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997 The ECHELON-2 Trial: Results of a Randomized, Double-Blind, Active-Controlled Phase 3 Study of Brentuximab Vedotin and CHP (A+CHP) Versus CHOP in the Frontline Treatment of Patients with CD30+ Peripheral T-Cell Lymphomas

Program: Oral and Poster Abstracts
Type: Oral
Session: 624. Hodgkin Lymphoma and T/NK Cell Lymphoma—Clinical Studies: T Cell Lymphoma: Chemotherapy and Targeted Approaches
Hematology Disease Topics & Pathways:
Diseases, Biological, Therapies, Elderly, T-Cell Lymphoma, immunotherapy, Lymphoid Malignancies
Monday, December 3, 2018: 6:15 PM
Room 6F (San Diego Convention Center)

Steven M. Horwitz, MD1, Owen A. O'Connor, M.D., Ph.D.2, Barbara Pro, MD3,4, Tim M. Illidge, MD, PhD5*, Michelle A. Fanale, MD6, Ranjana H. Advani, MD7, Nancy L. Bartlett, MD8, Jacob Haaber Christensen9*, Franck Morschhauser, MD10*, Eva Domingo-Domenech, MD11*, Giuseppe Rossi, MD12, Won Seog Kim, MD, PhD13*, Tatyana A. Feldman, MD14, Anne Lennard, MBBS, FRCP, FRCPath15*, David Belada, MD, PhD16,17*, Árpád Illés18*, Kensei Tobinai, MD, PhD19, Kunihiro Tsukasaki, MD, PhD20, Su-Peng Yeh, MD21*, Andrei R. Shustov, MD22, Andreas Hüttmann, MD23, Kerry J Savage, BSc, MD, MSc24, Sam Yuen25*, Pier Luigi Zinzani, MD26, Zhaowei Hua27*, Meredith Little, MPH27*, Shangbang Rao, PhD28*, Joseph Woolery, PharmD28, Thomas Manley, MD29 and Lorenz Truemper, MD, PhD30

1Memorial Sloan Kettering Cancer Center, Basking Ridge, NJ
2Columbia University Medical Center, New York, NY
3Division of Hematology and Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL
4Northwestern University, Chicago, IL
5Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, NIHR Biomedical Research Centre, Manchester Academic Health Sciences Centre, Christie Hospital NHS Foundation Trust, Manchester, United Kingdom
6University of Texas MD Anderson Cancer Center, Houston, TX
7Stanford Cancer Center, Blood and Marrow Transplant Program, Stanford, CA
8Siteman Cancer Center, Washington University School of Medicine, Saint Louis, MO
9Odense University Hospital, Odense, Denmark
10CHRU de Lille, Lille cedex, Nord-Pas-de-Calais, France
11Institut Catala D'oncologia, L'Hospitalet de Llobregat, Barcelona, Spain
12Azienda Ospedaliera Spedali Civili di Brescia, Brescia, Italy
13Samsung Medical Center, Seoul, Korea, Republic of (South)
14Hackensack University Medical Center, Hackensack, NJ
15Freeman Hospital, Newcastle upon Tyne, United Kingdom
164th Department of Internal Medicine – Hematology, University Hospital, Hradec Králové, Czech Republic
17Charles University, Faculty of Medicine, Prague, Czech Republic
18Debreceni Egyetem, Debrecen, Hungary
19National Cancer Center Hospital, Tokyo, Japan
20Saitama Medical University, International Medical Center, Department of Hematology, Saitama, Japan
21China Medical University Hospital, Taichung, Taiwan
22University of Washington Medical Center, Seattle, WA
23Universitatsklinikum Essen, Essen, Germany
24University of British Columbia and the Department of Medical Oncology, British Columbia Cancer Agency Centre for Lymphoid Cancer, Vancouver, BC, Canada
25Calvary Mater Newcastle Hospital, Newcastle, NSW, Australia
26Institute of Hematology "Seràgnoli, University of Bologna, Bologna, Italy
27Takeda Pharmaceuticals International Company, Cambridge, MA
28Seattle Genetics, Bothell, WA
29Seattle Genetics, Inc., Bothell, WA
30Universitätsmedizin Göttingen, Göttingen, Germany

Background

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of aggressive non-Hodgkin lymphomas (NHL). PTCL accounts for approximately 10% of all NHL cases in the US and Europe, and may be as high as 24% in Asia. The most common frontline treatment of PTCL is anthracycline-based chemotherapy with CHOP or CHOP-like regimens which do not produce durable remissions in the majority of subtypes, including ALK+ systemic anaplastic large cell lymphoma (sALCL) with high International Prognostic Index (IPI) scores. Brentuximab vedotin is an antibody‑drug conjugate directed against CD30 currently approved for the treatment of relapsed or refractory sALCL with demonstrated antitumor activity in frontline PTCL. A phase 1 trial combining brentuximab vedotin with cyclophosphamide, doxorubicin, and prednisone (CHP [CHOP without vincristine to eliminate additive neurotoxicity]) as frontline treatment of PTCL demonstrated estimated 5-year progression-free survival (PFS) and overall survival (OS) rates of 52% and 79% (Fanale 2018). Based on the encouraging activity and manageable safety profile of the combination, the ECHELON-2 trial was initiated to compare the efficacy and safety of brentuximab vedotin in combination with CHP (A+CHP) versus standard CHOP for the treatment of patients (pts) with PTCL (ClinicalTrials.gov No. NCT01777152). Here we report the blinded, pooled analyses per investigator of the ECHELON-2 trial.

Methods

ECHELON-2 is a phase 3, randomized, double-blind, active-controlled, multicenter study. Adults with newly diagnosed CD30+ (≥10% of neoplastic cells by local review) PTCL were enrolled. Pts with ALK+ sALCL were required to have an IPI ≥2. The primary endpoint of ECHELON-2 is PFS per an independent review facility. Pts were randomized 1:1 to receive 21‑day cycles of either CHOP or A+CHP for 6 to 8 cycles. Consolidative SCT or radiotherapy was permitted at the investigator’s discretion after end of treatment.

Results

A total of 452 pts across 17 countries were randomized between January 2013 and November 2016 in Europe (44%), North America (29%), and other (26%) regions including Asia and Australia. The median age was 58 years (range, 18‑85) and 63% were male. Most pts were white (62%) or Asian (22%). Most pts entering the study had an ECOG performance status of 0 or 1 (39% each) and the remaining 22% of pts had a performance status of 2. Most pts had advanced‑stage disease (Stage III [27%] or IV [53%]) at diagnosis and 78% had IPI scores ≥2 (2 [34%], 3 [29%], 4 [12%]. 5 [3%]). PTCL subtypes included sALCL (316 pts [70%]: ALK+ 98 pts [22%]; ALK– 218 pts [48%]), PTCL ‑ not otherwise specified (72 pts [16%]), angioimmunoblastic T-cell lymphoma (54 pts [12%]), adult T-cell leukemia/lymphoma (7 pts [2%]), and enteropathy-associated T-cell lymphoma (3 pts [1%]).

Of the 452 randomized pts, 449 received at least 1 dose of study treatment and all pts had either completed (82%) or discontinued treatment as of April 2017. Treatment was discontinued for adverse events (AEs) (7%), progressive disease (7%), investigator decision (2%), and patient decision (2%). Preliminary results by investigator assessment, show an overall blinded pooled objective response rate (ORR) following completion of the frontline treatment of 79% (95% CI: 75.4‑83.1) with 64% achieving a complete response (CR) (95% CI: 59.1‑68.2). With a median follow-up of 35.2 mos, the 3-year PFS and OS for all pts were 52.9% (95% CI: 47.7-57.7) and 73.1% (95% CI: 68.3-77.2).

The incidence of AEs was consistent with the known safety profiles of brentuximab vedotin and CHOP chemotherapy, including the AE of interest, peripheral sensory neuropathy (43%). Grade 3 or higher AEs reported in ≥10% of pts were neutropenia (33%), febrile neutropenia (17%), and anemia (12%).

Conclusions

ECHELON-2 is the largest prospective, randomized, double-blind study to compare the efficacy and safety of standard CHOP with an alternative regimen that includes a CD30-targeted agent in frontline treatment of sALCL and other CD30+ PTCLs. Blinded pooled data from ECHELON-2 show that the treatment was well tolerated with encouraging 3-year PFS and OS rates. The primary analysis by treatment regimen will be unblinded prior to the meeting and presented at the conference.

Disclosures: Horwitz: Seattle Genetics: Consultancy, Research Funding; Aileron Therapeutics: Consultancy, Research Funding; Innate Pharma: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Forty Seven: Consultancy, Research Funding; Corvus: Consultancy; Mundipharma: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Trillium: Consultancy; Celgene: Consultancy, Research Funding; Portola: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Spectrum: Research Funding; Kyowa-Hakka-Kirin: Consultancy, Research Funding. O'Connor: Celgene: Research Funding; ADC Therapeutics: Research Funding; Seattle Genetics: Research Funding. Pro: kiowa: Honoraria; Seattle Genetics: Consultancy, Other: Travel expenses, Research Funding; portola: Honoraria; Takeda Pharmaceuticals: Honoraria, Other: Travel expenses. Illidge: Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Research Funding; Takeda: Consultancy, Honoraria. Fanale: Amgen: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Merck & Co: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Takeda: Honoraria, Other: Travel expenses, Research Funding. Advani: Agensys: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Merck: Research Funding; Janssen: Research Funding; Autolus: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Celgene: Research Funding; Kyowa: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Regeneron: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Infinity: Research Funding; Kura: Research Funding; Celgene: Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Gilead/Kite: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Cell Medica: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Millenium: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Forty Seven Inc.: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board. Bartlett: KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Astra Zeneca: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ImaginAB: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck & Co: Research Funding; Immune Design: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Forty Seven: Research Funding; Affimed: Research Funding; Celgene: Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding; Novartis: Research Funding; Bristol-Meyers Squibb: Research Funding; Millennium: Research Funding. Christensen: Seattle Genetics: Research Funding. Morschhauser: Janssen: Other: Scientific Lectures; BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy; Roche: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. Domingo-Domenech: Affimed: Research Funding. Rossi: Novartis: Honoraria; Jazz: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Janssen: Membership on an entity's Board of Directors or advisory committees, Travel expenses; Roche: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Mundipharma: Honoraria; Sandoz: Honoraria; Seattle Genetics: Research Funding; Alexion: Other: Travel expenses. Feldman: Portola: Research Funding; Celgene: Speakers Bureau; Pharmacyclics: Speakers Bureau; Seattle Genetics: Research Funding, Speakers Bureau; KITE: Speakers Bureau; Johnson and Johnson: Speakers Bureau; Janssen: Speakers Bureau. Lennard: Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding. Belada: Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Illés: Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Tobinai: Zenyaku Kogyo: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; SERVIER: Research Funding; Abbvie: Research Funding; GlaxoSmithKline: Research Funding; Takeda: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; HUYA Bioscience International: Consultancy, Honoraria; Chugai Pharma: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Tsukasaki: Celgene: Honoraria; Eisai: Research Funding; Chugai Pharma: Honoraria, Research Funding; HUYA: Consultancy, Research Funding; Ono Pharma: Consultancy; Daiich-Sankyo: Consultancy; Mundy Pharma: Honoraria; Kyowa-hakko/Kirin: Honoraria; Seattle Genetics: Research Funding. Yeh: GNT Biotech & Medicals Crop.: Research Funding. Shustov: Seattle Genetics: Research Funding. Hüttmann: Roche: Other: Travel expenses; Celgene: Other: Travel expenses. Savage: Verastem: Consultancy, Honoraria; Takeda: Honoraria; Abbvie: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Servier: Consultancy; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Yuen: Seattle Genetics: Research Funding. Zinzani: PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astra Zeneca: Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Speakers Bureau; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Honoraria, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Honoraria, 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; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hua: Takeda Pharmaceuticals International Co.: Employment. Little: Takeda Pharmaceuticals: Employment. Rao: Seattle Genetics: Employment, Equity Ownership. Woolery: Seattle Genetics: Employment, Equity Ownership. Manley: Seattle Genetics: Employment, Equity Ownership. Truemper: Seattle Genetics: Research Funding.

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