Inclusion Criteria:
1. Male/female participants who are at least 18 years of age on the day of signing informed consent with histologically confirmed diagnosis of metastatic uveal melanoma (UM).
2. (i) Not having been treated with Tebentafusp for cohort 1 (Tebentafusp-naive patients) OR (ii) Having been previously treated with Tebentafusp for cohort 2.
3. Life expectancy \> 3 months.
4. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Evaluation of ECOG has to be performed at inclusion.
5. Male participants must agree to use contraception
6. A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
1. Not a woman of childbearing potential (WOCBP) OR
2. A WOCBP who agrees to follow the contraceptive guidance
7. Measurable disease based on RECIST 1.1. lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
8. The participant (or legally acceptable representative if applicable) provides written informed consent for the trial.
9. Have provided a newly obtained (or archival if no systemic treatment since the sampling) core or excisional biopsy of a tumor lesion not previously irradiated.
10. Patients with French Social Security in compliance with the French law relating to biomedical research
11. 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.
12. Have adequate organ function as defined in the protocol.
Exclusion Criteria:
1. A WOCBP who has a positive urine pregnancy test within 72 hours prior to allocation.
2. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX 40, and CD137) for metastatic UM.
In contrast, prior therapy with Tebentafusp is permitted.
3. Has recently received prior systemic anti-cancer therapy including investigational agents or biological agents \[eg cytokines, antibodies or small molecules kinase inhibitors within 3 weeks or nitrosoureas/mitomycin C within 6 weeks\] prior to allocation. Prior liver surgery or local treatment of metastases is allowed if there is an unequivocal progression.
Note: Participants must have recovered from all AEs due to previous therapies to ≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy may be eligible.
Note: Do not administer for at least 2 weeks following major surgery and until adequate wound healing.
4. Has received prior radiotherapy within 2 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
5. Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed. Only mRNA vaccines are authorized to prevent SARS-CoV-2 infection (COVID-19) during the trial.
6. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention.
7. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
8. Has a history of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years.
Note: The time requirement does not apply to participants who underwent successful definitive resection of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, in situ cervical cancer, or other in-situ cancers
9. Has known active CNS metastases and/or carcinomatous meningitis. Brain imaging is not required at inclusion if asymptomatic. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study intervention.
10. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or lenvatinib and/or any of their excipients.
11. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed.
12. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
13. Has an active infection requiring systemic therapy. Patients requiring systemic antibiotics for infection must have completed therapy at least 1 week prior to the first dose of study drug.
14. Has a known history of Human Immunodeficiency Virus (HIV) infection. HIV testing is not required at allocation.
15. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen \[HBsAg\] reactive) or known active Hepatitis C virus (defined as HCV RNA \[qualitative\] is detected) infection. Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.
16. Has a known history of active TB (Bacillus Tuberculosis).
17. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
18. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
19. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment.
20. Has had an allogenic tissue/solid organ transplant.
21. Concurrent or recent (less than 1 week prior inclusion) immunosuppressive medications (including corticosteroids exceeding 10 mg daily of prednisone equivalent, azathioprin); hydrocortisone at physiological doses is allowed;
22. Uncontrolled blood pressure (Systolic BP\>150 mmHg and/or diastolic BP \>90 mmHg) in spite of an optimized regimen of antihypertensive medication.
23. Electrolyte abnormalities that have not been corrected as assessed by the investigator.
24. Significant cardiovascular impairment: history of congestive heart failure from New York Heart Association (NYHA) Class III or IV, unstable angina, myocardial infarction or stroke within 12 months of the first dose of study drug, or cardiac arrhythmia with hemodynamic instability. Note : medically controlled arrhythmia would be permitted.
25. Bleeding or thrombotic disorders or subjects at risk for severe hemorrhage. The degree of tumor invasion/infiltration of major blood vessels (e.g. carotid artery) should be considered because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis following lenvatinib therapy.
26. Subjects having \> 1+ proteinuria on urine dipstick testing unless a 24-hour urine collection for quantitative assessment indicates that the urine protein is \<1 g/24 hours.
27. Subjects who have not recovered adequately from any toxicity from other anti-cancer treatment regimens and/or complications from major surgery prior to starting therapy.
28. Has had major surgery within 3 weeks prior to first dose of study interventions. Note: Adequate wound healing after major surgery must be assessed clinically, independent of time elapsed for eligibility.
29. Has preexisting ≥Grade 3 gastrointestinal or non-gastrointestinal fistula
30. Has a LVEF below the institutional (or local laboratory) normal range, as determined by multigated acquisition (MUGA) or echocardiogram (ECHO).
31. Prolongation of QTcF interval to \>480 ms.
32. Gastrointestinal malabsorption or any other condition that might affect the absorption of lenvatinib
33. Active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks prior to the first dose of study drug.
