ECHELON-1 Analysis Shows Brentuximab Vedotin Activity in Nonpediatric AYA Hodgkin Lymphoma

Howland E. Crosswell, MD

Nonpediatric young adults with stage III/IV Hodgkin lymphoma had significantly better progression-free survival (PFS) when treated with brentuximab vedotin (Adcetris) and conventional chemotherapy compared with standard therapy, according to a subgroup analysis of the ECHELON-1 trial that was presented at the 2018 ASH Annual Meeting.¹

The addition of brentuximab vedotin to doxorubicin, vinblastine, and dacarbazine (A+AVD) was associated with 30% to 40% reductions in the PFS hazard ratio compared with patients treated with AVD plus bleomycin (ABVD). PFS improved significantly whether AYA was defined as age <39 or <30. Additionally, PFS improved whether defined conventionally or by a modified version (mPFS) consisting of disease progression, death, or receiving additional anticancer therapy.

“Adcetris has been approved for treatment of relapsed and refractory Hodgkin lymphoma for a number of years,” said lead study author Howland E. Crosswell, MD, pediatric and adolescent oncology-trained specialist, of Bon Secours Hematology and Oncology and St. Francis Health System, in a poster presentation of the data. “This is an analysis of the pivotal trial that led to the approval for first-line treatment. It’s one of the largest trials that included AYA patients. [This is an] international study that included not only academic centers, but community centers, as well.”

The subgroup analysis provided evidence of the generalizability of the findings to the broader population of patients with advanced Hodgkin lymphoma, he added.

The randomized, phase III ECHELON-1 trial compared A+AVD with AVBD in 1334 patients with patients with newly diagnosed advanced Hodgkin lymphoma. The overall trial results showed that treatment with A+AVD led to a 23% reduction in the risk of progression, death, or initiation of new therapy.²

Crosswell reported results of a post-hoc analysis of nonpediatric adolescent and young adult (AYA) patients enrolled in the trial. The primary objective was to determine whether younger patient subgroups have unique clinical outcomes and safety profiles compared with the overall population of patients treated with either regimen.

The subgroup analysis comprised 771 patients <40 years of age, a group that included 468 patients <30 and 255 patients <25. The age stratification reflected the varying definitions of AYA patients. The median follow-up in the subgroup was approximately 24 months, consistent with follow-up in the overall trial population.

Analysis of mPFS showed that A+AVD was associated with a 41.3% reduction in relative risk (P = .017) in patients younger than 30 and a 30.3% reduction in the under-40 group (P = .037). The hazard ratio decreased by 28% with A+AVD in the age group of 18 to 24 (P = NS), by 54% in the age group of 25 to 29 (95% CI, 0.24-0.88), 11% in the 30 to 39 group (NS), 18% in the 40-59 group (NS), and 27% in patients <60 (95% CI, 0.56-0.96).

Findings from an analysis of conventionally defined PFS was consistent with the results of the mPFS analysis, yielding a 33% reduction in the hazard for the patients <60 and reductions of 52% (25-29) to 26% (30-39). Statistically significant reductions were observed in the <60 age group and the 25 to 29 age group.

A multivariate analysis showed no association between patient age and treatment effect or the PFS hazard, Crosswell reported.

The incidence of treatment-emergent adverse events (TEAEs) in patients randomized to A+AVD or ABVD was similar across age groups and comparable with findings in the overall patient population. In particular, the incidence of pulmonary toxicity was low in the overall study population and in patients <30 (2%-3%) or <40 (~3%).

Across age groups, grade ≥3 adverse events (AEs) occurred more often with A+AVD (80%-85% vs 60%-70%), as did dose reductions (18%-23% vs 6%-7%), and dose delays (45%-48% vs 29%-32%). On-study and TEAE-related deaths were uncommon.

Peripheral neuropathy, an AE of interest, occurred in 64% of the A+AVD group and about 40% of patients treated with ABVD. This improved or resolved during the study in a majority of patients in both treatment groups and across all age groups.

Febrile neutropenia occurred in 16 patients of the A+AVD group and 5 patients of the ABVD group, declining to 9% and 5% in patients who received primary prophylaxis with G-CSF.

“Consistent with the overall trial results, this exploratory analysis demonstrated that adolescents and young adults receiving A+AVD had significantly improved modified PFS with manageable tolerability profile as compared with AYA patients receiving ABVD,” the investigators concluded. “A+AVD can be considered a treatment option for nonpediatric adolescents and young adult patients with advanced-stage classical Hodgkin lymphoma.

References

1. Crosswell HE, LaCasce AS, Bartlett NL, et al. Brentuximab vedotin with chemotherapy in adolescents and young adults (AYA) with stage III or IV Hodgkin lymphoma: a subgroup analysis from the phase 3 ECHELON-1 study. In: Proceedings from the 2018 ASH Annual Meeting; December 1-4, 2018; San Diego, California. Abstract 1647.
2. Connors J, Jurczak W, Straus D J., et al. Brentuximab vedotin plus doxorubicin, vinblastine, dacarbazine (A+AVD) as frontline therapy demonstrates superior modified progression-free survival versus ABVD in patients with previously untreated stage III or IV Hodgkin lymphoma (HL): the phase 3 echelon-1 study. Presented at: ASH Annual Meeting and Exposition; December 9-12, 2017; Atlanta. Abstract 6.