preheader BJH 1

header website

Subgroup and sensitivity analyses of ECHELON-1 evaluating brentuximab vedotin + AVD vs. ABVD in the frontline management of advanced classical Hodgkin lymphoma

Chemotherapy with doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine (ABVD) is the current standard of care in the first-line treatment of patients with advanced stage Hodgkin lymphoma (HL). Last year, this standard was challenged by the results of the phase III ECHELON-1 trial, demonstrating a 23% reduction in the risk of progression, death, or need for additional anticancer therapy with a combination of brentuximab vedotin (Adcetris) plus doxorubicin, vinblastine, dacarbazine (A+AVD) compared to ABVD.1 During the 2018 annual meeting of the American Society of Hematology (ASH), subgroup analyses of this study were presented focusing on elderly and adolescent patients.2,3 In addition, a traditional progression-free survival (PFS) assessment of this trial, including only progression or death as relevant events, demonstrated that A+AVD resulted in a 30% reduction in the risk of progression or death compared to ABVD.4

In ECHELON-1, 1,334 patients with stage III (36%) or IV (64%) cHL were randomized (1:1) to receive A+AVD (N=664) or ABVD (N=670) on days 1 and 15, for up to six 28-day cycles. The primary endpoint of ECHELON-1 was modified PFS (mPFS), defined as the time until progressive disease, death, or subsequent anticancer therapy following detection of a non-complete response at the end of frontline therapy. As indicated before, A+AVD proved to be superior to ABVD for this endpoint with a hazard ratio (HR) of 0.77 and 2-year mPFS rates of 82.1% and 77.2% with A+AVD and ABVD, respectively. The choice for this endpoint instead of traditional PFS is based on the fact that cHL patients who do not achieve a satisfactory response to frontline therapy may initiate subsequent anticancer therapy prior to response criteria-defined progression. As a result, the measurement of traditional PFS becomes confounded, as patients may effectively be rescued from criteria-defined progression by subsequent treatment, resulting in an overestimation of PFS with frontline therapy.

During ASH 2018, Connors et al. presented the results of additional analyses conducted to examine how the inclusion of subsequent therapy as modified events affected the efficacy outcomes in ECHELON-1. These supportive analyses demonstrate a benefit in favor of A+AVD over ABVD consistent with the primary outcome of ECHELON-1. A+AVD had superior efficacy to ABVD in the treatment of patients with advanced stage cHL, with a lower combined risk of progression, death, or non-complete response and use of subsequent anticancer therapy when assessed by investigator (HR: 0.72; p=0.006), with 2-year mPFS rates of 81.0% vs. 74.4%. This benefit was maintained regardless of the inclusion or exclusion of modified events. In fact, the assessment of PFS including the use of chemotherapy, but not radiotherapy, in patients without CR at end of therapy as an event also demonstrated superiority of A+AVD compared to ABVD (HR: 0.69; p=0.003), with 2-year rates of 84.0% and 77.3% for A+AVD and ABVD, respectively. Finally, the assessment of PFS, including only progression and death as events, demonstrated superiority of A+AVD compared to ABVD (HR: 0.70; p:0.006) with 2-year rates of 84.2% vs. 78.0%. With a longer follow-up (median of approximately 37 months), the PFS benefit for A+AVD as compared with ABVD was maintained (HR: 0.70; p=0.005), with a 7.1% point difference in 3-year PFS estimates (83.1% vs. 76.0%).4

Survival rates for older patients with advanced HL (aged ≥60 years) are historically poor with ABVD, mainly due to decreased treatment tolerability and the presence of comorbidities. To assess the performance of A+AVD in elderly patients, Evens et al. evaluated the efficacy and safety results from ECHELON-1 for older patients with cHL and compared them with those for patients aged <60 years.2 In total, 14% (186/1,334) of patients in the ECHELON-1 population were aged ≥60 years and were included in this analysis. Among older patients (≥60 years) in ECHELON-1, mPFS findings were comparable for A+AVD and ABVD (2-year mPFS: 70.3% vs. 71.4%; HR[95%CI]: 1.00[0.58-1.172]). In contrast, patients younger than 60 years did have a significantly better mPFS with A+AVD compared to ABVD (2-year PFS: 83.7% vs. 78.2%; HR[95%CI]: 0.73[0.56-0.96]; p=0.025).2 Not surprisingly, older patients in the ECHELON-1 study exhibited a higher incidence of treatment-emergent adverse events (AEs) than the younger patient group (grade 3/4 toxicity with A+AVD 88% in older patients vs. 82% in younger patients; 80% vs. 63% with ABVD). The incidence of pulmonary toxicities was lower in the A+AVD arm compared with the ABVD arm, both in older (2% vs. 13%) and younger patients (2% vs. 6%). The use of G-CSF primary prophylaxis was not mandated on study. However, the high incidence of febrile neutropenia in older patients treated with A+AVD (37%) indicates that G-CSF primary prophylaxis is warranted. Within each arm, the rates of any-grade peripheral neuropathy (PN) were similar between older and younger patients (65% vs. 67%). However, the incidence of grade 3/4 PN was higher in older patients treated with A+AVD (18% vs. 9%). As such, all patients should be monitored for PN and these events should be managed appropriately.

A third ECHELON-1 abstract at ASH 2018 looked at the other end of the age spectrum and assessed whether adolescents and young adults (AYA) have a unique response outcome and safety profile in both treatment arms of the study.3 The AYA population consisted of 771 patients comprising 57.8% of the total trial population. This cohort was comprised of 255 patients in the aged <25 years group, 468 patients in the aged <30 years group, and 771 patients in the aged <40 years group. This included 213 patients aged 25 years to 29 years and 303 patients aged 30 years to 39 years. AYA patients receiving A+AVD had an improved overall mPFS compared with patients receiving ABVD (≤39 years of age, HR[95%CI]: 0.697 [0.495-0.980]; <30 years of age, HR[95%CI]: 0.587 [0.376-0.916]). The 2-year mPFS rate for patients ≤39 years who received A+AVD was 84.6% as compared to 78.6% for those who received ABVD. Patients aged <30 years receiving A+AVD also had an improved 2-year mPFS rate compared with patients receiving ABVD (86.7% vs. 74.4% respectively). The rate of treatment-emergent AEs in patients receiving A+AVD or ABVD was similar across age groups and reflected that of the overall trial population.3



1. Connors JM, Jurczak W, Straus DJ, et al. Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin's lymphoma. N Engl J Med 2018;378:331-344.
2. Evens A, et al. Older patients (pts) with previously untreated classical hodgkin lymphoma (cHL): a detailed analysis from the phase 3 ECHELON-1 study. Presented at ASH 2018; Abstract 1618.
3. Crosswel A, et al. Brentuximab vedotin with chemotherapy in adolescents and young adults (AYA) with stage III or IV HodgkinlLymphoma: a subgroup analysis from the phase 3 Echelon-1 study. Presented at ASH 2018; Abstract 1647.
4. Connors J, et al. Brentuximab vedotin plus chemotherapy in patients with advanced-stage classical hodgkin lymphoma (cHL): evaluation of modified progression-free survival (mPFS) and traditional PFS in the phase 3 ECHELON-1 study. Presented at ASH 2018; Abstract 2904.

Speaker Joseph Connors


Joseph Connors, MD, British Columbia Cancer Centre for Lymphoid Cancer, Vancouver, BC, Canada


See: Keyslides


Back to Top