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The phase III ECHELON-1 study in Hodgkin lymphoma compared the use of A+AVD with standard chemotherapy of doxorubicin, bleomycin, vinblastine, and dacarbazine.
Joseph M. Connors, MD
Patients with advanced-stage Hodgkin lymphoma (HL) saw a 23% risk reduction in progression, death, or need for additional therapy with the use of brentuximab vedotin (Adcetris) plus doxorubicin, vinblastine, dacarbazine (A+AVD) as frontline therapy.
The phase III ECHELON-1 study compared the use of A+AVD with standard chemotherapy of doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine (ABVD).
The results were presented at the 2017 ASH Annual Meeting and simultaneously published online in the New England Journal of Medicine.
“The study results represent the first successful effort in more than 30 years to improve outcomes of first-line treatment in patients with advanced HL without escalating the toxicity of the chemotherapy to unacceptable levels,” said Joseph M. Connors, MD, clinical director of the British Columbia Cancer Agency Centre for Lymphoid Cancer in Vancouver, Canada, and lead author on the study.
The study, conducted at 218 sites in 21 countries around the world, enrolled 1334 patients with stage III or IV HL, who had no prior therapy and an ECOG performance score of 2 or less. Patients ranged in age from 18-83, the median age was 36 years, and 58% were men.
Patients were randomly assigned 1:1 to receive A+AVD (brentuximab vedotin 1.2 mg/kg, doxorubicin 25 mg/m2, vinblastine 6 mg/m2, dacarbazine 375 mg/m2) or ABVD (doxorubicin 25 mg/m2, bleomycin 10 units/m2, vinblastine 6 mg/m2, dacarbazine 375 mg/m2) IV on days 1 and 15 of up to 6 28-day cycles. Patients were followed-up every 3 months for 36 months, then every 6 months until the closure of the study.
At the end of chemotherapy patients were reassessed with CT and PET scanning, and then followed for the success of the treatment.
“The unique aspect of HL is that you can get an early look at how well the treatment is working after 2 cycles when a PET scan can be performed,” said Connors.
The primary endpoint was modified progression-free survival (PFS)—defined as time to progression, death, or evidence of incomplete response followed by subsequent anticancer therapy, and determined by an independent review facility assessment.
PFS was met with 117 events in the A+AVD arm and 146 events in the AVBD arm. Modified PFS events were attributed to disease progression (90 vs 102); death (18 vs 22) or receipt of additional anticancer therapy for incomplete response (chemotherapy: 7 vs 15; radiotherapy: 2 vs 7). At a median follow-up of 24.9 months, the 2‑year modified PFS was 82.1% (95% CI 78.7—85.0) with A+AVD compared with 77.2% (95% CI 73.7–80.4) with ABVD.
“The difference in the 2 outcomes at the 2-year mark is just shy of 5% and documents that about a quarter of patients that otherwise would have had a failure of their primary therapy were successfully treated with the new combination further reducing the likelihood that patients would experience eventual progression of treatment refractory disease,” said Connors.
In addition, researchers found that 33% fewer patients treated with the A+AVD regimen received subsequent chemotherapy or high-dose chemotherapy and transplant compared with the patients treated with ABVD.
Safety profiles were consistent with known toxicities of the single agents, according to Connors. Grade ≥3 infections were more common in the A+AVD arm (18%) than the ABVD arm (10%).
Neutropenia was reported in 58% of patients who received A+AVD compared with 45% who received ABVD. In the A+AVD arm, the rate of febrile neutropenia was lower among the 83 patients who received primary prophylaxis with granulocyte colony-stimulating factor (GCSF) than among those who did not (11% vs 21%).
Peripheral neuropathy occurred in 67% of patients receiving A+AVD and 43% receiving ABVD.
“The good news is that over time this side effect resolves and, with appropriate reduction in dose or change in scheduling, the majority of patients recover from the peripheral neuropathy,” said Connors. Researchers also found that interstitial lung disease occurred more frequently and severely in patients receiving AVBD (Grade ≥3, 3% ABVD vs <1% A+AVD).
There were 28 deaths in the A+AVD arm and 39 in the ABVD arm (hazard ratio [HR] for interim overall survival, 0.72 [95% CI, 0.44-1.17]; P = 0.19). Among the deaths that occurred during treatment, 7 of 9 in the A+AVD group were associated with neutropenia and 11 of 13 in the ABVD group were associated with pulmonary-related toxicity.
The FDA granted a breakthrough therapy designation for brentuximab vedotin in combination with chemotherapy for frontline advanced classical Hodgkin lymphoma in October 2017.
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; Dec. 9-12, 2017; Atlanta. Abstract 6.