Study of Pembrolizumab (MK-3475) Versus Placebo After Complete Resection of High-Risk Stage III Melanoma (MK-3475-054/1325-MG/KEYNOTE-054)

Adjuvant Immunotherapy With Anti-PD-1 Monoclonal Antibody Pembrolizumab (MK-3475) Versus Placebo After Complete Resection of High-risk Stage III Melanoma: A Randomized, Double- Blind Phase 3 Trial of the EORTC Melanoma Group

This study will assess whether post-surgery therapy with pembrolizumab improves recurrence-free survival (RFS) as compared to placebo for high-risk participants with melanoma (Stage IIIA [> 1 mm metastasis], IIIB and IIIC). The study will also assess whether pembrolizumab improves RFS versus placebo in the subgroup of participants with programmed cell death-ligand 1 (PD-L1)-positive tumor expression. Participants will be stratified for stage of disease and region and then will be randomly assigned to receive either pembrolizumab or placebo as post-surgery therapy in Part 1. In Part 2, participants who experience a disease recurrence are eligible for pembrolizumab treatment (if treated with placebo in Part 1) or pembrolizumab rechallenge (if treated with pembrolizumab in Part 1).

As of Amendment 8, enrollment in Part 2 has closed, and an optional pembrolizumab extension study will not be available to participants after study closure.

Inclusion criteria:

• Completely resected Stage III melanoma
• Tumor tissue available for evaluation of PD-L1 expression
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Adequate organ function
• No prior therapy for melanoma except surgery for primary melanoma lesions (or previously treated with interferon for thick primary melanomas without evidence of lymph node involvement are eligible)
• Female participants of childbearing potential should be willing to use adequate methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication
• Male participants should agree to use an adequate method of birth control starting with the first dose of study therapy through 120 days after the last dose of study medication

Exclusion criteria:

• Mucosal or ocular melanoma
• History of (non-infectious) pneumonitis that required steroids or current pneumonitis
• History of or current interstitial lung disease
• History of hematologic or primary solid tumor malignancy, unless no evidence of that disease for 5 years
• Active autoimmune disease that has required systemic treatment in past 2 years
• Active infection requiring therapy
• Unstable hyperthyroidism or hypothyroidism
• Diagnosis of immunodeficiency
• Systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study medication
• Known history of human immunodeficiency virus (HIV), active Hepatitis B or C
• Treatment with live vaccine within 30 days prior to the first dose of study medication are not eligible
• Prior treatment with any anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) monoclonal antibody or 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 prior participation in any Merck pembrolizumab clinical trial
• Currently participating and receiving study therapy, or participated in a study of an investigational agent and received study therapy or used an investigation device within 4 weeks of the first dose of study medication
• Pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of study medication
• Participant is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or child) who is investigational site or Sponsor staff directly involved with this trial without prospective Institutional Review Board approval (by chair or designee) is given