Neoadjuvant Pembrolizumab for Unresectable Stage III and Unresectable Stage IV Melanoma

Inclusion Criteria:

1. Be able to provide written informed consent.
2. Be 18 years old at time of consent.
3. Have measurable disease by RECIST 1.1.
4. Has a diagnosis of unresectable Stage III or Stage IV melanoma with anatomic site(s) of metastasis that could be amenable to curative resection if the site(s) decreased in size by up to 50% (at the investigators' discretion).
5. Have provided tissue sample of a tumor lesion.
6. Have an ECOG Performance status 0 or 1.
7. Demonstrate adequate organ function according to pre-defined criteria
8. Females of childbearing potential should have a negative pregnancy test within 72 hours prior to receiving the first dose.
9. Females of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity during the study through 120 days after last dose. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for \> 1 year.

10 . Males should agree to use an adequate method of contraception starting with the first dose of therapy through 120 days after last dose.

Exclusion Criteria:

1. Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment.
2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of treatment.
3. Has had a prior monoclonal antibody within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered \> 4 weeks earlier.
4. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.
5. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell and squamous cell skin cancers, or in situ cervical cancer.
6. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging 4 weeks prior to the first dose and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for 7 days prior to trial treatment.
7. Has an active autoimmune disease requiring systemic treatment within the past 3 months or a history of severe autoimmune disease or syndrome that requires steroids or immunosuppressive agents.
8. Has interstitial lung disease or active, non-infectious pneumonitis.
9. Has an active infection requiring systemic therapy.
10. Has a history or current evidence of any condition, therapy, or lab abnormality that might confound the results, interfere with the subject's participation, or is not in the best interest of the subject to participate, in the opinion of the investigator.
11. Has known psychiatric or substance abuse disorders that would interfere with the requirements of the trial.
12. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial.
13. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2 treatment.
14. Has a history of HIV.
15. Has active Hepatitis B or Hepatitis C
16. Has received a live vaccine within 30 days prior to first dose.
17. Is currently being treated with ipilimumab (defined as ipilimumab \< 6 weeks before first dose of treatment).