Background: Classical Hodgkin lymphoma (cHL) and primary mediastinal B-cell lymphoma (PMBCL) frequently harbor amplifications at 9p24.1, leading to overexpression of PD-L1 and PD-L2, suggesting a genetically driven vulnerability to programmed death 1 (PD-1) blockade. The PD-1 inhibitor pembrolizumab, dosed at 200 mg every 3 weeks (Q3W), demonstrated strong antitumor activity and acceptable safety that led to approvals for adult and pediatric patients with relapsed or refractory (R/R) cHL and R/R PMBCL. Efficacy, safety, and pharmacokinetic (PK) results from studies in solid tumors have since led to accelerated approval for the pembrolizumab 400 mg Q6W regimen for all indications in adults; however, further efficacy and safety data are needed for hematologic indications. The open-label, single-arm, multisite, global, phase 2 KEYNOTE-B68 study (NCT04875195) evaluates the safety, efficacy, and PK profile of pembrolizumab 400 mg Q6W in patients with R/R cHL or PMBCL. Methods: Patients must have histologically confirmed R/R cHL (cohort 1) or R/R PMBCL (cohort 2) per WHO classification and radiographically measurable disease per the Lugano 2014 classification criteria and must not have previously received treatment with anti–PD-1 therapy. Eligible patients must have failed to respond to or relapsed after receiving an autologous stem cell transplant (ASCT) or must be ineligible for ASCT and must have failed to respond or relapsed after ≥1 (cHL) or ≥2 (PMBCL) prior lines of therapy; patients with PMBCL must have received ≥1 line of therapy containing rituximab. Approximately 60 patients will be enrolled. They will receive pembrolizumab 400 mg IV Q6W for up to 18 cycles. Disease assessments will occur Q12W by investigator per the Lugano 2014 response criteria. Local radiographic assessments will be collected by computed tomography Q12W and by positron emission tomography at weeks 12 and 24 and to confirm complete response. Adverse events will be monitored and assessed by investigators throughout the study, and their severity will be graded per NCI Common Terminology Criteria for Adverse Events, version 5.0 guidelines. Patients who receive an allogeneic SCT within 2 years of the last dose of study treatment will be monitored for 18 months after SCT for events of clinical interest. The primary end point (assessed per cohort) is objective response rate by investigator per the Lugano 2014 classification criteria. Secondary end points (assessed per cohort) include duration of response by investigator assessment, characterization of the PK profile and immunogenicity for pembrolizumab 400 mg Q6W, and safety. Exploratory end points assessed per cohort include overall survival, progression-free survival per the Lugano 2014 criteria, and molecular biomarker analyses. Clinical trial information: NCT04875195.