Joseph M Connors1, Wojciech Jurczak1, David J Straus1, Stephen M Ansell1, Won S Kim1, Andrea Gallamini1, Anas Younes1, Sergey Alekseev1, Árpád Illés1, Marco Picardi1, Ewa Lech-Maranda1, Yasuhiro Oki1, Tatyana Feldman1, Piotr Smolewski1, Kerry J Savage1, Nancy L Bartlett1, Jan Walewski1, Robert Chen1, Radhakrishnan Ramchandren1, Pier L Zinzani1, David Cunningham1, Andras Rosta1, Neil C Josephson1, Eric Song1, Jessica Sachs1, Rachael Liu1, Hina A Jolin1, Dirk Huebner1, John Radford1. 1. From the University of British Columbia and the Department of Medical Oncology, British Columbia Cancer Agency Centre for Lymphoid Cancer, Vancouver, Canada (J.M.C., K.J.S.); the Department of Hematology, Jagiellonian University, Krakow (W.J.), the Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw (E.L.-M.), the Department of Hematology and Transfusion Medicine, Center of Postgraduate Medical Education, Warsaw (E.L.-M.), the Department of Experimental Hematology, Medical University of Lodz, Lodz (P.S.), and the Department of Lymphoid Malignancy, the Maria Sklodowska-Curie Memorial Institute and Oncology Center, Warsaw (J.W.) - all in Poland; Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York (D.J.S., A.Y.); the Department of Internal Medicine, Division of Hematology, Mayo Clinic, Rochester, MN (S.M.A.); the Division of Hematology and Oncology, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, South Korea (W.S.K.); Research Innovation and Statistics, Antoine-Lacassagne Cancer Center, Nice, France (A.G.); Petrov Research Institute of Oncology, St. Petersburg, Russia (S.A.); the Department of Hematology, Faculty of Medicine, University of Debrecen, Debrecen (Á.I.), and the Department of Hematology, National Institute of Oncology, Budapest (A.R.) - both in Hungary; the Department of Advanced Biomedical Science, Federico II University Hospital, Naples (M.P.), and the Institute of Hematology Seràgnoli, University of Bologna, Bologna (P.L.Z.) - both in Italy; the Department of Lymphoma and Myeloma, M.D. Anderson Cancer Center, Houston (Y.O.); John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ (T.F.); the Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis (N.L.B.); the Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA (R.C.); the Department of Hematology-Oncology, Barbara Ann Karmanos Cancer Center, Detroit (R.R.); Gastrointestinal and Lymphoma Unit, The Royal Marsden NHS Foundation Trust, Sutton (D.C.), and the Department of Medical Oncology, University of Manchester and the Christie NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester (J.R.) - both in the United Kingdom; the Department of Clinical Development, Seattle Genetics, Bothell, WA (N.C.J., E.S.); and Oncology Clinical Research (J.S., H.A.J., D.H.) and Global Biostatistics (R.L.), Millennium Pharmaceuticals, Cambridge, MA.
Abstract
BACKGROUND: Brentuximab vedotin is an anti-CD30 antibody-drug conjugate that has been approved for relapsed and refractory Hodgkin's lymphoma. METHODS: We conducted an open-label, multicenter, randomized phase 3 trial involving patients with previously untreated stage III or IV classic Hodgkin's lymphoma, in which 664 were assigned to receivebrentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) and 670 were assigned to receive doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). The primary end point was modified progression-free survival (the time to progression, death, or noncomplete response and use of subsequent anticancer therapy) as adjudicated by an independent review committee. The key secondary end point was overall survival. RESULTS: At a median follow-up of 24.6 months, 2-year modified progression-free survival rates in the A+AVD and ABVD groups were 82.1% (95% confidence interval [CI], 78.8 to 85.0) and 77.2% (95% CI, 73.7 to 80.4), respectively, a difference of 4.9 percentage points (hazard ratio for an event of progression, death, or modified progression, 0.77; 95% CI, 0.60 to 0.98; P=0.04). There were 28 deaths with A+AVD and 39 with ABVD (hazard ratio for interim overall survival, 0.73 [95% CI, 0.45 to 1.18]; P=0.20) [corrected]. All secondary efficacy end points trended in favor of A+AVD. Neutropenia occurred in 58% of the patients receiving A+AVD and in 45% of those receiving ABVD; in the A+AVD group, the rate of febrile neutropenia was lower among the 83 patients who received primary prophylaxis with granulocyte colony-stimulating factor than among those who did not (11% vs. 21%). Peripheral neuropathy occurred in 67% of patients in the A+AVD group and in 43% of patients in the ABVD group; 67% of patients in the A+AVD group who had peripheral neuropathy had resolution or improvement at the last follow-up visit. Pulmonary toxicity of grade 3 or higher was reported in less than 1% of patients receiving A+AVD and in 3% of those receiving ABVD. Among the deaths that occurred during treatment, 7 of 9 in the A+AVD group were associated with neutropenia and 11 of 13 in the ABVD group were associated with pulmonary-related toxicity. CONCLUSIONS: A+AVD had superior efficacy to ABVD in the treatment of patients with advanced-stage Hodgkin's lymphoma, with a 4.9 percentage-point lower combined risk of progression, death, or noncomplete response and use of subsequent anticancer therapy at 2 years. (Funded by Millennium Pharmaceuticals and Seattle Genetics; ECHELON-1 ClinicalTrials.gov number, NCT01712490 ; EudraCT number, 2011-005450-60 .).
RCT Entities:
BACKGROUND: Brentuximab vedotin is an anti-CD30 antibody-drug conjugate that has been approved for relapsed and refractory Hodgkin's lymphoma. METHODS: We conducted an open-label, multicenter, randomized phase 3 trial involving patients with previously untreated stage III or IV classic Hodgkin's lymphoma, in which 664 were assigned to receive brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) and 670 were assigned to receive doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). The primary end point was modified progression-free survival (the time to progression, death, or noncomplete response and use of subsequent anticancer therapy) as adjudicated by an independent review committee. The key secondary end point was overall survival. RESULTS: At a median follow-up of 24.6 months, 2-year modified progression-free survival rates in the A+AVD and ABVD groups were 82.1% (95% confidence interval [CI], 78.8 to 85.0) and 77.2% (95% CI, 73.7 to 80.4), respectively, a difference of 4.9 percentage points (hazard ratio for an event of progression, death, or modified progression, 0.77; 95% CI, 0.60 to 0.98; P=0.04). There were 28 deaths with A+AVD and 39 with ABVD (hazard ratio for interim overall survival, 0.73 [95% CI, 0.45 to 1.18]; P=0.20) [corrected]. All secondary efficacy end points trended in favor of A+AVD. Neutropenia occurred in 58% of the patients receiving A+AVD and in 45% of those receiving ABVD; in the A+AVD group, the rate of febrile neutropenia was lower among the 83 patients who received primary prophylaxis with granulocyte colony-stimulating factor than among those who did not (11% vs. 21%). Peripheral neuropathy occurred in 67% of patients in the A+AVD group and in 43% of patients in the ABVD group; 67% of patients in the A+AVD group who had peripheral neuropathy had resolution or improvement at the last follow-up visit. Pulmonary toxicity of grade 3 or higher was reported in less than 1% of patients receiving A+AVD and in 3% of those receiving ABVD. Among the deaths that occurred during treatment, 7 of 9 in the A+AVD group were associated with neutropenia and 11 of 13 in the ABVD group were associated with pulmonary-related toxicity. CONCLUSIONS: A+AVD had superior efficacy to ABVD in the treatment of patients with advanced-stage Hodgkin's lymphoma, with a 4.9 percentage-point lower combined risk of progression, death, or noncomplete response and use of subsequent anticancer therapy at 2 years. (Funded by Millennium Pharmaceuticals and Seattle Genetics; ECHELON-1 ClinicalTrials.gov number, NCT01712490 ; EudraCT number, 2011-005450-60 .).
Authors: K Spaepen; S Stroobants; P Dupont; J Thomas; P Vandenberghe; J Balzarini; C De Wolf-Peeters; L Mortelmans; G Verhoef Journal: Br J Haematol Date: 2001-11 Impact factor: 6.998
Authors: T A Lister; D Crowther; S B Sutcliffe; E Glatstein; G P Canellos; R C Young; S A Rosenberg; C A Coltman; M Tubiana Journal: J Clin Oncol Date: 1989-11 Impact factor: 44.544
Authors: Bruce D Cheson; Beate Pfistner; Malik E Juweid; Randy D Gascoyne; Lena Specht; Sandra J Horning; Bertrand Coiffier; Richard I Fisher; Anton Hagenbeek; Emanuele Zucca; Steven T Rosen; Sigrid Stroobants; T Andrew Lister; Richard T Hoppe; Martin Dreyling; Kensei Tobinai; Julie M Vose; Joseph M Connors; Massimo Federico; Volker Diehl Journal: J Clin Oncol Date: 2007-01-22 Impact factor: 44.544
Authors: J A Barnes; A S LaCasce; K Zukotynski; D Israel; Y Feng; D Neuberg; C E Toomey; E P Hochberg; G P Canellos; J S Abramson Journal: Ann Oncol Date: 2010-10-15 Impact factor: 32.976
Authors: Anas Younes; Joseph M Connors; Steven I Park; Michelle Fanale; Megan M O'Meara; Naomi N Hunder; Dirk Huebner; Stephen M Ansell Journal: Lancet Oncol Date: 2013-11-15 Impact factor: 41.316
Authors: Angie Mae Rodday; Theresa Hahn; Anita J Kumar; Peter K Lindenauer; Jonathan W Friedberg; Andrew M Evens; Susan K Parsons Journal: Br J Haematol Date: 2020-02-23 Impact factor: 6.998
Authors: Scott F Huntington; Gottfried von Keudell; Amy J Davidoff; Cary P Gross; Sapna A Prasad Journal: J Clin Oncol Date: 2018-10-04 Impact factor: 44.544