David J Straus1, Monika Długosz-Danecka2, Joseph M Connors3, Sergey Alekseev4, Árpád Illés5, Marco Picardi6, Ewa Lech-Maranda7, Tatyana Feldman8, Piotr Smolewski9, Kerry J Savage3, Nancy L Bartlett10, Jan Walewski11, Radhakrishnan Ramchandren12, Pier Luigi Zinzani13, Martin Hutchings14, Javier Munoz15, Hun Ju Lee16, Won Seog Kim17, Ranjana Advani18, Stephen M Ansell19, Anas Younes20, Andrea Gallamini21, Rachael Liu22, Meredith Little22, Keenan Fenton23, Michelle Fanale23, John Radford24. 1. Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: strausd@mskcc.org. 2. Department of Clinical Oncology, Maria Skłodowska-Curie National Research Institute of Oncology, Kraków, Poland. 3. Centre for Lymphoid Cancer and Department of Medical Oncology, BC Cancer, Vancouver, BC, Canada. 4. Petrov Research Institute of Oncology, St Petersburg, Russia. 5. University of Debrecen, Debrecen, Hungary. 6. Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy. 7. Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland. 8. John Theurer Cancer Center, Hackensack Meridian Health School of Medicine, Hackensack, NJ, USA. 9. Medical University of Lodz, Poland. 10. Washington University School of Medicine Siteman Cancer Center, St Louis, MO, USA. 11. Maria Sklodowska-Curie National Research Institute of Oncology, European Reference Network, Warszawa, Poland. 12. The University of Tennessee Graduate School of Medicine, Knoxville, TN, USA. 13. IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia Seràgnoli, Bologna, Italy; Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università degli Studi, Bologna, Italy. 14. Department of Haematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. 15. Banner MD Anderson Cancer Center, Gilbert, AZ, USA. 16. University of Texas MD Anderson Cancer Center, Houston, TX, USA. 17. Division of Hematology-Oncology, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. 18. Department of Medicine, Division of Oncology, Stanford University, Stanford, CA, USA. 19. Division of Hematology, Mayo Clinic, Rochester, MN, USA. 20. Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; AstraZeneca Pharmaceuticals, LP Wilmington, DE, USA. 21. Research Innovation and Statistics, Antoine-Lacassagne Cancer Centre, Nice, France. 22. Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceuticals, Cambridge, MA, USA. 23. Seagen, Bothell, WA, USA. 24. University of Manchester and the Christie NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
Abstract
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/m2 of body surface area, vinblastine 6 mg/m2, and dacarbazine 375 mg/m2) or ABVD (doxorubicin 25 mg/m2, bleomycin 10 U/m2, vinblastine 6 mg/m2, and dacarbazine 375 mg/m2) 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.
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/m2 of body surface area, vinblastine 6 mg/m2, and dacarbazine 375 mg/m2) or ABVD (doxorubicin 25 mg/m2, bleomycin 10 U/m2, vinblastine 6 mg/m2, and dacarbazine 375 mg/m2) 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.
Authors: Andrew M Evens; Joseph M Connors; Anas Younes; Stephen M Ansell; Won Seog Kim; John Radford; Tatyana Feldman; Joseph Tuscano; Kerry J Savage; Yasuhiro Oki; Andrew Grigg; Christopher Pocock; Monika Dlugosz-Danecka; Keenan Fenton; Andres Forero-Torres; Rachael Liu; Hina Jolin; Ashish Gautam; Andrea Gallamini Journal: Haematologica Date: 2022-05-01 Impact factor: 11.047