Pembrolizumab, a humanized IgG4 monoclonal antibody targeting programmed death-1 protein, has demonstrated efficacy in relapsed/refractory classical Hodgkin lymphoma (cHL). To assess the complete metabolic response (CMR) rate and safety of pembrolizumab monotherapy in newly diagnosed cHL, we conducted a multicenter, single-arm, phase II investigator-initiated trial of sequential pembrolizumab and doxorubicin, vinblastine, and dacarbazine (AVD) chemotherapy. Patients > 18 years of age with untreated early unfavorable or advanced stage disease were eligible for treatment. Thirty patients with either early unfavorable (n=12) or advanced (n=18) stage cHL were treated with 3 cycles of pembrolizumab monotherapy followed by AVD for 4-6 cycles depending on stage and bulk. Twelve had either large mediastinal masses and/or bulky disease (>10 cm). Following pembrolizumab monotherapy, 11 patients (37%) demonstrated CMR’s, and an additional 7 of 28 (25%) patients with quantifiable positron emission tomography/computed tomography scanning (PET-CT) had >90% reductions in metabolic tumor volume. All patients achieved CMR following 2 cycles of AVD and maintained their responses at end of treatment. With a median follow-up of 22.5 months (range: 14.2-30.6) there have been no changes in therapy, progressions, or deaths. No patients received consolidation radiotherapy, including those with bulky disease. Therapy was well-tolerated. The most common immune-related adverse events were grade 1 rash (n=6), and grade 2 infusion reactions (n=4). One patient had a reversible grade 4 transaminitis and a second had a reversible Bell’s palsy. Brief pembrolizumab monotherapy followed by AVD proved both highly effective and safe in newly diagnosed cHL patients including those with bulky disease. This trial was registered at www.clinicaltrials.gov as #NCT03226249.Copyright © 2020 American Society of Hematology.