Tebentafusp Regimen Versus Investigator's Choice in Previously Treated Advanced Melanoma (TEBE-AM)

Inclusion Criteria:

1. HLA-A*02:01-positive
2. unresectable Stage III or Stage IV non-ocular melanoma
3. archival tumor tissue sample or a newly obtained biopsy of a tumor lesion not previously irradiated has been provided.
4. measurable or non-measurable disease per RECIST 1.1
5. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1
6. If applicable, must agree to use highly effective contraception
7. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the Informed Consent (ICF) and protocol
8. Must agree to provide protocol specified samples for biomarker analyses.

Exclusion Criteria:

1. Pregnant or lactating women
2. diagnosis of ocular or metastatic uveal melanoma
3. history of a malignant disease other than those being treated in this study
4. ineligible to be retreated with pembrolizumab due to a treatment-related AE
5. known untreated or symptomatic central nervous system (CNS) metastases and/or carcinomatous meningitis
6. previous severe hypersensitivity reaction to treatment with another monoclonal antibody (mAb)
7. active autoimmune disease requiring immunosuppressive treatment with clinically significant cardiac disease or impaired cardiac function
8. known psychiatric or substance abuse disorders
9. received prior treatment with a licensed or investigative Immune-mobilizing monoclonal T-cell receptor Against Cancer (ImmTAC) medication who have not completed adequate washout from prior medications.
10. received chemotherapy or biological cancer therapy (excluding anti-PD(L)1 mAb, ipilimumab, and BRAF TKI regimen) within 14 days of first dose
11. received cellular therapies within 90 days of study intervention
12. ongoing Common Terminology Criteria for Adverse Events(CTCAE) Grade ≥ 2 clinically significant who in the opinion of the investigator could affect the outcome of the study
13. received systemic treatment with steroids or any other immunosuppressive drug within 2 weeks of first dose
14. have not progressed on treatment with an anti-PD(L)1 mAb
15. have not received prior treatment with an approved anti-CTLA-4 mAb
16. a BRAF V600 mutation, who have not received a prior BRAF/MEK TKI regimen
17. currently participating or have participated in a study of an investigational agent or using an investigational device within 30 days of the first dose
18. known history of chronic viral infections such as hepatitis B virus (HBV) or hepatitis C virus (HCV)
19. Out of range Laboratory values
20. history of allogenic tissue/solid organ transplant