Replacing bleomycin with brentuximab vedotin (Adcetris) in the standard treatment regimen of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) significantly improved overall survival (OS) in untreated stage III/IV Hodgkin lymphoma, a researcher reported.
In an OS analysis of the phase III ECHELON-1 trial, treatment with brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) resulted in a 41% reduction in the risk of death versus standard ABVD (HR 0.59, 95% CI 0.396-0.879, P=0.009), reported John Radford, MD, of the University of Manchester in England.
At a median follow-up of 73 months, the estimated 6-year OS rates were 93.9% for A+AVD and 89.4% for ABVD, according to the findings presented at the European Hematology Association annual meeting.
“The ECHELON-1 study shows that A+AVD is the first regimen to show an improvement in a head-to-head comparison in terms of overall survival compared with six cycles of standard ABVD,” Radford said. “We believe A+AVD should be considered a preferred first-line treatment option for patients with previously untreated stage III or IV Hodgkin lymphoma.”
Analyses of ECHELON-1 after 5 years of follow-up demonstrated a progression-free survival (PFS) benefit with A+AVD over ABVD, which held up in the current analysis as well (6-year PFS rates of 82.3% vs 74.5%, respectivey; HR 0.68, 95% CI 0.53-0.86, P=0.002).
“That really has been very stable over the last several years,” Radford noted.
Brentuximab vedotin gained FDA approval in 2018 as treatment for adults with previously untreated stage III/IV classical Hodgkin lymphoma in combination with chemotherapy based on findings from the trial.
The OS benefit was generally consistent across prespecified subgroups, he explained, with significant benefit in the following:
- Stage IV at diagnosis: HR 0.478 (95% CI 0.286-0.799)
- PET-negative at cycle 2: HR 0.583 (95% CI 0.338-0.856)
- PET-positive at cycle 2: HR 0.163 (95% CI 0.037-0.717)
- From North America: HR 0.327 (95% CI 0.153-0.699)
Radford cautioned that none of these subgroups were powered to draw meaningful conclusions, however, but noted that the OS benefit with A+AVD “was preserved” in multivariable analysis that adjusted for baseline demographic and disease factors (HR 0.53, 95% CI 0.34-0.83).
A look at subsequent therapy among the study population showed that 20% of patients in the brentuximab vedotin arm had further treatment compared with 24% of patients in the bleomycin arm, and there was “substantial use of subsequent brentuximab vedotin in the ABVD arm,” Radford pointed out.
“So it would appear that using ABVD in combination with chemotherapy upfront is a more desirable option than using brentuximab vedotin in the setting of a salvage approach,” he observed.
As for long-term safety outcomes, the investigators found that fewer second malignancies were reported in the brentuximab vedotin arm (3.5% vs 4.8%). A greater number of female patients in the brentuximab vedotin group had pregnancies (49 vs 28) and live births (42 vs 19) compared to the bleomycin group, and there were no stillbirths reported during the study.
Incidence of peripheral neuropathy was higher in the brentuximab vedotin group at the completion of therapy (67% vs 43%) but neuropathy resolved or continued to improve in 86% and 87% of the two groups, respectively.
ECHELON-1 was conducted in 21 countries across six continents and randomized in 1,334 previously untreated adults with stage III/IV classical Hodgkin lymphoma 1:1 to either standard treatment of six cycles of ABVD or six cycles of A+AVD. Patients all had an ECOG performance status of ≤2 and underwent follow-up every 3 months for 36 months, then every 6 months until study closure. At the present analysis, there were 39 deaths in the A+AVD arm compared with 64 deaths in the ABVD arm.
The study was funded by Takeda and Seagen. Some co-authors are Takeda or Seagen employees.
Radford disclosed relationships with, and/or support from, Takeda, ADC Therapeutics, Kite Pharma, and AstraZeneca.
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