The purpose of this study is to determine the effects (good and bad) that Tebentafusp in combination with Yttrium-90 (Y-90) radioembolization has on patients with metastatic uveal melanoma that has spread to the liver.

Inclusion Criteria:

1. Metastatic uveal melanoma, confined mainly to the liver, and documented by pathology review
2. Serum bilirubin <2 mg/dl, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 5 x upper limit of normal (ULN)
3. Mapping angiogram procedure shows radioembolization is feasible and safe to perform
4. Human leukocyte antigen-A*02:01(HLA A⁕ 02:01) positive
5. Patient age ≥ 18 years old
6. Ability to provide and understand written informed consent
7. Eastern Cooperative Oncology Group (ECOG) performance status 0-1
8. Patients must have measurable disease or non-measurable disease according to RECIST 1.1 (Eisenhauer et al, 2009).

Exclusion Criteria:

1. Patient with any tumor size > 8 cm

2. Total bilirubin > 1.5 × ULN, except for patients with Gilbert's syndrome, who are excluded if total bilirubin > 3.0 × ULN or direct bilirubin > 1.5 × ULN

3. Clinical laboratory measurements that meet any of the following criteria:

   • Alanine aminotransferase (ALT) > 3 × ULN
   • Aspartate aminotransferase (AST) > 3 × ULN
   • Absolute neutrophil count (ANC) < 1.0 × 10^9 cells/L
   • Absolute lymphocyte count < 0.5 × 10^9 cells/L
   • Platelet count < 75 × 109 platelets/L
   • Hemoglobin < 8 g/dL

4. Angiogram shows vascular shunting which prevents radioembolization

5. History of severe hypersensitivity reactions (eg, anaphylaxis) to other biologic drugs or monoclonal antibodies

6. Patients with clinically significant cardiac disease or impaired cardiac function, including any of the following:

   • Congestive heart failure (New York Heart Association Class ≥ 3).
   • Uncontrolled hypertension (consistent findings of systolic blood pressure [BP] > 160 mmHg or diastolic BP > 110 mmHg).
   • History of ventricular arrhythmia currently requiring medical treatment.
   • Uncontrolled atrial fibrillation.
   • Electrocardiogram (ECG) QT interval corrected for heart rate by Fridericia's method (QTcF) > 470 msec during screening obtained on triplicate ECGs or known history of congenital prolonged QT syndrome.
   • Acute myocardial infarction or unstable angina pectoris ≤ 6 months prior to screening.

7. Presence of symptomatic or untreated central nervous system (CNS) metastases or CNS metastases that require doses of corticosteroids within 14 days prior to study treatment Day 1.

8. Active infection requiring systemic antibiotic therapy. Patients requiring systemic antibiotics for infection must have completed therapy at least 1 week prior to the first dose of Tebentafusp.

9. Known history of human immunodeficiency virus (HIV) infection. Testing for HIV status is not necessary unless clinically indicated.

10. Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection per institutional protocol. Testing for HBV or HCV status is not necessary unless clinically indicated or the patient has a history of HBV or HCV infection.

11. Malignant disease other than that being treated in this study. Exceptions to this exclusion include the following: malignancies that were treated curatively and have not recurred within 2 years prior to study treatment; completely resected basal cell and squamous cell skin cancers; any malignancy considered to be indolent and that has never required therapy; and completely resected carcinoma in situ of any type.

12. Any medical condition that would, in the Investigator's or Sponsor's judgment, prevent the patient's participation in the clinical study due to safety concerns, compliance with clinical study procedures, or interpretation of study results

13. Patients who received systemic treatment with steroids or any other immunosuppressive drug within 2 weeks of the planned first dose of study intervention. The following exceptions are permitted (Section 4.9.1):

    • Treatment for well-controlled and asymptomatic adrenal insufficiency, but replacement dosing is limited to prednisone ≤ 12 mg daily or the equivalent.
    • Local steroid therapies (eg, optic, ophthalmic, intra-articular, or inhaled medications).
    • Premedication for allergy to contrast reagent.
    • Steroids for management of CNS metastases > 14 days prior to the planned first dose of study intervention.
    • To treat asthma or chronic obstructive pulmonary disease exacerbations > 14 days prior to the planned first dose of study intervention (only short-term oral or IV use in doses > 12 mg/day prednisone equivalent).
    • For inhalation in the management of asthma or chronic obstructive pulmonary disease.
    • Any premedications required per protocol.

14. Patient with morning cortisol < lower limit of normal (unless the participant has asymptomatic adrenal insufficiency and is receiving stable replacement doses). For additional information regarding patients with adrenal insufficiency.

15. History of interstitial lung disease

16. History of pneumonitis that required corticosteroid treatment or current pneumonitis

17. Patients with active autoimmune disease requiring immunosuppressive treatment, including inflammatory bowel disease (ulcerative colitis or Crohn's disease), within 2 years of screening. Note: The following exceptions are permitted:

    • Vitiligo
    • Alopecia
    • Managed hypothyroidism (on stable replacement doses)
    • Asymptomatic adrenal insufficiency (on stable replacement doses) (For additional information regarding patients with adrenal insufficiency.
    • Psoriasis
    • Resolved childhood asthma/atopy
    • Well-controlled asthma
    • Type I diabetes mellitus

18. Major surgery within 2 weeks of the first dose of study drug (minimally invasive procedures such as bronchoscopy, tumor biopsy, insertion of a central venous access device, and insertion of a feeding tube are not considered major surgery and are not exclusionary)

19. Radiotherapy within 2 weeks of the first dose of study drug, with the exception of palliative radiotherapy to a limited field, such as for the treatment of bone pain or a focally painful tumor mass

20. Use of hematopoietic colony-stimulating growth factors (eg, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF)) ≤ 3 weeks prior to start of Tebentafusp. An erythroid-stimulating agent is allowed as long as it was initiated at least 3 weeks prior to the first dose of study treatment and the patient is not red blood cell (RBC) transfusion dependent. For more information on the timing and use of hematopoietic colony-stimulating growth factors during study.

21. Patient receiving a live or attenuated vaccine(s) ≤ 28 days prior to the first dose of study intervention. Note: Non-live vaccines (including adenoviral and messenger ribonucleic acid (mRNA)-based coronavirus disease-2019 (COVID-19) vaccines) are allowed but are not to be administered for at least 2 weeks before and 3 weeks after start of study treatment and within 24 hours before or after study treatment administration following the first 3 weeks of study treatment.

22. Pregnant, likely to become pregnant, or lactating women (where pregnancy is defined as the state of a female after conception and until the termination of gestation)

23. Women of childbearing potential (WoCBP) who are sexually active with a non-sterilized male partner, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective contraception during study treatment (defined in Section 4.12), and must agree to continue using such precautions for 6 months after the final dose of Tebentafusp; cessation of birth control after this point should be discussed with a responsible physician. Highly effective methods of contraception are described in Section 4.12.

24. Male patients must be surgically sterile or use double barrier contraception methods as described in Section 4.12 from enrollment through treatment and for 6 months following administration of the last dose of Tebentafusp.

25. Prior radioembolization or other regional, liver-directed therapy, including chemotherapy or embolization to same site in the liver

26. Patients with impaired decision-making capacity.