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Brentuximab Vedotin Plus Chemotherapy in North American Subjects with Newly Diagnosed Stage III Or IV Hodgkin Lymphoma Radhakrishnan Ramchandren1, Ranjana H

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Brentuximab Vedotin Plus Chemotherapy in North American Subjects with Newly Diagnosed Stage III Or IV Hodgkin Lymphoma Radhakrishnan Ramchandren1, Ranjana H Published OnlineFirst January 7, 2019; DOI: 10.1158/1078-0432.CCR-18-2435 Clinical Trials: Targeted Therapy Clinical Cancer Research Brentuximab Vedotin plus Chemotherapy in North American Subjects with Newly Diagnosed Stage III or IV Hodgkin Lymphoma Radhakrishnan Ramchandren1, Ranjana H. Advani2, Stephen M. Ansell3, Nancy L. Bartlett4, Robert Chen5, Joseph M. Connors6, Tatyana Feldman7, Andres Forero-Torres8, Jonathan W. Friedberg9, Ajay K. Gopal10, Leo I. Gordon11, John Kuruvilla12, Kerry J. Savage6, Anas Younes13, Gerald Engley14, Thomas J. Manley14, Keenan Fenton14, and David J. Straus13 Abstract Purpose: To evaluate safety and efficacy outcomes for sub- among subjects who received AþAVD compared with ABVD jects on the ECHELON-1 study treated in North America (NA). (HR ¼ 0.60; P ¼ 0.012). For PFS, the risk of progression or Experimental Design: ECHELON-1 is a global, open-label, death was also reduced (HR ¼ 0.50; P ¼ 0.002). Subsequent randomized phase III study comparing doxorubicin, vinblas- anticancer therapies were lower in the AþAVD arm. Grade 3 or tine, and dacarbazine in combination with brentuximab vedo- 4 adverse events (AEs) were more common, but there were tin (AþAVD) versus ABVD (AVD þ bleomycin) as first-line fewer study discontinuations due to AEs in the AþAVD arm therapy in subjects with stage III or IV classical Hodgkin as compared with ABVD. Noted differences between arms lymphoma (cHL; NCT01712490). Subjects were randomized included higher rates of febrile neutropenia (20% vs. 9%) 1:1 to receive AþAVD or ABVD intravenously on days 1 and and peripheral neuropathy (80% vs. 56%), but lower rates of 15 of each 28-day cycle for up to 6 cycles. pulmonary toxicity (3% vs. 10%) in subjects treated with Results: The NA subgroup consisted of 497 subjects in the AþAVD versus ABVD. AþAVD (n ¼ 250) and ABVD (n ¼ 247) arms. Similar to the Conclusions: The efficacy benefit and manageable toxicity primary analysis based on the intent-to-treat population, profile observed in the NA subgroup of ECHELON-1 support the primary endpoint [modified progression-free survival AþAVD as a frontline treatment option for patients with (PFS) per independent review] demonstrated an improvement stage III or IV cHL. Introduction 1Department of Hematology/Oncology, Barbara Ann Karmanos Cancer Cen- ter, Detroit, Michigan. 2Department of Medicine, Stanford University, Palo Approximately 8,200 cases of classical Hodgkin lymphoma Alto, California. 3Division of Hematology, Mayo Clinic, Rochester, Minnesota. (cHL) are diagnosed annually in the United States (1). For over 4 Division of Oncology, Siteman Cancer Center, Washington University School 40 years, the first-line standard of care for cHL in North America of Medicine, St. Louis, Missouri. 5Department of Hematology and Hemato- (NA) has been chemotherapy with ABVD (2–4). Despite high poietic Cell Transplantation, City of Hope National Medical Center, Duarte, California. 6University of British Columbia and the Department of Medical response rates, approximately 30% of patients with advanced Oncology, British Columbia Cancer Centre for Lymphoid Cancer, Vancouver, stage Hodgkin lymphoma are refractory or relapse following British Columbia, Canada. 7John Theurer Cancer Centre, Hackensack Uni- first-line treatment with ABVD (5–7). versity Medical Center, Hackensack, New Jersey. 8Department of Medicine, ECHELON-1 is an international, phase III trial comparing 9 University of Alabama at Birmingham, Birmingham, Alabama. James P doxorubicin, vinblastine, and dacarbazine (AVD) in combination Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, 10 with brentuximab vedotin (ADCETRIS; AþAVD) versus ABVD New York. Fred Hutchinson Cancer Research Center, University of þ fi Washington, Seattle, Washington. 11Robert H. Lurie Comprehensive Cancer (AVD bleomycin) as rst-line therapy in subjects with stage III Center, Northwestern University, Chicago, Illinois. 12Division of Medical or IV cHL (8). The primary endpoint was modified progression- Oncology and Hematology, Princess Margaret Hospital, Toronto, Ontario, free survival (PFS) per independent review facility (IRF), defined Canada. 13Lymphoma Service, Department of Medicine, Memorial Sloan as progression, death, or the receipt of additional treatment for 14 Kettering Cancer Center, New York, New York. Seattle Genetics, Inc., subjects not achieving complete response (CR) at the completion Bothell, Washington. of first-line therapy. It showed that AþAVD was superior to ABVD Note: Supplementary data for this article are available at Clinical Cancer (HR ¼ 0.77, P ¼ 0.035) with 2-year modified PFS rates of 82.1% Research Online (http://clincancerres.aacrjournals.org/). and 77.2%, respectively, with no significant difference in overall Corresponding Author: Radhakrishnan Ramchandren, The University of survival (OS) at the OS interim analysis. Treatment with AþAVD Tennessee, 1926 Alcoa Hwy, Knoxville, TN 37920. Phone: 865-305-9162; E-mail: was associated with higher rates of febrile neutropenia and [email protected] peripheral neuropathy, and lower rates of pulmonary-related doi: 10.1158/1078-0432.CCR-18-2435 toxicity compared with ABVD. AþAVD is the first treatment Ó2019 American Association for Cancer Research regimen utilizing a targeted agent to show superior efficacy in www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst January 7, 2019; DOI: 10.1158/1078-0432.CCR-18-2435 Ramchandren et al. another cancer within 3 years before the first dose, or clinically Translational Relevance relevant cardiovascular conditions. For over 40 years, the standard of care for first-line Hodgkin lymphoma in North America has been chemotherapy with Disease assessments ABVD or an ABVD-like regimen. The novel AþAVD regimen Modified PFS by independent review facility (IRF) was the incorporates a targeted agent, the CD30-directed antibody- primary objective of the ECHELON-1 trial. Regional analysis of drug conjugate brentuximab vedotin (ADCETRIS), into a modified PFS per IRF, including North America, was a prespecified backbone of AVD chemotherapy. The phase 3, ECHELON-1 sensitivity analysis. All additional analyses for the regional sub- trial established AþAVD as the first frontline regimen with a groups were exploratory. Disease progression was evaluated in targeted agent to demonstrate a modified progression-free accordance with the Revised Response Criteria for Malignant survival benefit in comparison with ABVD for stage III or IV Lymphoma (Cheson 2007; ref. 10) by both a blinded IRF and classical Hodgkin lymphoma (cHL). A preplanned subgroup investigator (INV) assessment. analysis of ECHELON-1 revealed regional variation with a Modified PFS per IRF was defined as time from randomization trend toward greater efficacy in North America; we present the to first documentation of progressive disease (per Cheson 2007), efficacy, safety, and disease management of subjects in death due to any cause, or confirmed nonresponse [End of North America to better understand AþAVD as a first-line Treatment (EOT) Deauville score 3) for subjects who received treatment option for patients with stage III or IV cHL. Although additional anticancer therapy. Modified PFS per INV was defined these findings are hypothesis-generating, they may provide as time from randomization to first documentation of progressive meaningful information for managing patients with AþAVD disease (per Cheson 2007), death due to any cause, or confirmed and influence future cHL studies. nonresponse (per Cheson 2007) for subjects who received addi- tional anticancer therapy. PFS per INV was defined as time from randomization to first documentation of progressive disease (per Cheson 2007) or death due to any cause. terms of modified PFS compared with ABVD while also elim- An additional secondary endpoint was rate of CR defined as inating the need for bleomycin in subjects with previously best overall response achieved at the end of randomized regimen untreated stage III or IV cHL. For the ECHELON-1 primary per IRF assessment (10). Subject disease status, following cycle 2 endpoint of modified PFS, assessment by region of the world and at EOT, by PET scan (using the Deauville criteria) was also was among the preplanned subgroup analyses, and consistent assessed by IRF. with the primary analysis showed an improvement in modified All survival endpoints were summarized using the Kaplan– PFS for subjects randomized to AþAVD compared with those Meier method and evaluated with the use of a log-rank test. A Cox randomized to ABVD within the NA region (Canada and the regression model was used to estimate the HR and the 95% United States). Here, we present additional safety and efficacy confidence interval (CI) for the treatment effect. outcomes for subjects on the ECHELON-1 study treated in NA. Safety evaluations included incidence of adverse events (AEs), as well as severity and type of AE defined according to the Medical Dictionary for Regulatory Activities (MedDRA), version 19.0, with Materials and Methods grading of AEs defined according to the National Cancer Institute Trial design Common Terminology Criteria for Adverse Events [NCI-CTCAE], ECHELON-1 is a global, open-label, randomized phase III version 4.03. study of AþAVD versus ABVD as first-line therapy in subjects with stage III or IV cHL (NCT01712490). Subjects were randomly Oversight assigned in a 1:1 ratio, stratified by region [Americas (39%), The ECHELON-1 trial was conducted
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