Adjuvant Therapy with Pembrolizumab versus Placebo in Resected Highrisk Stage II Melanoma: A Randomized, Double-blind Phase 3 Study (KEYNOTE 716)

This 2-part study will evaluate the safety and efficacy of pembrolizumab (MK-3475) compared
to placebo in participants with surgically resected high-risk Stage II melanoma. Participants
in Part 1 will receive either pembrolizumab or placebo in a double-blind design every 3 weeks
(Q3W) for up to 17 cycles/~1 year (each cycle = 21 days). Participants who complete the
initial treatment of 17 cycles of pembrolizumab in Part 1 and experience disease recurrence
may be eligible for re-challenge with pembrolizumab at the same dose and schedule of 200 mg
Q3W (21-day cycles) for up to 35 cycles (up to ~2 years) in Part 2 in an open label design.
Participants who complete the initial treatment of placebo and experience disease recurrence
may be eligible to switch over to pembrolizumab 200 mg Q3W (21-day cycles) for up to 35
cycles (up to ~2 years) in Part 2 in an open label design. The primary hypothesis of this
study is that pembrolizumab increases recurrence-free survival (RFS) compared to placebo.

Per protocol, response/ progression or adverse events (AEs) during re-challenge/switch-over
in Part 2 will not be counted towards the RFS outcome measure or safety outcome measures
respectively.

Inclusion:

- Has surgically resected and histologically/pathologically confirmed new diagnosis of
Stage IIB or IIC cutaneous melanoma per American Joint Committee on Cancer (AJCC) 8th
edition guidelines

- Has not been previously treated for melanoma beyond complete surgical resection

- Has ≤12 weeks between final surgical resection and randomization

- Has no evidence of metastatic disease on imaging as determined by investigator

- Has a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)
Performance Scale or Lansky Play-Performance Scale (LPS) score ≥50 for participants
≤16 years old, or a Karnofsky Performance Scale (KPS) score ≥50 for participants >16
and <18 years old

- Has recovered adequately from toxicity and/or complications from surgery prior to
study start

- Female participants must not be pregnant or breastfeeding, and must agree to use
contraception during the treatment period and for at least 120 days after the last
dose of study treatment if they are women of childbearing potential (WOCBP)

Exclusion:

- Has a known additional malignancy that is progressing or has required active
antineoplastic therapy (including hormonal) within the past 5 years with the exception
of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma
in situ (e.g., breast carcinoma, cervical cancer in situ) that have undergone
potentially curative therapy

- Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
or any other form of immunosuppressive therapy within 7 days prior to the first dose
of study treatment

- WOCBP who has a positive urine pregnancy test within 72 hours prior to randomization.
If the urine test is positive or cannot be confirmed as negative, a serum pregnancy
test will be required

- Has received prior therapy with an anti-Programmed Cell Death Receptor 1 (PD-1),
anti-Programmed Cell Death Receptor Ligand 1 (PD-L1) or anti-Programmed Cell Death
Receptor Ligand 2 (PD-L2) agent or with an agent directed to another stimulatory or
coinhibitory T-cell receptor (e.g., cytotoxic T-lymphocyte-associated protein 4
[CTLA-4], OX-40, CD137)

- Has received prior systemic anti-cancer therapy for melanoma including investigational
agents

- Has received a live vaccine within 30 days prior to the first dose of study treatment

- 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 treatment

- Has severe hypersensitivity (≥Grade 3) to any excipients of pembrolizumab

- Has an active autoimmune disease that has required systemic treatment in the past 2
years

- Has a history of (non-infectious) pneumonitis that required steroids or has current
pneumonitis

- Has an active infection requiring systemic therapy

- Has a known history of human immunodeficiency virus (HIV) infection

- Has a known history of hepatitis B (defined as hepatitis B surface antigen reactive)
or known active hepatitis C virus (defined as hepatitis C virus ribonucleic acid [RNA]
[qualitative] is detected) infection

- Has a history of active tuberculosis (Bacillus tuberculosis)

- Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the study, interfere with the participant's
participation for the full duration of the study, or is not in the best interest of
the participant to participate, in the opinion of the treating investigator

- Has a known psychiatric or substance abuse disorder that would interfere with the
participant's ability to cooperate with the requirements of the study

- Has had an allogeneic tissue/solid organ transplant