PLUG-IN: Pembrolizumab Combined With Enfortumab Vedotin for Advanced Melanoma Patients

Inclusion Criteria: Participants are eligible to be included in the study only if all of the following criteria apply: 1. Male/female participants who are at least 18 years of age on the day of signing informed consent with histologically confirmed diagnosis of unresectable or metastatic melanoma will be enrolled in this study. 2. Participants must have measurable disease by investigator assessment according to RECIST v1.1 Participants with prior definitive radiation therapy must have measurable disease per RECIST v1.1 that is outside the radiation field or has demonstrated unequivocal progression since completion of radiation therapy. 3. Male participants: a. A male participant must agree to use a contraception as detailed in Appendix 3 of this protocol during the treatment period and for 9 months after last dose of EV or 4 months after pembrolizumab, whichever occurs last; and refrain from donating sperm during this period. 4. Female participants: A female participant is eligible to participate if she is not pregnant (see Appendix 3), not breastfeeding, and at least one of the following conditions applies: 1. Not a woman of childbearing potential (WOCBP) as defined in Appendix 3. OR 2. WOCBP should remain on contraception for 12 months after the last dose of EV or 4 months after pembrolizumab, whichever occurs last. 5. Participants must have received prior systemic therapy for locally advanced or metastatic melanoma: a. Participants must have progressed on treatment with an anti-PD-1/L1 mAb administered either as monotherapy or in combination with other checkpoint inhibitors or other therapies. PD-1 treatment progression is defined by meeting all of the following criteria: i. Has received at least 2 doses of an approved anti-PD-1/L1 mAb. * Has demonstrated disease progression after anti-PD-1/L1 as defined by RECIST v1.1. * The initial evidence of PD is to be confirmed by a second assessment no less than 4 weeks from the date of the first documented disease progression, in the absence of rapid clinical progression. ii. Progressive disease / recurrence has been documented within 12 weeks from the last dose of anti-PD-1/L1 mAb. Progressive disease is determined according to iRECIST. This determination is made by the investigator. Once disease progression is confirmed, the initial date of disease progression documentation will be considered the date of disease progression. b. BRAF mutated patients should have received BRAF/MEK inhibitors and PD1/PDL1 therapy c. Prior CTLA4 therapy is allowed. 6. Participants who have AEs due to previous anticancer therapies must have recovered to ≤Grade 1 or baseline. Participants with endocrine-related AEs who are adequately treated with hormone replacement or participants who have ≤Grade 2 neuropathy are eligible. Note: Patients who had cutaneous adverse events grade 3 or superior are not eligible for the study. 7. Provide representative formalin-fixed paraffin-embedded/FFPE paraffin block obtained after last treatment progression. Patients who have no archival tumor tissue after the last treatment progression will be required to provide a fresh biopsy, if the procedure is feasible and safe for the patient. Older archival tumor samples are allowed for patients with no recent archival tissue (after last treatment progression) and not capable of undergoing a new tumor biopsy before the first dose of study treatment.. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. 8. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Evaluation of ECOG is to be performed within 7 days prior to the first dose of study intervention. 9. Have adequate organ function as defined in the following table (see Table 3 in protocol). Specimens must be collected within 10 days prior to the start of study intervention. Exclusion Criteria: 1. Participants are excluded from the study if any of the following criteria apply: A WOCBP who has a positive urine pregnancy test within 72 hours prior to allocation (see Appendix 3). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. 2. Participants who have previously received enfortumab vedotin or other MMAE-based ADCs. 3. Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to the scheduled date of starting the study treatment. 4. Has received prior radiotherapy within 2 weeks of start of study intervention or radiation-related toxicities requiring corticosteroids. Note: Two weeks or fewer of palliative radiotherapy for non-CNS disease, with a 1-week washout, is permitted. 5. Has received a live vaccine or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines is allowed. 6. Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration. 7. Participants with uncontrolled diabetes. Uncontrolled diabetes is defined as hemoglobin A1c (HbA1c) ≥8% or HbA1c 7% to \<8% with associated diabetes symptoms that are not otherwise explained. 8. 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. 9. Known additional malignancy that is progressing or has required active treatment within the past 2 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ, excluding carcinoma in situ of the bladder, that have undergone potentially curative therapy are not excluded. 10. Has known active CNS metastases and/or carcinomatous meningitis. Note: 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. 11. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients. Participants with known severe (≥ Grade 3) hypersensitivity to any enfortumab vedotin excipient contained in the drug formulation of enfortumab vedotin (including histidine, trehalose dihydrate, and polysorbate 20). 12. Participants with active keratitis or corneal ulcerations. Participants with superficial punctate keratitis are allowed if the disorder is being adequately treated in the opinion of the investigator. 13. Has active autoimmune disease that has required systemic treatment in the past 2 years except replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid) 14. Participants with conditions requiring systemic doses of corticosteroids (\>10 mg/day of prednisone or equivalent) or other immunosuppressive medications are excluded. 15. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required corticosteroids or has current pneumonitis/interstitial lung disease. 16. Has an active infection requiring systemic therapy. 17. Has a known history of Human Immunodeficiency Virus (HIV) infection. 18. Concurrent active Hepatitis B (defined as HBsAg positive and/or detectable HBV DNA) and Hepatitis C virus (defined as anti-HCV Ab positive and detectable HCV RNA) infection. Note: Hepatitis B and C screening tests are not required unless: Known history of HBV and HCV infection As mandated by local health authority 19. Has not adequately recovered from major surgery or has ongoing surgical complications. 20. Has a history or current evidence of any condition, therapy, or laboratory abnormality or other circumstance that might confound the results of the study, interfere with the participant's participation for the full duration of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator. 21. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. 22. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of contraception period. 23. Has had an allogenic tissue/solid organ transplant. 24. History of Clinical Tuberculosis