This study is being done to see if using the study drug, pembrolizumab, can shrink down melanoma tumors enough so that they will be small enough to cut out, so that there will be no cancer left in the body.

Eligible participants include those who have not received any systemic melanoma therapies (i.e. participants do not have to fail ipilimumab or BRAF inhibitor) and those who have failed all available systemic options (if the participant meets other inclusion / exclusion criteria).

This study is being done to see if using the study drug, pembrolizumab, can shrink down melanoma tumors enough so that they will be small enough to cut out, so that there will be no cancer left in the body.

Eligible participants include those who have not received any systemic melanoma therapies (i.e. participants do not have to fail ipilimumab or BRAF inhibitor) and those who have failed all available systemic options (if the participant meets other inclusion / exclusion criteria).

For most melanoma cases, surgery is the recommended treatment. Until recently surgery was not used for patients with advanced melanoma (melanoma that has spread to lymph nodes or melanoma that has spread to other organs like the lung, liver, brain) because it was thought that surgery wouldn't help patients live longer when the melanoma tumors had spread beyond the skin. Recent studies have shown that patients with advanced melanoma who have surgery as one of their treatments may live longer than patients who only have systemic therapy (IV drugs or pills) and do not have surgery at all.

Unfortunately, when patients with advanced melanoma come to the doctor, surgery is not a good choice for most patients because they have 'unresectable' melanoma. 'Unresectable' melanoma means they have melanoma tumors in the body that are too big or too close to important parts in the body (like big blood vessels) to be cut out safely. We are studying if we can use a drug to shrink tumors down to make them small enough to cut out; this is called a "neoadjuvant" approach to treating melanoma. By removing all of the cancer from body by using the combination of drug and surgery, we think this could help people live longer.

Pembrolizumab is a drug that is given in the veins and can make the immune system stronger so that it can fight cancer cells. Pembrolizumab is in the class of drugs called immunotherapy.

Immunotherapy uses parts of a person's immune system to fight the disease. Pembrolizumab is designed to restore the natural ability of the immune system to recognize and target melanoma cells to be attacked. In addition to possibly shrinking tumors, it may change your immune system so that it can fight melanoma in the future.

We are also trying to learn more about how pembrolizumab works in the body. In this study, we will look at the skin, blood, and bone marrow to see if we can see any signs to tell doctors whether pembrolizumab is working or tell us which patients it may work on.

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).

24 months or: Subjects who meet all of the following criteria may discontinue follow up prior to 24 months: 1. CR or rPR with complete metastectomy has been confirmed. 2. Patient has received at least 24 weeks (8 cycles) of pembrolizumab therapy. 3. Patient has received at least 2 cycles of pembrolizumab after CR or rPR with complete metastectomy is documented.

Limitations: a small number, 10 subjects, 9 of whom were male, participating in a study performed at a single institution.

Caveat: there was a disproportionate number of subjects with cutaneous disease only, i. e. no visceral metastases.