J. Radford1, A. Gallamini2, W. Jurczak3, D. J. Straus4, S. M. Ansell5, W. S. Kim6, A. Younes4, S. Alekseev7, Á. Illés8, M. Picardi9, E. Lech-Maranda10, Y. Oki11, T. Feldman12, P. Smolewski13, K. J. Savage14, N. L. Bartlett15, J. Walewski16, R. Chen17, R. Ramchandren18, P. L. Zinzani19, D. Cunningham20, D. S. Heo21, A. Rosta22, N. C. Josephson23, E. Song23, J. Sachs24, R. Liu24, H. Jolin24, D. Huebner24, J. M. Connors14
1University of Manchester and the Christie NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom,2Research, Innovation and statistics department, A Lacassagne Cancer Centre, Nice, France,3Department of Hematology, Jagiellonian University, Kraków, Poland,4Memorial Sloan Kettering Cancer Center, New York, NY, USA,5Mayo Clinic, Rochester, MN, USA,6Samsung Medical Center, Seoul, South Korea,7Petrov Research Institute of Oncology, Saint Petersburg, Russia,8University of Debrecen, Debrecen, Hungary,9Federico II University Hospital, Napoli, Italy,10Institute of Hematology and Transfusion Medicine, and Centre of Postgraduate Medical Education, Warsaw, Poland,11MD Anderson Cancer Center, Houston, TX, USA,12Hackensack University Medical Center, Hackensack, NJ, USA,13Medical University of Łódz’, Łódz’, Poland,14British Columbia Cancer Agency Centre for Lymphoid Cancer, Vancouver, BC, Canada,15Washington University School of Medicine, St Louis, WA, USA,16The Maria Sklodowska-Curie Memorial Institute and Oncology Centre, Warsaw, Poland,17City of Hope National Medical Center, Duarte, CA, USA,18Barbara Ann Karmanos Cancer Center, Detroit, MI, USA,19Institute of Hematology ‘Seràgnoli’, University of Bologna, Bologna, Italy,20The Royal Marsden NHS Foundation Trust, Sutton, UK,21Seoul National University Hospital, Seoul, South Korea,22National Institute of Oncology, Budapest, Hungary,23Seattle Genetics, Inc., Bothell, WA, USA,24Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA
Background: Approximately 30% of patients (pts) with advanced-stage classical Hodgkin Lymphoma (cHL) have refractory disease or relapse after frontline doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). We compared frontline brentuximab vedotin (a CD30-directed antibody-drug conjugate) + doxorubicin, vinblastine, and dacarbazine (A+AVD) with ABVD in pts with advanced cHL.
Methods: 1334 pts with Stage III (36%) or IV (64%) cHL were randomized 1:1 to A+AVD or ABVD (days 1 and 15, up to six 28-day cycles). Late in enrolment, pts newly randomized to A+AVD were recommended G-CSF primary prophylaxis (PP) due to increased febrile neutropenia (FN). Primary endpoint was modified progression-free survival (mPFS; defined as time to progression, death, or evidence of noncomplete response followed by subsequent anticancer therapy) per independent review facility (IRF). Key secondary endpoint was overall survival (OS).
Results: Primary endpoint of mPFS per IRF was met (HR 0.77 [95%CI 0.60–0.98]; p = 0.04) (Figure 1), was consistent with mPFS per investigator (INV) (HR 0.72 [95%CI 0.57–0.91]; p = 0.006) and PFS per INV (data to be presented). mPFS events per IRF for A+AVD vs ABVD were progression (90 vs 102), death (18 vs 22), and additional therapy for noncomplete response (9 vs 22). Two-year mPFS per IRF was 82.1% (95%CI 78.8–85.0) with A+AVD vs 77.2% (95%CI 73.7–80.4) with ABVD; mPFS per INV was 81.0% (95%CI 77.6–83.9) with A+AVD vs 74.4% (95%CI 70.7–77.7] with ABVD. 28 deaths occurred in the A+AVD arm and 39 in the ABVD arm (interim OS HR 0.73 [95%CI 0.45–1.18]; p = 0.20). FN occurred in 19% of A+AVD pts and 8% of ABVD pts. In A+AVD pts, G-CSF PP (n = 83) reduced FN from 21% to 11% and grade (G) ≥3 infections/infestations from 18% to 11%. Peripheral neuropathy (PN) occurred in 67% of A+AVD pts and 43% of ABVD pts (G≥3: 11% A+AVD [1 pt with G4] vs 2% ABVD); 67% of pts experiencing PN in the A+AVD arm had resolution or improvement of PN at last follow-up. Pulmonary toxicity was more frequent and severe with ABVD (G≥3: 3% ABVD vs <1% A+AVD). 7/9 A+AVD on-study deaths were neutropenia-associated, occurring in pts without G-CSF PP. 11/13 ABVD on-study deaths were due to, or associated with, pulmonary toxicity.
Conclusions: Compared with ABVD, frontline A+AVD improved outcomes for pts with advanced cHL, reducing risk of progression, death, or need for additional anticancer therapy by 23%. Results support possible frontline use of A+AVD in pts with advanced-stage cHL.