Introduction Brentuximab vedotin (BV) and nivolumab are well tolerated and active treatments for patients (pts) with classical Hodgkin lymphoma (cHL). These agents were previously studied in first salvage therapy (overall response rate [ORR] 85%; complete response [CR] 67%) (Advani 2021) and as first-line therapy in older adults (ORR 95%) (Yasenchak 2020). In ECHELON-1 study, BV plus doxorubicin, vinblastine, and dacarbazine (A+AVD) improved overall survival (OS) by 4.5 percentage points over doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) (6-year OS estimate of 93.9% vs 89.4%) in pts with previously untreated stage III or IV cHL (Ansell 2022). In pts with limited stage I or II cHL, BV plus doxorubicin and dacarbazine (AD) treatment resulted in a CR rate of 97% at end of treatment (EOT), promising 4-year progression-free survival (PFS) estimate of 88%, and no cases of ≥ Grade 3 peripheral neuropathy (Abramson 2021). In Part B of SGN35-027, treatment with BV, nivolumab, doxorubicin, and dacarbazine (AN+AD) showed promising preliminary activity in pts with bulky stage II or stage III/IV cHL (at EOT: ORR 93%; CR 88%) with no cases of febrile neutropenia or Grade 5 adverse events (AEs) (Lee 2021). Herein, we present updated efficacy and safety results from Part B of this study. Methods SGN35-027 (NCT03646123) is an open-label, multiple part, multicenter, phase 2 clinical trial. In Part B, enrolled pts had Ann Arbor stage I or II cHL with bulky mediastinal disease (defined as ≥10 cm) or stage III or IV cHL. Pts were treated with up to 6 cycles of AN+AD (BV 1.2 mg/kg [A], nivolumab 240 mg [N], doxorubicin 25 mg/m2 [A], and dacarbazine 375 mg/m2 [D]). All study drugs were administered intravenously on Days 1 and 15 of each 28-day cycle. The primary endpoint was CR rate at EOT. Key secondary endpoints included safety, tolerability, ORR, duration of objective response (DOR), duration of complete response (DOCR), and PFS. Disease response and progression were assessed by investigator using Lugano Classification Revised Staging System for malignant lymphoma (Cheson 2014) incorporating Lymphoma Response to Immunomodulatory Therapy Criteria (LYRIC) for nodal non-Hodgkin and Hodgkin Lymphomas (Cheson 2016). Results In Part B, 58 pts were enrolled of which, 57 received at least 1 dose of study treatment. Most treated pts were White (88%) and <65 years old (95%), and approximately half were male (53%). The median age was 35.0 years (range: 19, 78 years). Thirty percent of treated pts had stage II cHL with bulky mediastinal disease, while the remainder had stage III (18%) or IV (51%) cHL. Of the 57 pts treated, the overall CR rate was 88% (95% CI: 76.3, 94.9) at EOT. ORR (CR or partial response [PR]) was 93% (95% CI: 83.0, 98.1) at EOT. With a median follow-up of 15.1 months, 4 pts (7%) had progressive disease and 1 pt (2%) died. The estimated PFS rate was 93% (95% CI: 81.6, 97.2) at 12 months. As of the data cutoff date (02-May-2022), 93% of pts (95% CI: 81.7, 97.2) had a DOR of least 12 months and 92% of pts (95% CI: 80.0, 96.9) had a DOCR of at least 12 months. Of the 58 pts enrolled, 4 pts had discontinued treatment (study treatment) early due to treatment-emergent adverse events (TEAEs) and 74% of pts had any dose modifications including any dose delay (28%), reduction (25%), and elimination (39%) due to AEs. Within 30 days of last dose of BV or 100 days of last dose of nivolumab, 51% of pts experienced ≥ Grade 3 TEAEs. Nausea, fatigue, and peripheral sensory neuropathy were the most frequently reported treatment-related TEAEs (65%, 47%, and 42% of pts, respectively). Notably, only 2 pts (4%) experienced ≥ Grade 3 peripheral sensory neuropathy, of which were considered treatment-related. No TEAEs led to death, and no cases of febrile neutropenia were reported. Eight pts (14%) experienced treatment-related serious TEAEs; most commonly pneumonitis (5%) and pyrexia (5%). Twenty pts (35%) experienced treatment-emergent immune-mediated AEs; most commonly hypothyroidism (9%), pneumonitis (5%), and maculo-papular rash (5%). Conclusions Efficacy results continue to show that AN+AD is a promising treatment for adult pts with bulky stage II or stage III/IV cHL. Updated safety results demonstrate continued tolerability with AN+AD and no new safety signals observed. Omitting bleomycin and vinblastine may have contributed to the absence of certain AEs, such as febrile neutropenia. This study is ongoing and updated results will be presented.