Brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (a regimen known as A+AVD) significantly reduced the risk of mortality vs standard treatment with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in patients with previously untreated stage III or IV classical Hodgkin lymphoma, according to 6-year follow-up of the phase III ECHELON-1 trial.1 The safety profiles of both regimens were generally comparable. However, over the long term, there were fewer second malignancies and more pregnancies and live births in patients treated with A+AVD compared with ABVD. These updated findings of ECHELON-1 were presented at the 2022 ASCO Annual Meeting by lead author Stephen Ansell, MD, PhD, Professor of Medicine, Mayo Clinic, Rochester, Minnesota.
Stephen Ansell, MD, PhD
At a median follow-up of 73 months, the estimated 6-year overall survival rate was 93.9% with A+AVD vs 89.4% with ABVD, representing a 41% reduction in the risk of death that was statistically significant (P = .009). Median overall survival was not yet reached in either arm.
“ABVD sets a high bar for the treatment of Hodgkin lymphoma. Several strategies have shown improvements in some areas, but none has shown a meaningful survival advantage against ABVD. Brentuximab vedotin plus AVD is the first regimen to show an improvement in overall survival compared with standard ABVD chemotherapy in patients with previously untreated, advanced-stage, classical Hodgkin lymphoma,” stated Dr. Ansell.
“Based on these data, showing a reduction in disease-related deaths and fewer second malignancies, AVD chemotherapy plus brentuximab vedotin should be considered a preferred first-line treatment in patients with previously untreated, advanced-stage classical Hodgkin lymphoma,” Dr. Ansell stated. The shift to A+AVD would represent a change in standard treatment.
The ECHELON-1 trial randomly assigned 1,334 patients in a 1:1 ratio to receive up to six cycles of A+AVD (n = 664) or ABVD (n = 670) intravenously on days 1 and 15 every 28 days.2 The key secondary endpoint was overall survival in the intent-to-treat population. Long-term follow-up assessments included progression-free survival per investigator, subsequent treatment use, and safety outcomes (including second malignancies, outcomes of pregnancy among patients and their partners, and peripheral neuropathy resolution and improvement rates).
At baseline, both treatment arms were well balanced for factors such as age, advanced stage, and poor prognosis. “About 15% of patients were older than 60, and they are typically not included in Hodgkin lymphoma trials,” Dr. Ansell said.
Many participants were male (n = 776; 58%), and the median patient age was 36 (range, 26–52 years). About two-thirds (64%) had stage IV disease at diagnosis; 53% had an International Prognostic Score of 2 or 3; and 87% had a negative interim PET scan. At the data cutoff of June 1, 2021, 39 and 64 overall survival events had been reported in the A+AVD and ABVD arms, respectively.
A consistent overall survival benefit was observed across prespecified subgroups for A+AVD compared with ABVD. Factors with the strongest association with overall survival included age < 45 years, non-White race, Eastern Cooperative Oncology Group performance status of 2, and a positive interim PET scan.
“Of note, men seemed to benefit from A+AVD more than women. This finding needs further comprehensive study,” said Dr. Ansell.
The estimated 6-year progression-free survival rate was 82.3% with A+AVD compared with 74.5% for ABVD, a 32% reduction in the risk of disease progression or death favoring the experimental arm (P = .002). A total of 112 and 159 progression-free survival events had occurred in the A+AVD and ABVD arms, respectively.
The use of at least one subsequent therapy was less common with A+AVD (20%) compared with ABVD (24%). The type of subsequent therapy in the A+AVD and ABVD arms included brentuximab vedotin or chemotherapy regimens (12% vs 16%, respectively), radiation therapy (8% in both arms; chemotherapy and radiation therapy in 1% of both arms), allogeneic transplantation (< 1% and 2%, respectively), and immunotherapy (3% vs 4%, respectively).
No new safety signals emerged during the study and follow-up. The safety profiles of both regimens were mainly similar.
Fewer disease-related or treatment-related deaths were reported with A+AVD (n = 39) compared with ABVD (n = 64). Deaths due to second malignancies were reported in 1 vs 11 patients, respectively. Second malignancies were found in 23 patients in the A+AVD arm compared with 32 patients in the ABVD arm. The number of solid tumors was similar in both arms, but hematologic malignancies were less common in the experimental arm (9 and 17, respectively). In the A+AVD arm, 19 patients had documented disease progression compared with 28 patients in the ABVD arm.
Pregnancy and peripheral neuropathy data were consistent with prior findings. More female patients in the A+AVD vs ABVD arms reported pregnancies (113 vs 78, respectively) and live births (56 and 23, respectively).
The 2-year incidence of peripheral neuropathy was 67% with A+AVD vs 43% with ABVD. At 6 years, treatment-emergent peripheral neuropathy continued to resolve or improve in both arms, with 86% and 87% of cases in the A+AVD and ABVD arms, respectively, completely or partially resolved by last follow-up. The median time to resolution of peripheral neuropathy was 16 and 10 weeks, respectively.
For more on the update from the ECHELON-1 trial of brentuximab vedotin plus chemotherapy for stage III or IV classical Hodgkin lymphoma, see an interview with Stephen M. Ansell, MD, PhD, on The ASCO Post Newsreels at ascopost.com/videos.
“A+AVD improved overall survival compared with ABVD despite the wide availability and use of active salvage treatment, including substantial use of subsequent brentuximab vedotin in the ABVD arm. The overall survival benefit with A+AVD was coupled with fewer second malignancies vs ABVD. The observed overall survival benefit with A+AVD, fewer disease-related deaths, and a concomitant reduction in disease progression suggest that A+AVD has potentially cured more patients of their disease,” Dr. Ansell stated.
DISCLOSURE: Dr. Ansell has received honoraria from Research to Practice and WebMD; and has received institutional research funding from Takeda, ADC Therapeutics, Affimed Therapeutics, AstraZeneca, Bristol Myers Squibb, Regeneron, and Seattle Genetics.
1. Ansell SM, Connors JM, Radford JA, et al: First-line brentuximab vedotin plus chemotherapy to improve overall survival in patients with stage III/IV classical Hodgkin lymphoma: An updated analysis of ECHELON-1. 2022 ASCO Annual Meeting. Abstract 7503. Presented June 3, 2022.
2. Straus DJ, Dlugosz-Danecka M, Connors JM, et al: 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. Lancet Haematol 8:e410-e421, 2021.
Alison Moskowitz, MD
The invited discussant of the ECHELON-1 trial, Alison Moskowitz, MD, Associate Attending Physician, Memorial Sloan Kettering Cancer Center, New York, commented: “In the past decade, three effective drugs for Hodgkin lymphoma have emerged—brentuximab vedotin, nivolumab,...