Brentuximab vedotin with chemotherapy for stage III or IV classical Hodgkin lymphoma (ECHELON-1): 5-year update of an international, open-label, randomised, phase 3 trial.

Background: Despite advances in the treatment of Hodgkin lymphoma with the introduction of PET-adapted regimens, practical challenges prevent more widespread use of these approaches. The ECHELON-1 study assessed the safety and efficacy of front-line A+AVD (brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine) versus ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) in patients with stage III or IV classical Hodgkin lymphoma. The primary analysis showed improved modified progression-free survival with A+AVD. We present an updated analysis of ECHELON-1 at 5 years, an important landmark for this patient population.
Methods: ECHELON-1 was an international, open-label, randomised, phase 3 trial done at 218 clinical sites, including hospitals, cancer centres, and community clinics, in 21 countries. Previously untreated patients (≥18 years with an Eastern Cooperative Oncology Group performance status of ≤2) with stage III or IV classical Hodgkin lymphoma were randomly assigned (1:1) to receive A+AVD (brentuximab vedotin, 1·2 mg/kg of bodyweight, doxorubicin 25 mg/m ² of body surface area, vinblastine 6 mg/m ² , and dacarbazine 375 mg/m ² ) or ABVD (doxorubicin 25 mg/m ² , bleomycin 10 U/m ² , vinblastine 6 mg/m ² , and dacarbazine 375 mg/m ² ) intravenously on days 1 and 15 of each 28-day cycle for up to six cycles. Stratification factors included region (Americas vs Europe vs Asia) and International Prognostic Score risk group (low, intermediate, or high risk). The primary endpoint was modified progression-free survival; this 5-year update includes analysis of progression-free survival as per investigator assessment in the intention-to-treat population, which was an exploratory endpoint, although the 5-year analysis was not prespecified in the protocol. This trial is registered with ClinicalTrials.gov (NCT01712490) and EudraCT (2011-005450-60), and is ongoing.
Findings: Between Nov 19, 2012, and Jan 13, 2016, 1334 patients were randomly assigned to receive A+AVD (n=664) or ABVD (n=670). At a median follow-up of 60·9 months (IQR 52·2-67·3), 5-year progression-free survival was 82·2% (95% CI 79·0-85·0) with A+AVD and 75·3% (71·7-78·5) with ABVD (hazard ratio [HR] 0·68 [95% CI 0·53-0·87]; p=0·0017). Among PET-2-negative patients, 5-year progression-free survival was higher with A+AVD than with ABVD (84·9% [95% CI 81·7-87·6] vs 78·9% [75·2-82·1]; HR 0·66 [95% CI 0·50-0·88]; p=0·0035). 5-year progression-free survival for PET-2-positive patients was 60·6% (95% CI 45·0-73·1) with A+AVD versus 45·9% (32·7-58·2) with ABVD (HR 0·70 [95% CI 0·39-1·26]; p=0·23). Peripheral neuropathy continued to improve or resolve over time with both A+AVD (375 [85%] of 443 patients) and ABVD (245 [86%] of 286 patients); more patients had ongoing peripheral neuropathy in the A+AVD group (127 [19%] of 662) than in the ABVD group (59 [9%] of 659). Fewer secondary malignancies were reported with A+AVD (19 [3%] of 662) than with ABVD (29 [4%] of 659). More livebirths were reported in the A+AVD group (n=75) than in the ABVD group (n=50).
Interpretation: With 5 years of follow-up, A+AVD showed robust and durable improvement in progression-free survival versus ABVD, regardless of PET-2 status, and a consistent safety profile. On the basis of these findings, A+AVD should be preferred over ABVD for patients with previously untreated stage III or IV classical Hodgkin lymphoma.
Funding: Millennium Pharmaceuticals (a wholly owned subsidiary of Takeda Pharmaceutical Company), and Seagen.
Competing Interests: Declaration of interests DJS reports personal fees from Seagen and Takeda during the conduct of the study; and personal fees from Seagen and Takeda outside the submitted work. MD-D reports personal fees from Takeda during the conduct of the study; and personal fees from Janssen, AbbVie, Roche, and Servier outside the submitted work. JMC reports grants from Takeda and personal fees from Seagen during the conduct of the study. EL-M reports advisory board membership with Amgen, AbbVie, Astellas, Roche, Novartis, Janssen-Cilag, Sanofi, and Gilead outside the submitted work. TF reports personal fees from Seagen, Bristol Myers Squibb, Celgene, Karyopharm, AbbVie, Daiichi, Pharmacyclics, Janssen, Kite Pharma, and Takeda outside the submitted work. PS reports personal fees from Takeda during the conduct of the study; and personal fees from Roche Poland outside the submitted work. KJS reports honoraria from and consulting with Seagen during the conduct of the study; honoraria, research funding, and consulting with Bristol Myers Squibb; honoraria and consulting with Merck; honoraria and consulting with AbbVie; honoraria and consulting with Gilead; honoraria and consulting with AstraZeneca; honoraria and consulting with Novartis; and steering committee membership for Beigene outside the submitted work. NLB reports research funding from ADC Therapeutics, Affimed, Autolus, Bristol Myers Squibb, Celgene, Forty Seven, Gilead, Immune Design, Janssen, Kite Pharma, Merck, Millennium, Pfizer, Pharmacyclics, Roche–Genentech, and Seagen; advisory board membership for Roche–Genentech, Seagen, BTG, ADC Therapeutics, and Acerta outside the submitted work. JW reports grants and personal fees from Seagen during the conduct of the study; grants and personal fees from GSK–Novartis and Roche, personal fees from AbbVie, Amgen, Bristol Myers Squibb, Celgene, Gilead, Janssen-Cilag, Servier, and Takeda outside the submitted work. RR reports personal fees from Seagen during the conduct of the study; advisory board membership for and consultancy fees from Bristol Myers Squibb, and research funding from Merck outside the submitted work. PLZ reports personal fees from AbbVie, Gilead, Eusapharma, Merck, Roche, Takeda, Kyowa Kirin, Janssen, and TG Therapeutics outside the submitted work. MH reports research funding from Takeda during the conduct of the study. JM reports personal fees and research funding from Pharmacyclics, Bayer, Gilead-Kite Pharma, Janssen, and Seagen; personal fees from Pfizer, Juno-Celgene, Bristol Myers Squibb, Kyowa, Alexion, Beigene, Fosunkite, Innovent, Pharmacyclics-Janssen, Acrotech-Aurobindo, Verastem, AstraZeneca, Genentech-Roche, and AbbVie; and research funding from Celgene, Merck, Portola, Incyte, Genentech, Millenium outside of the submitted work. HJL reports research funding from Bristol Myers Squibb–Celgene, Takeda, Seagen, Janssen, Merck, Oncternal, and Onyx during the conduct of the study; advisory board membership for Kite and Bristol Myers Squibb; and honoraria from Aptitude Health, Pharmacyclics, Cancer Experts, and Guidepoint. WSK reports research funding from Roche, Johnson & Johnson, Takeda, Kyowa-Kirin, Donga, Celltrion, and Pfizer. RA reports grants from Merck, Millenium, and Seagen; personal fees from Merck, ADC Therapeutics, Takeda, Bristol Myers Squibb–Celgene, and Seagen during the conduct of the study; grants from Agensys, Celgene, Forty Seven–Gilead, Genentech–Roche, Infinity, Janssen Pharmaceutical, Kura, Pharmacyclics, Regeneron, and Cyteir Therapeutics; personal fees from Kura, Karyopharm, Takeda, BeiGene, AstraZeneca, Bayer Healthcare Pharmaceuticals, Cell Medica, and Celgene outside the submitted work. SMA reports research funding from Takeda and Seagen during the conduct of the study; and research funding from Affimed, ADC Therapeutics, Regeneron, Trillium, and AI Therapeutics outside the submitted work. AY reports personal fees from Bayer, Bristol Myers Squibb, Celgene, Genentech, Incyte, Janssen, Merck, Millennium, Sanofi, Seagen, and Takeda; employment with AstraZeneca; and research funding from Bristol Myers Squibb, Curis, Johnson & Johnson, Novartis, and Roche outside the submitted work. AG reports personal fees from A Lacassagne Cancer Center during the conduct of the study; and personal fees from Takeda and Roche outside the submitted work. RL reports employment with Takeda during the conduct of the study. ML reports employment with Takeda during the conduct of the study, and employment with Agios Pharmaceuticals outside the submitted work. KF and MF report employment with and equity ownership of Seagen. JR reports personal fees and grants from Takeda during the conduct of the study, and equity ownership of ADC Therapeutics and AstraZeneca outside the submitted work. All other authors declare no competing interests.
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