (CBR) [CR, PR,SD] as assessed by RECIST v1.1 in patients with advanced HCC who receive immunotherapy combination and those who receive TKI treatment after Y90.

V. To compare the Overall Survival (OS) in patients with advanced HCC who receive immunotherapy combination and those who receive TKI treatment after Y90.

VI. To compare the safety and tolerability of patients with advanced HCC who receive immunotherapy combination and those who receive TKI treatment after Y90, as defined by NCI CTCAEv5.

OUTLINE:

Patients will first be treated one time with liver directed therapy, Therasphere® (Y-90), following institutional procedures. After completion of Y- 90, patients will have some recovery time (14-21 days) prior to starting systemic therapy.

Patients will be followed up for 2 years after completion of study treatment.

Inclusion Criteria:

• 3.1.1 Patients must have a diagnosis of hepatocellular carcinoma (HCC) confirmed by American Association for Study of Liver Diseases (AASLD) guidelines with a Childs-Pugh score of A or B7 [Appendix 5] NOTE: If the patient does not have histological confirmation of disease by biopsy, diagnosis of HCC must be documented with approval by a tumor board or other multidisciplinary conference. Please refer to the appropriate source documents.
• 3.1.2 Patients must have at least 1 lesion that is measurable using RECIST guidelines. NOTE: A previously irradiated lesion can be considered a target lesion if the lesion is well defined, measurable per RECIST, and has clearly progressed.
• 3.1.3 Patients may be treatment -naïve or have received any number of prior therapies. NOTE: Prior cancer targeted immunotherapy for any other cancer is contraindicated and not permitted.
• 3.1.4 Adults ≥18 years old of either gender are eligible.
• 3.1.5 Patients must exhibit an ECOG performance status of 0, 1, or 2 [Appendix 1]
• 3.1.6 Patients must have adequate organ function prior to registration as determined by: Hemoglobin (HgB) ≥ 8.5 g/dL (without the use of growth factors, transfusion permitted), Absolute Neutrophil Count (ANC) ≥ 50 x 109/L (without use of growth factors [i.e., IL-11], transfusion permitted to achieve this value), Prothrombin time (PT)/ International normalized ratio ≤ 2.3 or PT ≤ 6 seconds above control, Calculated creatinine clearance (CrCl) or 24-hour urine CrCl > 30 mL/min, Serum Bilirubin ≤ 3 times the upper limit of normal (ULN), AST 10X ULN, ALT 10X ULN
• 3.1.7 Females of childbearing potential (FOCBP), and non-sterilized males who are sexually active must agree to the use of two methods of contraception, with one method being highly effective and the other method being either highly effective or less effective as listed in Appendix 3. They must also refrain from egg and/or sperm cell donation and breastfeeding for 90 days after the final dose of investigational product(s). FOCBP are defined as those who are not surgically sterile (i.e., bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or postmenopausal (defined as 12 months with no menses without an alternative medical cause) FOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment. Men who are sexually active with FOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment.
• 3.1.8 FOCBP must have a negative pregnancy test (Serum or urine pregnancy test per site investigator discretion) prior to registration.
• 3.1.9 Patients must have the ability to understand and the willingness to sign a written informed consent prior to registration on study.

Exclusion Criteria:

• 3.2.1 Patients who are concurrently enrolled in another clinical study unless it is an observational (noninterventional) clinical study or the follow-up period of an interventional study.
• 3.2.2 Patients who are receiving any other investigational agents within 28 days of registration.
• 3.2.3 Patients who have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to Y-90, PD-1 &PD-L1 antagonists and TKI's. Note: Patients must not have a history of severe allergic reactions (i.e., Grade 4 allergy, anaphylactic reaction from which the subject did not recover within 6 hours of initiation of supportive care) to any unknown allergens or any components of the systemic therapy
• 3.2.4 Patients must not have had prior treatment any PDL1 or PD-1 antagonists.
• 3.2.5 Patients who have known additional malignancy that progressed or required treatment within the last 3 years. Note: Exceptions include adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated Stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for at least three years.
• 3.2. 6 Patients with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including chronic prolonged systemic corticosteroids (defined as corticosteroid use of duration one month or greater), should be excluded.
• 3.2.7 Patients with renal failure currently requiring dialysis of any kind.
• 3.2.8 Patients with untreated central nervous system (CNS) metastatic disease (including spinal cord and leptomeningeal disease) are excluded. Note: Subjects with previously treated CNS metastases that are radiographically and neurologically stable for at least 6 weeks and do not require corticosteroids (of any dose) for symptomatic management are permitted to enroll.
• 3.2.9 Patients with chronic Hepatitis B with evidence of ongoing viral replication (detectable HBsAg, HBeAg, or HBV DNA). They must have HBV DNA viral load >100 IU/mL at screening. Note: One viral load is sufficient as long as it meets this criterion. However, patient may need another viral load done per treating physician's discretion to confirm eligibility. Note:. Both HBeAg positive and negative patients will are eligible.
• 3.2.10 Patients with a known history of Human immunodeficiency virus(HIV) who are not on effective anti-retroviral therapy.
• 3.2.11 Patients with a known history of hepatitis C virus (HCV) infection who have not been treated and cured. Note: For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral.
• 3.2.12 Patients receiving any concurrent chemotherapy, biologic, or hormonal therapy for cancer treatment within 28 days of registration. Note: Prior cancer immunotherapy for any other cancer is not permitted. Note: Concurrent use of hormones for non-cancer-related conditions (e.g., insulin for diabetes and hormone replacement therapy) is acceptable.
• 3.2.13 Patients who have unresolved toxicities from prior anticancer therapy, defined as having not resolved to NCI CTCAE v 5 [Appendix 6] Grade 0 or 1 with the exception of alopecia and laboratory values listed per the inclusion criteria. Note: Subjects with any grade irreversible toxicity that is not reasonably expected to be exacerbated by any of the investigational products may be included (e.g., hearing loss) after consultation with the PI and NU QAM.
• 3.2.14 Patients receiving radiation therapy within 14 days of registration.
• 3.2.15 Patients receiving live vaccines within 28 days of study registration.
• 3.2.16 No systemic glucocorticoids will be permitted within 48 hours prior to study registration. Note: Topical steroids, bronchodilators and local steroid injections are permitted if clinically required.
• 3.2.17 Patients with cardiac disease defined as one of the following are not eligible: Congestive heart failure > class II NYHA.[Appendix 4], Unstable angina (anginal symptoms at rest) or new onset angina (began within the last 90 days ), Myocardial infarction within the past 180 days.
• 3.2.18 Patients who have had major surgery within 4 weeks prior to registration.
• 3.2.19 Patients with prior transplant of any kind
• 3.2.20 Patients who are pregnant or nursing.
• 3.2.21 Patients who have an uncontrolled intercurrent illness.
• 3.2.22 Active alcohol use, drug use, or a psychiatric disease that would, in the opinion of the PI or a subinvestigator (sub-I), prevent the subject from complying with the study protocol and/or endanger the subject during their participation in the study.