Updated results from the ECHELON-1 clinical trial showed that the combination of brentuximab vedotin (Adcetris; BV) plus doxorubicin, vinblastine, and dacarbazine (AVD) as first-line therapy improves overall survival (OS) in patients with stage III-IV classical Hodgkin lymphoma compared with standard therapy with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). “It is a great honor and privilege to present updated results that are quite remarkable in untreated, advanced stage lymphoma,” said David J. Straus, MD, Attending Physician, Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, speaking at the 2022 National Comprehensive Cancer Network Annual Congress: Hematologic Malignancies.
“BV plus AVD is the first regimen to show an improvement in OS versus classical [ABVD] in patients with previously untreated advanced classical Hodgkin lymphoma. The OS benefit was coupled with fewer second malignancies and fewer deaths versus [standard] ABVD. The observed OS benefit with BV plus AVD, fewer disease-related deaths, and a concomitant reduction in disease progression, suggest that BV plus AVD has potentially cured more patients of their disease. Based on these data, BV plus AVD should be considered a first-line treatment option for patients with previously untreated stage III or IV classical Hodgkin lymphoma,” Dr Straus stated.
Over the past few years, 3 new drugs have shifted the treatment paradigm for patients with Hodgkin lymphoma: BV (an antibody–drug conjugate), and 2 checkpoint inhibitors: nivolumab (Opdivo) and pembrolizumab (Keytruda).
“These three agents have activity roughly twice that of conventional chemotherapy and were speedily approved in the relapsed/refractory setting,” he explained.
The antibody–drug conjugate BV is targeted to CD30 and linked to a potent tubulin inhibitor. The drug attaches to CD30 on Hodgkin cells and delivers the potent chemotherapy payload to the cell nucleus, disrupting tubulin function and synthesis.
ECHELON-1 Study Details
The large global ECHELON-1 trial compared 6 cycles of BV plus AVD versus 6 cycles of BV plus ABVD in more than 13,000 patients with stage III-IV classical Hodgkin lymphoma.
“This is one of the largest trials comparing a new therapy to ABVD, the standard of care,” Dr Straus told attendees.
2- and 5-Year Improvements
At 2 years, the difference in modified progression-free survival (PFS) favored the experimental arm. With further 5 years of follow-up, the difference in this primary end point was sustained and even slightly greater at 5 years than at 2 years—an absolute difference of approximately 7%.1
Moreover, OS also favored the experimental arm. BV plus AVD reduced the incidence of death or progression by 32% compared with BV plus ABVD. The 6-year estimated PFS was 82.3% for the experimental arm versus 74.5% with standard of care.
“What was quite remarkable was that for the first time, a randomized trial in newly diagnosed Hodgkin lymphoma demonstrated improved survival that was significantly superior,” Dr Straus said.
Six-year survival rates were 93.9% and 86%, respectively, for an absolute difference of 4.5% favoring BV plus AVD with a 41% decrease in risk for death (P = .009).
“I want to emphasize that this is not just PFS in Hodgkin lymphoma—this is actual deaths. The benefits of BV plus AVD for PFS and OS were generally favorable for all prognostic groups, except in those over age 60, where both arms were similar. However, I think BV plus AVD can still be considered for this age group, since age is a risk factor for bleomycin toxicity,” Dr Straus said.
There were 39 deaths in the BV plus AVD arm versus 64 for BV plus ABVD, with most deaths due to Hodgkin lymphoma or were treatment related.
Second Malignancies and Peripheral Neuropathy
BV plus AVD was associated with fewer second malignancies compared with standard of care (32 vs 45, respectively). One death due to second malignancies was reported in the BV plus AVD arm versus 11 in the standard arm. More hematologic cancers were observed in the ABVD arm: 9% for BV plus AVD versus 17% for BV plus ABVD. The percentage of solid tumors was 14% in both arms.
“It appears that decreased fertility and pregnancy problems were less frequent with BV plus AVD than BV plus ABVD,” Dr Straus commented.
Notably, interim positron emission tomography (PET) scan performed in the study did not lead to treatment changes.
“Although interim PET was performed in the study, and PFS was inferior for PET-positive patients, only about one third [of them] relapsed. This is the same result as a PET-guided risk-adapted trial where you can change to a more intensive regimen for PET-positive patients. For that reason, we have given up interim PET when we use BV plus AVD. This simplifies treatment and reduces anxiety for patients,” Dr Straus explained. “It also avoids the complexity of variable institutions doing PET in the real world,” he added.
- Straus DJ, Długosz-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. 2021;8:e410-e421.