Background: The PD-1 ligands, PD-L1 and PD-L2, are frequently overexpressed in relapsed or refractory classical Hodgkin lymphoma (R/R cHL), and this is typically associated with chromosome 9p24.1 amplification. In the phase 1b KEYNOTE-013 study, PD-1 blockade with pembrolizumab demonstrated high antitumor activity (65% ORR) in heavily pretreated patients with cHL. KEYNOTE-204 (NCT02684292) is a randomized, international, open-label phase 3 study designed to compare the efficacy and safety of pembrolizumab versus brentuximab vedotin (BV) in patients with R/R cHL. Methods: This study will enroll patients aged ≥18 years with R/R cHL who (1) have failed to achieve a response or progressed after autologous stem-cell transplantation (auto-SCT) and have not had previous treatment with BV; or (2) are not auto-SCT candidates because of chemotherapy-resistant disease (unable to achieve complete remission or partial remission to salvage chemotherapy), advanced age, or comorbidities, and have received at least 2 prior multi-agent chemotherapy regimens that did not include BV. ~300 patients will be randomized 1:1 to receive either pembrolizumab 200 mg Q3W or BV 1.8 mg/kg Q3W. Treatments will continue for up to 35 cycles or until documented disease progression, unacceptable adverse events (AEs), or investigator decision. Response will be assessed Q12W by PET/CT scans per International Working Group (IWG) Revised Response Criteria for Malignant Lymphoma by central imaging vendor review. After the end of treatment, patients will be followed for 30 days for AE monitoring (90 days for serious AEs and events of clinical interest). All patients will be followed for overall survival until death, withdrawal of consent, or the end of the study, whichever comes first. Primary end points are PFS and OS; secondary end points are ORR and complete remission rate (CRR). Exploratory end points include PK profile, duration of response, and comparison of ORR in patients with PD-L1–positive versus PD-L1–negative lymphoid tumors. Assessment of primary efficacy end points are based on blinded independent central review according to IWG criteria; secondary/exploratory efficacy analyses are based on investigator assessment. Enrollment to KEYNOTE-204 is ongoing.