Elsevier

The Lancet

Volume 393, Issue 10168, 19–25 January 2019, Pages 229-240
The Lancet

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

https://doi.org/10.1016/S0140-6736(18)32984-2Get rights and content

Summary

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.

Introduction

Peripheral T-cell lymphoma is a heterogeneous group of aggressive non-Hodgkin lymphoma, accounting for approximately 10% of all non-Hodgkin lymphoma cases in the USA and Europe and as high as 24% in parts of Asia.1 The most common peripheral T-cell lymphomas are the so-called nodal peripheral T-cell lymphomas, which include peripheral T-cell lymphoma not otherwise specified, angioimmunoblastic T-cell lymphoma, and anaplastic lymphoma kinase (ALK)-positive or ALK-negative systemic anaplastic large cell lymphoma. These subtypes are usually treated similarly with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP-like regimens.2, 3 However, anthracycline-containing regimens result in low complete remission (CR) rates and poor progression-free survival and overall survival.4, 5, 6 Even with the more favourable ALK-positive systemic anaplastic large cell lymphoma, 5-year overall survival is less than 50% for older patients (>40 years) and those with adverse prognostic factors (International Prognostic Index [IPI] ≥2).7 Despite intensified approaches in front-line therapy, such as the addition of etoposide to CHOP and consolidation with stem cell transplantation, patients are still at considerable risk of disease relapse or early progression,8, 9 underscoring the high unmet need in these patients. Moreover, few randomised studies that guide therapy in peripheral T-cell lymphoma are available (and they are underpowered and do not give clear conclusions), with management approaches primarily derived from phase 2 studies, retrospective series, and clinical experience.4, 7, 8, 10, 11, 12

Research in context

Evidence before this study

Peripheral T-cell lymphoma is a heterogeneous group of rare, aggressive lymphoproliferative disorders that represent approximately 10–15% of non-Hodgkin lymphoma cases worldwide.

Clinical outcomes for patients with previously untreated peripheral T-cell lymphoma depend upon histological subtype but are typically poor. Most subtypes of peripheral T-cell lymphoma are treated similarly with combination chemotherapy, most commonly cyclophosphamide (C), doxorubicin (H), vincristine (O), and prednisone (P; CHOP) or CHOP-like regimens.

Several of the peripheral T-cell lymphoma subtypes express CD30, most notably systemic anaplastic large cell lymphoma, for which CD30 expression is a hallmark of the diagnosis. Brentuximab vedotin is an antibody–drug conjugate with shown efficacy in the treatment of relapsed or refractory systemic anaplastic large cell lymphoma. Additionally, combination treatment of brentuximab vedotin with CHP (A+CHP) in a phase 1 trial showed encouraging activity and a manageable safety profile. Given the results of brentuximab vedotin monotherapy in the relapsed and refractory systemic anaplastic large cell lymphoma setting, and its tolerability when combined with CHP, the ECHELON-2 trial was designed to assess the efficacy and safety of A+CHP versus CHOP in patients with previously untreated CD30-positive peripheral T-cell lymphoma.

We searched the scientific literature to identify reports of patients with peripheral T-cell lymphoma given brentuximab vedotin or CHOP chemotherapy. We searched PubMed from June 1, 2012, to Oct 01, 2018, using the terms (“ADCETRIS” or “Brentuximab vedotin” or “BV”) AND (“CHOP” OR “CHP”) AND (“PTCL” or “MTCL”) and identified no other clinical trials of brentuximab vedotin in combination with CHP. Additionally, no reports had been published from randomised, prospective, phase 3 clinical trials establishing the superiority of any regimen over CHOP in untreated patients with peripheral T-cell lymphoma.

Added value of this study

Previous trials that have attempted to improve upon CHOP have shown either no or only modest improvements in response rates or progression-free survival, often with high rates of toxicity. To our knowledge, this trial is the first randomised, double-blind study of a targeted drug combination treatment against standard therapy for this indication and is the first reported prospective phase 3 trial in previously untreated patients with peripheral T-cell lymphoma to show an overall survival benefit over CHOP chemotherapy. Our results show that A+CHP improved progression-free survival and overall survival compared with CHOP alone in patients with CD30-positive peripheral T-cell lymphoma. Importantly, these improvements in survival came without an apparent increase in toxicity.

Implications of all the available evidence

We consider these results to be potentially practice-changing and approval was granted in November, 2018, by the US Food and Drug Administration. Regulatory approval is being sought from additional health authorities worldwide for the use of A+CHP in the treatment of patients with previously untreated CD30-positive peripheral T-cell lymphoma.

CD30 is universally expressed and is pathognomonic in systemic anaplastic large cell lymphoma. Among non-systemic anaplastic large cell lymphoma subtypes CD30 expression is variable, with estimates from approximately 58–64% in peripheral T-cell lymphoma not otherwise specified, 43–63% in angioimmunoblastic T-cell lymphoma, 55% in adult T-cell leukaemia or lymphoma, and 0–100% in enteropathy-associated T-cell lymphoma.13, 14 Brentuximab vedotin is an antibody–drug conjugate composed of an anti-CD30 monoclonal antibody conjugated by a protease-cleavable linker to the microtubule-disrupting drug monomethyl auristatin E. It has been approved for several indications, including the treatment of adults with systemic anaplastic large cell lymphoma and previously untreated CD30-expressing peripheral T-cell lymphoma (US Food and Drug Administration).15 Based on the encouraging activity and manageable safety profile observed in a phase 1 trial16 combining brentuximab vedotin with cyclophosphamide, doxorubicin, and prednisone (CHP [CHOP without vincristine] to eliminate the risk of overlapping neurotoxicity that could be worsened by delivering two microtubule-disrupting drugs), the double-blinded phase 3 ECHELON-2 trial was initiated to compare the efficacy and safety of brentuximab vedotin in combination with CHP (A+CHP) with standard CHOP for the treatment of previously untreated patients with CD30-positive peripheral T-cell lymphoma.

Section snippets

Study design and participants

ECHELON-2 is a double-blind, double-dummy, randomised, placebo-controlled, active-comparator phase 3 study done at 132 sites (including four satellite sites) in 17 countries across North America, Europe, Asia Pacific, and the Middle East (appendix). Eligible patients were aged 18 years or older and had previously untreated, CD30-positive (≥10% of cells by local review; appendix) peripheral T-cell lymphoma according to the WHO 2008 classification system17 by local assessment. Eligible

Results

Patients were enrolled between Jan 24, 2013, and Nov 7, 2016. The data cutoff date for this primary analysis was Aug 15, 2018. Of 601 patients assessed for eligibility, a total of 452 patients across 17 countries were recruited and randomly assigned to the A+CHP group (n=226) or the CHOP group (n=226; figure 1). Baseline characteristics were generally balanced between the two treatment groups (table 1; appendix). Overall, the median age was 58 years (IQR 45–67). The study enrolled patients with

Discussion

ECHELON-2 is the first prospective trial in peripheral T-cell lymphoma to show an overall survival benefit over an established standard therapy, CHOP. In this double-blind, double-dummy, randomised, placebo-controlled, active-comparator phase 3 study, enrolling 452 patients with previously untreated CD30-positive peripheral T-cell lymphoma, A+CHP showed superior progression-free survival and significantly longer overall survival than CHOP. Treatment with A+CHP led to a 29% reduction in the risk

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*

Authors on the steering committee contributed equally to the oversight of the study, including study design and maintaining the quality of study conduct

All ECHELON-2 investigators are listed in the appendix

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