Background: Pembro, a highly selective humanized monoclonal antibody that directly blocks the interaction between programmed death 1 (PD-1) and its ligands PD-L1 and PD-L2, is indicated for the treatment of adults with advanced melanoma. PD-L1 is expressed on the surface of several tumor types, including melanoma and lymphomas, and may enable some tumors to evade a normal immune response. Pembro has shown promising antitumor activity in patients (pts) with melanoma and is generally well tolerated. KEYNOTE-051 (NCT02332668) is a 2-part study to determine the recommended phase 2 dose (RP2D) and activity of pembro in pediatric tumors, especially those refractory to available treatments. Methods: Pts aged 6 months to < 18 years, with advanced melanoma or a PD-L1⁺ advanced, relapsed, or refractory solid tumor or lymphoma that is incurable and has failed prior therapy or for which standard therapy is either unavailable or inappropriate, measurable disease per RECIST v1.1, known tumor PD-L1 status using immunohistochemical staining (prescreening), and performance score ≥ 50 using Lansky Play Scale (aged ≤ 16 years old) or Karnofsky Scale (aged > 16 years) are eligible. Following a 3 + 3 design in part 1, initial cohorts of 3-6 pts are to be enrolled to determine a maximum tolerated dose (MTD), or in the absence of dose-limiting toxicity, a maximum administered dose (MAD). The starting dose is 2 mg/kg Q3W (the equivalent of the clinical adult dose), with dose escalation to ≤ 10 mg/kg Q2W if exposure at the starting dose is < 50% of the adult value. In part 2, pediatric pts are to receive pembro at the RP2D until documented disease progression or ≥ 2 years. The primary objectives of part 2 are to further evaluate the safety and efficacy of pembro at the pediatric RP2D in children with advanced melanoma or PD-L1⁺ advanced relapsed/refractory solid tumors and lymphoma. Enrollment of PD-L1^- pts may be initiated if an efficacy bound is passed during subsequent sequential monitoring for response in PD-L1⁺ pts. Enrollment in KEYNOTE-051 is underway; it is expected that 60 to ≤ 310 pts will be enrolled based on efficacy boundaries. Clinical trial information: NCT02332668