Tebentafusp in HLA-A*0201 Positive Previously Untreated Metastatic Uveal Melanoma

This is a phase II open-label, single-arm, multi-center study of tebentafusp in HLA- A\*0201 positive previously untreated (1L) untreated metastatic uveal melanoma (mUM) with an integrated circulating tumor DNA (ctDNA) biomarker.

Inclusion Criteria: Histologically or cytologically confirmed untreated metastatic uveal melanoma (mUM). HLA-A\*0201 genotype positive as assessed using a CLIA-certified blood typing method and confirmed by central review. * If HLA-A status is not known, blood for HLA-A testing must be submitted during Screening, and HLA-A\*0201 positive status confirmed prior to enrollment using a CLIA- certified blood typing method. * If the patient is known to be HLA-A\*0201 positive, this information must be provided in the Screening packet and centrally reviewed by treating PI and Sponsor-Investigator prior to enrollment. * The following HLA testing methodologies are suitable to determine HLA-A\*0201 positivity: * Multiplex real-time PCR based testing performed by entities including but not limited to Labcorp, and American Red Cross. * HLA testing as part of peripheral blood molecular profiling technology including but not limited to Caris Life Sciences Molecular Profiling Technology. * Patients be willing to undergo ctDNA assessment using Signatera assay. * Have provided newly obtained core biopsy of a tumor lesion not previously irradiated. * Adequate organ function on screening labs obtained within 4 weeks of Week 1 day 1 * Must meet the following criteria related to prior treatment: * No prior systemic therapy in the metastatic or advanced setting including chemotherapy, or targeted therapy. * NOTE: Patients must be tebentafusp naïve. * NOTE: Patients must not have received prior PD-1, CTLA-4, LAG-3 directed Immune Checkpoint Inhibitor therapy delivered in the adjuvant, and/or neoadjuvant settings unless such therapy was received \>6 months prior initial diagnosis of mUM. * No prior regional, liver-directed therapy including chemotherapy, radiotherapy, or embolization. * Prior surgical resection of oligometastatic disease is allowed. * Prior neoadjuvant or adjuvant therapy is allowed provided administered in the curative setting in patients with localized disease. * Life expectancy of \>6 months as estimated by the investigator. * Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 at Screening. * Patients have measurable disease according to RECIST v.1.1. * All other relevant medical conditions must be well-managed and stable, in the opinion of the investigator, for at least 28 days prior to first administration of study drug. Exclusion Criteria: * History of severe hypersensitivity reactions (eg, anaphylaxis) to other biologic drugs or monoclonal antibodies. * Clinically significant cardiac disease or impaired cardiac function, including any of the following: * Clinically significant and/or uncontrolled heart disease such as congestive heart failure (New York Heart Association grade ≥ 2), uncontrolled hypertension, or clinically significant arrhythmia currently requiring medical treatment. * QTcF \> 470 msec on screening electrocardiogram (ECG) or congenital long QT syndrome. * NOTE: If the initial automated QTcF interval is \> 470 msec at screening, for the purpose of determining eligibility, the mean QTcF, based on at least 3 ECGs obtained over a brief time interval (ie, within 30 minutes), should be manually determined by a medically qualified person. * NOTE: Acute myocardial infarction or unstable angina pectoris \< 6 months prior to Screening. * Presence of symptomatic or untreated central nervous system (CNS) metastases, or CNS metastases that require doses of corticosteroids within the prior 3 weeks to study Day 1. * Presence of active brain metastases. * NOTE: Patients with brain metastases are eligible if all lesions have been treated surgically and/or radiosurgically and there is no evidence of progression for at least 2 weeks by MRI prior to the first dose of study drug. * NOTE: Patients with any evidence of leptomeningeal disease are excluded. * Active infection requiring systemic antibiotic therapy. • NOTE: Patients requiring systemic antibiotics for infection must have completed therapy at least 1 week prior to the first dose of study drug. * Known history of uncontrolled active human immunodeficiency virus (HIV), hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infection. * NOTE: Testing for HIV, HBV and/or HCV is not necessary unless clinically indicated or the patient has a history of HBV/HCV and/or HIV infection. * NOTE: Patients with curatively treated HBV and/or HCV infection may be enrolled. In these instances, HBV (quantitative HBV DNA) and/or HCV (quantitative HCV RNA) resolution must be documented using a quantitative viral load assay. * NOTE: Patients with HIV who are stably controlled on highly active antiretroviral therapy (HAART) therapy with a low HIV viral load may be enrolled. In these instances, stable control is defined as HAART compliant with a CD4 count of ≥200 cells/μL, and low viral load is defined as \