Background: Based on the encouraging activity and manageable safety profile observed in a phase 1 study, the ECHELON-2 trial was initiated to compare the efficacy and safety of brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone (A+CHP) versus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) for the treatment of CD30-positive peripheral T-cell lymphomas. Methods: ECHELON-2 is a double-blind, double-dummy, randomised, placebo-controlled, active-comparator phase 3 study. Eligible adults from 132 sites in 17 countries with previously untreated CD30-positive peripheral T-cell lymphomas (targeting 75% with systemic anaplastic large cell lymphoma) were randomly assigned 1:1 to receive either A+CHP or CHOP for six or eight 21-day cycles. Randomisation was stratified by histological subtype according to local pathology assessment and by international prognostic index score. All patients received cyclophosphamide 750 mg/m2 and doxorubicin 50 mg/m2 on day 1 of each cycle intravenously and prednisone 100 mg once daily on days 1 to 5 of each cycle orally, followed by either brentuximab vedotin 1·8 mg/kg and a placebo form of vincristine intravenously (A+CHP group) or vincristine 1·4 mg/m2 and a placebo form of brentuximab vedotin intravenously (CHOP group) on day 1 of each cycle. The primary endpoint, progression-free survival according to blinded independent central review, was analysed by intent-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01777152. Findings: Between Jan 24, 2013, and Nov 7, 2016, 601 patients assessed for eligibility, of whom 452 patients were enrolled and 226 were randomly assigned to both the A+CHP group and the CHOP group. Median progression-free survival was 48·2 months (95% CI 35·2–not evaluable) in the A+CHP group and 20·8 months (12·7–47·6) in the CHOP group (hazard ratio 0·71 [95% CI 0·54–0·93], p=0·0110). Adverse events, including incidence and severity of febrile neutropenia (41 [18%] patients in the A+CHP group and 33 [15%] in the CHOP group) and peripheral neuropathy (117 [52%] in the A+CHP group and 124 [55%] in the CHOP group), were similar between groups. Fatal adverse events occurred in seven (3%) patients in the A+CHP group and nine (4%) in the CHOP group. Interpretation: Front-line treatment with A+CHP is superior to CHOP for patients with CD30-positive peripheral T-cell lymphomas as shown by a significant improvement in progression-free survival and overall survival with a manageable safety profile. Funding: Seattle Genetics Inc, Millennium Pharmaceuticals Inc, a wholly owned subsidiary of Takeda Pharmacuetical Company Limited, and National Institutes of Health National Cancer Institute Cancer Center.
Bibliographical noteFunding Information:
SH reports receiving grant support from Spectrum, grant support and personal fees from Seattle Genetics, Takeda, Kyowa Hakka Kirin, Verastem Oncology, Aileron, ADC Therapeutics, Celgene, and Forty Seven, and personal fees from Portola, Corvus, Miragen, and Innate. OAO'C reports receiving grant support from Seattle Genetics to do the study. Seattle Genetics also made a gift to the Global T-cell Lymphoma Consortium, for which OAO'C is a co-director. BP reports receiving grant support and personal fees from Seattle Genetics and personal fees from Takeda. TI reports receiving personal fees from Takeda. MF reports receiving grant support and personal fees from Seattle Genetics during the conduct of the study, grant support, personal fees, employment, and holding shares in Seattle Genetics, grant support and personal fees from Takeda, Celgene, Bristol-Myers Squibb, and Merck, grant support from ADC Therapeutics, MedImmune, Gilead, Molecular Templates, and Genentech, and personal fees from Spectrum and Bayer. RA reports receiving grant support from Agensys, Celgene, Forty Seven, Infinity, Janssen, Kura Oncology, Merck, Millennium, and Regeneron, grant support and consulting and advisory fees from Bristol-Myers Squibb, Genentech/Roche, Pharmacyclics, and Seattle Genetics, consulting and advisory fees from AstraZeneca, Autolus, Bayer Healthcare Pharmaceuticals, Gilead, Juno, Kite, Kyowa Hakko Kirin, NanoString, Spectrum, Sutro Biopharma, and Takeda, and Data Safety Monitoring Board fees from Cell Medica. NLB reports receiving research funding from Celgene, Seattle Genetics, Genentech, Kite, Merck, Bristol-Meyers Squibb, Immune Designs, Forty Seven, Affimed, Janssen, Pharmacyclics, Millennium, and Gilead, and advisory board fees from Acerta and Pfizer. FM reports receiving honoraria from Takeda, advisory board fees from Bristol-Myers Squibb, lecture fees from Janssen, advisory board and lecture fees from Celgene and Roche, consultant fees from Epizyme, and consultant, advisory board, and lecture fees from Gilead. ED-D reports receiving non-financial support from Seattle Genetics and personal fees from Bristol-Myers Squibb and Takeda. GR reports receiving personal fees from Roche, Celgene, Janssen, Amgen, Gilead, Sanofi, Pfizer, AbbVie, Jazz Pharmaceuticals, Novartis, Bristol-Myers Squibb, and Sandoz. TF reports receiving consultant fees from Bristol-Myers Squibb, speaker's bureau fees and honoraria from Celgene, Pharmacyclis, Janssen, Kite, and AbbVie, and sponsor support, consultant and speaker's bureau fees, and honoraria from Seattle Genetics. DB reports receiving research support from Seattle Genetics and consultant and advisory board fees from Takeda. KTo reports receiving grant support from GlaxoSmithKline, Servier, and AbbVie, honoraria from Zenyaku Kogyo, and grant support and honoraria from Takeda, Eisai, Celgene, Mundipharma, Janssen, HUYA Bioscience International, Kyowa Hakko Kirin, Chugai Pharma, and Ono Pharma. KTs reports receiving grant support from Seattle Genetics and Eisai, consultant fees from Ono Pharma and Daiichi-Sankyo, honoraria from Kyowa Hakko Kirin, grant support and honoraria from Celgene and Chugai Pharma, and grant support, consultant fees, and honoraria from HUYA Bioscience International. AS reports receiving research funding from Seattle Genetics. AH reports receiving grant support, honoraria, and drug supply for the conduct of the study from Takeda. KJS reports receiving honoraria and advisory board fees from Seattle Genetics, and honoraria from Takeda during the conduct of the study, honoraria and advisory board frees from Bristol-Myers Squibb, Merck, Verastem, AbbVie, and consulting fees from Servier. SI reports receiving grant support from Seattle Genetics, Takeda, Roche, Rhizen, Spectrum, Celgene, Gilead, Novarits, Amgen, and Trillium. PLZ reports receiving advisory board fees and honoraria from Gilead, Sandoz, Johnson & Johnson, Bristol-Myers Squibb, Servier, Takeda, Celtrion, Roche, and Celgene. ML holds shares in and is employed by Takeda. SR is employed by and holds shares in Seattle Genetics. JW is employed by and holds shares in Seattle Genetics. TM is employed by and holds shares in Seattle Genetics and has patents 62/580,261, 62/739,631, and 62/739,635 licensed to Takeda (all ex-US, except Canada). LT reports receiving grant support from Seattle Genetics and the German Ministry of Education and Research (Bundesministerium für Bildung und Forschung) and grant and non-financial support from Genzyme. All other authors declare no competing interests.
We thank the patients who participated in this trial and their families, the investigators and staff at all ECHELON-2 clinical sites, the members of the independent data and safety monitoring committee, and the independent review committee. We also thank Dana Kennedy, Eric Sievers, and Jonathan Drachman for their contributions to the design of the study. Medical writing assistance was funded by Seattle Genetics, and provided by Katie Hutchinson of Seattle Genetics, and Elizabeth O'Connor of MMS Holdings. This research was funded by Seattle Genetics, and Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical Company. This research was supported in part through the National Institutes of Health National Cancer Institute Cancer Center support grant ( P30 CA008748 ).
The funders and ECHELON-2 steering committee members jointly designed the trial. The investigators and funders collected and interpreted the data, and the funders analysed the data. Medical writing assistance was funded by Seattle Genetics and was provided by Seattle Genetics and MMS Holdings. All authors had access to the data, contributed to the manuscript development, approved the manuscript for submission, and vouch for its integrity. The corresponding author (SH) had final authority over the manuscript and the decision to submit for publication.
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