Brentuximab Vedotin, Nivolumab, Doxorubicin, and Dacarbazine (AN+AD) for Advanced Stage Classic Hodgkin Lymphoma: Updated Efficacy and Safety Results from the Single-Arm Phase 2 Study (SGN35-027 Part B)

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.

Lee:Pharmacyclics: Research Funding; Takeda: Research Funding; Century Therapeutics: Membership on an entity's Board of Directors or advisory committees; Seagen: Research Funding; Aptitude Health: Honoraria; Cancer Experts: Honoraria; Korean Society of Cardiology: Honoraria; Olson Research: Honoraria; Deloitte: Honoraria; Guidepoint Global: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Octernal Therapeutics: Research Funding. Flinn:Secura Bio: Consultancy; Abbvie: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; InnoCare Pharma: Consultancy, Research Funding; Nurix Therapeutics: Consultancy, Research Funding; Agios: Research Funding; ArQule: Research Funding; Celgene: Research Funding; Constellation Pharmaceuticals: Research Funding; Curis: Research Funding; Forma Therapeutics: Research Funding; Forty Seven: Research Funding; Incyte: Research Funding; Infinity Pharmaceuticals: Research Funding; Loxo@Lilly: Research Funding; Merck: Research Funding; CALIBR: Research Funding; Iksuda Therapeutics: Consultancy; Gilead Sciences: Research Funding; Hutchison MediPharma: Consultancy; Genmab: Consultancy; Bristol Myers Squibb: Research Funding; Pfizer: Research Funding; Portola Pharmaceuticals: Research Funding; CALGB: Research Funding; Vincerx Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta Pharma: Research Funding; Xencor: Consultancy; AstraZeneca: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Century Therapeutics: Consultancy; Genentech: Consultancy, Research Funding; Kite Pharma: Consultancy, Research Funding; MorphoSys: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; IGM Biosciences: Research Funding; Verastem: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Unum Therapeutics: Research Funding; Roche: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Servier Pharmaceuticals: Consultancy; Takeda: Consultancy; Seattle Genetics: Research Funding; Epizyme: Research Funding; Rhizen Pharmaceuticals: Research Funding; Trillium Therapeutics: Research Funding; Myeloid Therapeutics: Research Funding; Biopath: Research Funding; CTI Biopharma: Research Funding; City of Hope National Medical Center: Research Funding; Fate Therapeutics: Research Funding; Millenium Pharmaceuticals: Research Funding; Tessa Therapeutics: Research Funding; TCR2 Therapeutics: Research Funding; Triphase Research & Development Corp: Research Funding; 2seventy bio: Research Funding. Melear:AstraZeneca: Speakers Bureau; Janssen: Speakers Bureau; TG Therapeutics: Speakers Bureau. Ramchandren:Curis: Research Funding; Seagen: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Merck: Consultancy; Bristol-Myers Squibb: Consultancy; Trillium: Research Funding. Friedman:GSK: Speakers Bureau; Astellas: Research Funding; Abbott: Current equity holder in publicly-traded company; Amgen: Honoraria, Speakers Bureau; Seagen: Research Funding; Celgene: Consultancy, Honoraria, Speakers Bureau; Incyte: Speakers Bureau; Jazz: Speakers Bureau. Burke:TG Therapeutics: Consultancy; SeaGen: Consultancy, Speakers Bureau; Roche/Genentech: Consultancy; Nurix: Consultancy; Morphosys: Consultancy, Research Funding; Kymera: Consultancy; Kura: Consultancy; Epizyme: Consultancy; BMS: Consultancy; BeiGene: Consultancy, Speakers Bureau; AstraZeneca: Consultancy; Adaptive Biotechnologies: Consultancy; Abbvie: Consultancy; Verastem: Consultancy; X4 Pharmaceuticals: Consultancy. Linhares:TG therapeutics: Other: advisory board; glaxosmithkline: Other: advisory board; ADC therapeutics: Other: advisory board, Research Funding; Gilead Sciences, Inc.: Other: advisory board; BeiGene USA, Inc.: Other: advisory board, Research Funding; Seagen Inc: Other: advisory board, Research Funding; Bristol Myers Squibb: Other: advisory board, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Other: advisory board; Kyowa Kirin: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Curio Science: Other: Workshop Participation and Moderation. Raval:Adaptive: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADCT Therapeutics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astrazeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Research Funding; Genentech: Research Funding; Seagen: Research Funding; Abbvie: Speakers Bureau; Alexion: Speakers Bureau; Astellas: Speakers Bureau; Beigene: Speakers Bureau; Incyte/Morphosys: Speakers Bureau; Merck Sharp and Dohme: Research Funding; Janssen: Research Funding; CTI biopharma: Speakers Bureau. Chintapatla:Seagen: Research Funding. Feldman:Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC: Speakers Bureau; Genomic Testing Cooperative: Other: Equity holder in privately-traded company; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astrazeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Speakers Bureau; SecuraBIO: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seagen: Speakers Bureau; BMS: Speakers Bureau; Daiichi Sakyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen Biotech, Inc.: Speakers Bureau; Genmab: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Speakers Bureau; MorphoSys: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees. Yimer:Sanofi: Speakers Bureau; Pharmacyclics: Speakers Bureau; GlaxoSmithKline: Speakers Bureau; Beigene: Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; epizyme: Divested equity in a private or publicly-traded company in the past 24 months; Karyopharm: Consultancy, Divested equity in a private or publicly-traded company in the past 24 months, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Amgen: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; AstraZeneca: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Texas Oncology: Current Employment; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau. Dean:Seagen: Speakers Bureau. Rana:Seagen: Speakers Bureau. Gandhi:TG Therapeutics: Honoraria; Janssen: Honoraria; Karyopharm: Honoraria; GlaxoSmithKline: Honoraria. Renshaw:Genetec: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Speakers Bureau; Jazz Pharma: Consultancy, Speakers Bureau; Seagen: Consultancy; Texas Oncology: Current Employment; Amgen: Speakers Bureau; Novocure: Consultancy; AADI: Consultancy. Ho:Seagen Inc.: Current Employment. Fanale:Seagen, Inc: Current Employment, Current equity holder in publicly-traded company. Guo:Seagen: Current Employment. Yasenchak:Beigene: Speakers Bureau; Takeda: Research Funding; Seagen Inc.: Consultancy, Research Funding.

Brentuximab vedotin (1.2 mg/kg), nivolumab (240 mg), doxorubicin (25 mg/m2), and dacarbazine (375 mg/m2) were administered, for up to 6 cycles on Days 1 and 15 of each 28-day cycle, to subjects with Ann Arbor stage I or II cHL with bulky mediastinal disease (defined as greater than or equal to 10 cm) or stage III or IV cHL.