Brentuximab Vedotin with Chemotherapy for CD30-Positive Peripheral T-cell Lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial.

By S. Horwitz, O. O'Connor, B. Pro, T. Illidge, M. Fanale, R. Advani, N. Bartlett, J. Christensen, F. Morschhauser, E. Domingo-Domènech and 137 more. The Lancet, 2018

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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 (PTCL). Methods ECHELON-2 (ClinicalTrials.gov No. NCT01777152) is a double-blind, double-dummy, randomised, placebo-controlled, active-comparator phase 3 study. Eligible adults with previously-untreated CD30-positive PTCL (targeting 75% with systemic anaplastic large cell lymphoma [sALCL]) were randomised 1:1 to receive either A+CHP or CHOP for six or eight 21-day cycles. All subjects received cyclophosphamide 750 mg/m2 and doxorubicin 50 mg/m2 on Day 1 of each cycle intravenously (IV) and prednisone 100 mg daily on Days 1 to 5 of each cycle orally, followed by either brentuximab vedotin 1·8 mg/kg and placebo form of vincristine on Day 1 of each cycle IV (A+CHP arm) or vincristine 1·4 mg/m2 and placebo form of brentuximab vedotin IV (CHOP arm). Randomization was stratified by histological subtype as per local pathology assessment and by international prognostic index (IPI) score. The primary endpoint, progression-free survival (PFS) per blinded independent central review, was analysed by the intent-to-treat. Findings A total of 452 subjects were enrolled between January 24, 2013 and November 07, 2016 and 226 subjects were randomly assigned to each arm. The hazard ratios of both the PFS (0·71 [95% CI: 0·54, 0·93], p=0·0110) and overall survival (OS) (0·66 [95% confidence interval {CI}: 0·46, 0·95], p=0·0244) favoured A+CHP over CHOP. The median PFS was 48·2 months (95% CI: 35·2, not evaluable) versus 20·8 months (95% CI: 12·7, 47·6), for A+CHP and CHOP, respectively. The median was not met for OS. Adverse events (AEs), including incidence and severity of febrile neutropenia (in 41 subjects (18%) in A+CHP arm and 33 (15%) in CHOP) and peripheral neuropathy (in 117 subjects (52%) in A+CHP arm and 124 (55%) in CHOP), were similar between arms. Fatal AEs occurred in 7 subjects (3%) in the A+CHP arm and 9 subjects (4%) in the CHOP arm. Interpretation Frontline treatment with A+CHP is superior to CHOP for subjects with CD30-positive PTCL as demonstrated by a statistically significant improvement in PFS and OS with a manageable safety profile. Funding Supported by Seattle Genetics, Inc. and Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. This research was funded in part through the National Institutes of Health/National Cancer Institute Cancer Center Support Grant P30 CA008748.

Subfields: Dermatology, Oncology, Pathology and Forensic Medicine

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