Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial

Abstract

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.

Conflict of interest statement

DECLARATION OF INTERESTS

Dr. Horwitz 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; Dr. O’Connor, receiving support from Seattle Genetics to conduct the study; Dr. Pro, receiving grant support and personal fees from Seattle Genetics and personal fees from Takeda; Dr. Illidge, receiving personal fees from Takeda; Dr. Fanale, receiving grant support and personal fees from Seattle Genetics during the conduct of the study, grant support, personal fees, and being employed by 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; Dr. Advani, 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 Astra Zeneca, 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; Dr. Bartlett, 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; Dr. Christensen has nothing to disclose; Dr. Morschhauser, 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; Dr. Domingo-Domenech, receiving non-financial support from Seattle Genetics and personal fees from Bristol-Myers Squibb and Takeda; Dr. Rossi, receiving personal fees from Roche, Celgene, Janssen, Amgen, Gilead, Sanofi, Pfizer, AbbVie, Jazz Pharmaceuticals, Novartis, Bristol-Myers Squibb, and Sandoz; Dr. Kim has nothing to disclose; Dr. Feldman, 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; Dr. Lennard has nothing to disclose; Dr. Belada, receiving research support from Seattle Genetics and consultant and advisory board fees from Takeda; Dr. Illés has nothing to disclose; Dr. Tobinai, 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; Dr. Tsukasaki, 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; Dr. Yeh, has nothing to disclose; Dr. Shustov, receiving research funding from Seattle Genetics; Dr. Hüttmann, receiving grant support, honoraria and drug supply for study conduct from Takeda; Dr. Savage, 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; Dr. Yuen, has nothing to disclose; Dr. Iyer, receiving grant support from Seattle Genetics, Takeda, Roche, Rhizen, Spectrum, Celgene, Gilead, Novarits, Amgen, and Trillium; Dr. Zinzani, receiving advisory board fees and honoraria from Gilead, Sandoz, Johnson & Johnson, Bristol-Myers Squibb, Servier, Takeda, Celtrion, Roche, and Celgene; Dr. Hua has nothing to disclose; Ms. Little, holding shares in and employment with Takeda; Dr. Rao, being employed by and holding shares in Seattle Genetics; Dr. Woolery, being employed by and holding shares in Seattle Genetics; Dr. Manley, being employed by and holding shares in Seattle Genetics and has a patents 62/580,261, 62/739,631, and 62/739,635 licensed to Takeda (all ex-US, except Canada); and Dr. Trümper, 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. No other potential conflict of interest relevant to this article was reported.

Copyright © 2019 Elsevier Ltd. All rights reserved.

Figures

Figure 1:. CONSORT diagram

A+CHP=brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone; CHOP=cyclophosphamide, doxorubicin, vincristine, and prednisone. *Screening informed consents were obtained for seven subjects to allow sites to perform screening activities that were not considered standard of care at their sites. The remaining 594 subjects signed the full informed consent for the study. †Includes three subjects who were randomised to the A+CHP arm but did not receive study treatment. ‡A total of 89 subjects in the A+CHP arm and 81 subjects in the CHOP arm were prespecified by the investigator at baseline to receive consolidative stem cell transplantation. §Other reasons for study discontinuation were change in diagnosis for one subject and one subject who was found to be ineligible after randomization and who did not receive any study treatment.

Figure 2:. Progression-free survival as assessed per Blinded Independent Central Review

Figure 2A: Kaplan–Meier estimates of progression-free survival, by treatment arm, according to Blinded Independent Central Review for the intent-to-treat population. The hazard ratio for treatment with A+CHP versus CHOP and the 95% CIs were computed from log-rank test using stratification factors (ALK-positive sALCL: yes/no and IPI score: 0-1/2-3/4-5) at randomization. Tick marks indicate censored data. A+CHP=brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone; ALK=anaplastic lymphoma kinase; CHOP=cyclophosphamide, doxorubicin, vincristine, and prednisone; CI=confidence interval; IPI=international prognostic index; sALCL=systemic anaplastic large cell lymphoma. Figure 2B: Forest-Plot analysis of progression-free survival This forest plot shows progression-free survival according to the Blinded Independent Central Review in key prespecified subgroups. The hazard ratio for treatment with A+CHP versus CHOP and the 95% CIs were based on the cox regression model considering stratification factors at randomization. A+CHP=brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone; AITL=angioimmunoblastic T-cell lymphoma; ALK=anaplastic lymphoma kinase; CHOP=cyclophosphamide, doxorubicin, vincristine, and prednisone; CI=contidence interval; ECOG=eastern cooperative oncology group; IPI=international prognostic index; ITT=intention-to-treat; PTCL-NOS=peripheral T-cell lymphoma-not otherwise specified; sALCL=systemic anaplastic large cell lymphoma.

Figure 3:. Overall survival for the ITT population

Figure 3A: Kaplan-Meier analysis of overall survival, by treatment arm, in the intent-to-treat population. Tick marks indicate censored data. A+CHP=brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone; CHOP=cyclophosphamide, doxorubicin, vincristine, and prednisone; CI=confidence interval; ITT=intent-to-treat. Figure 3B: Forest-Plot analysis of overall survival. This forest plot shows overall survival in key prespecified subgroups. The hazard ratio for treatment with A+CHP versus CHOP and the 95% CIs were based on the cox regression model considering stratification factors at randomization. A+CHP=brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone; AITL=angioimmunoblastic T-cell lymphoma; ALK=anaplastic lymphoma kinase; CHOP=cyclophosphamide, doxorubicin, vincristine, and prednisone; CI=confidence interval; ECOG=eastern cooperative oncology group; IPI=international prognostic index; ITT=intention-to-treat; PTCL-NOS=peripheral T-cell lymphoma-not otherwise specified; sALCL=systemic anaplastic large cell lymphoma.