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

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), a 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 interim efficacy and safety results from pts with non-bulky stage I and II cHL treated in Part C of SGN35-027.

Methods SGN35-027 (NCT03646123) is an open-label, multiple part, multicenter, phase 2 clinical trial. In Part C, enrolled pts had Ann Arbor stage I or II cHL without bulky disease. Pts were treated with 4 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 each administered intravenously on Days 1 and 15 of each 28-day cycle. The primary efficacy endpoint was CR rate at EOT. Key secondary endpoints included safety and 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 C, 129 pts were enrolled, of which 125 received at least 1 dose of study treatment. Most of the 125 pts treated were White (85%) and <65 years old (91%), while approximately half were female (55%). The median age was 33.0 years (range: 18, 77 years). Pts had stage I (11%) or II (89%) cHL, without bulky disease. Of the 125 pts treated, 76 had completed EOT response assessment or discontinued treatment/study without EOT assessment (Efficacy Evaluable [EE] population) as of the data cutoff date (16-Mar-2022).

Of the 76 pts in the EE population, the overall CR rate was 91% (95% CI: 81.9, 96.2) at EOT. The ORR was 93% (95% CI: 85.3, 97.8), with 69 pts achieving CR and 2 pts achieving partial response (PR) at EOT.

Of the 125 pts treated, no pts discontinued treatment (all study drugs) early due to treatment-emergent AEs (TEAEs) and 53% of pts had any dose modifications including any dose delay (25%), reduction (8%), and elimination (29%) due to AEs. As of 16-Mar-2022, 35% of pts experienced ≥ Grade 3 TEAEs. Nausea, peripheral sensory neuropathy, and fatigue were the most frequently reported treatment-related TEAEs (66%, 42%, and 38% of pts, respectively). Notably, only 2 pts (2%) 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. Ten pts (8%) experienced treatment-related serious TEAEs; most commonly pyrexia (2%) and pneumonitis (2%). Twenty-one pts (17%) experienced treatment-emergent immune-mediated AEs; most commonly hyperthyroidism (6%), hypothyroidism (6%), maculo-papular rash (3%), and pneumonitis (2%).

Conclusions Interim efficacy and safety results indicate that AN+AD has promising efficacy and is well tolerated by pts with early stage cHL. No new safety signals were observed, and no pts had discontinued the treatment regimen early due to AEs. Omitting bleomycin and vinblastine may have contributed to absence of certain AEs, such as febrile neutropenia. Part C of this study is ongoing and updated efficacy and safety results will be presented.

Lee:Deloitte: Honoraria; Curio Science: Honoraria; Korean Society of Cardiology: Honoraria; Olson Research: Honoraria; Guidepoint Global: Honoraria; Century Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pharmcyclics: Research Funding; Takeda: Research Funding; Seagen: Research Funding; Octernal Therapeutics: Research Funding; Janssen: Honoraria; Briston-Myers Squibb: Research Funding; Celgene: Research Funding; Cancer Experts: Honoraria; Aptitude Health: Honoraria. Abramson:Regeneron: Consultancy; MorphoSys: Consultancy; Mustang Bio: Consultancy; Ono Pharma: Consultancy; Genmab: Consultancy; Kite Pharma: Consultancy; Incyte: Consultancy; Bluebird bio: Consultancy; Kymera: Consultancy; BeiGene: Consultancy; Epizyme: Consultancy; Genentech: Consultancy; Abbvie: Consultancy; BMS: Consultancy, Research Funding; Century: Consultancy; Astra-Zeneca: Consultancy; Lilly: Consultancy; Janssen: Consultancy; Seattle Genetics: Research Funding. Bartlett:Merck: Research Funding; Kite Pharma: Research Funding; Janssen: Research Funding; Forty Seven: Research Funding; Celgene: Research Funding; Bristol-Myers Squibb: Research Funding; Autolos: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche/Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Washington University School of Medicine: Current Employment; Millennium: Research Funding; Pharmacyclics: Research Funding. 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. Lynch:TG Therapeutics: Research Funding; Incyte: Research Funding; Bayer: Research Funding; Cyteir: Research Funding; Genentech: Research Funding; Seagen: Research Funding; Rapt: Research Funding; Cancer Study Group: Consultancy. Eva:TAKEDA: Consultancy, Honoraria, Other: travel and accomodation; BEIGENE: Consultancy; ABBVIE: Other: TRAVEL. Hess:AstraZeneca: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy; ADC Therapeutics: 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. Ramchandren:Bristol-Myers Squibb: Consultancy; Merck: Consultancy; Pharmacyclics: Consultancy, Research Funding; Seagen: Consultancy, Research Funding; Curis: Research Funding; Trillium: Research Funding. Gandhi:TG Therapeutics: Honoraria; Karyopharm: Honoraria; Janssen: Honoraria; GlaxoSmithKline: Honoraria. Shah:BeiGene: Research Funding; Astrazeneca: Research Funding; ADCT: Research Funding; Seattle Genetics: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; Epizyme: Research Funding. Rossi:Servier: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Ho:Seagen Inc.: Current Employment. Guo:Seagen: Current Employment. Yasenchak:Seagen Inc.: Consultancy, Research Funding; Takeda: Research Funding; Beigene: Speakers Bureau. Straus:Takeda Pharmaceuticals: Consultancy; Seagen: Consultancy.

Brentuximab vedotin (1.2 mg/kg), nivolumab (240 mg), doxorubicin (25 mg/m2), and dacarbazine (375 mg/m2) were administered, for 4 cycles on Days 1 and 15 of each 28-day cycle, to subjects with Ann Arbor stage I or II cHL without bulky disease.