Photo courtesy of ASH
Joseph M. Connors, MD
ATLANTA—Phase 3 trial results suggest one 4-drug combination may be more effective than another as frontline treatment for advanced Hodgkin lymphoma (HL).
In the ECHELON-1 trial, treatment with brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) staved off progression, death, and the need for subsequent therapy more effectively than treatment with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD).
However, there was no significant difference between the treatment arms when it came to response rates or overall survival.
Neutropenia, febrile neutropenia, and peripheral neuropathy were more common with A+AVD, while pulmonary toxicity was more common with ABVD.
These data were presented at the 2017 ASH Annual Meeting (abstract 6) and simultaneously published in The New England Journal of Medicine. The trial was funded by Millennium Pharmaceuticals and Seattle Genetics, Inc.
“The standard of care in the treatment of Hodgkin lymphoma has not changed over the last several decades, and there remains an unmet need for additional regimens in frontline treatment,” said Joseph M. Connors, MD, of BC Cancer in Vancouver, British Columbia, Canada.
With this in mind, he and his colleagues conducted ECHELON-1. The study enrolled 1334 patients who had stage III or IV HL and had not previously received systemic chemotherapy or radiotherapy.
Fifty-eight percent of patients were male, and the median age was 36 (range, 18-83). Sixty-four percent of patients had stage IV disease, 62% had extranodal involvement at diagnosis, and 58% had B symptoms.
The patients were randomized to receive A+AVD (n=664) or ABVD (n=670) on days 1 and 15 of each 28-day cycle for up to 6 cycles. Baseline characteristics were well-balanced between the treatment arms.
The median follow-up was 24.9 months (range, 0-49.3).
Primary endpoint
The study’s primary endpoint is modified progression-free survival (PFS), which is defined as time to progression, death, or evidence of non-complete response after completion of frontline therapy followed by subsequent anticancer therapy.
According to an independent review facility, A+AVD provided a significant improvement in modified PFS compared to ABVD. The hazard ratio was 0.77 (P=0.035), which corresponds to a 23% reduction in the risk of progression, death, or the need for additional anticancer therapy.
“Reducing the risk of relapse is an important concern for patients and their physicians,” Dr Connors noted. “In the trial, 33% fewer patients [in the A+AVD arm] required subsequent salvage chemotherapy or high-dose chemotherapy and transplant compared to the patients treated with ABVD.”
According to the independent review facility, the 2-year modified PFS rate was 82.1% in the A+AVD arm and 77.2% in the ABVD arm.
Certain pre-specified subgroups of patients appeared to benefit more with A+AVD than with ABVD, including:
- Males
- Patients treated in North America
- Patients with involvement of more than 1 extranodal site
- Patients with International Prognostic Scores of 4 to 7
- Patients with stage IV disease
- Patients younger than 60.
Secondary endpoints
Secondary endpoints trended in favor of the A+AVD arm, although there were no significant differences between the treatment arms.
The objective response rate at the end of the randomized regimen was 86% in the A+AVD arm and 83% in the ABVD arm (P=0.12). The complete response rate was 73% and 70%, respectively (P=0.22).
The proportion of patients with a Deauville score ≤2 after the completion of frontline therapy was 85% in the A+AVD arm and 80% in the ABVD arm (P=0.03).
The interim 2-year overall survival rate was 97% in the A+AVD arm and 95% in the ABVD arm (hazard ratio=0.72; P=0.19).
Safety
“[T]he safety profile [of A+AVD] was generally consistent with that known for the single-agent components of the regimen,” Dr Connors said.
The overall incidence of adverse events (AEs) was 99% in the A+AVD arm and 98% in the ABVD arm. The incidence of grade 3 or higher AEs was 83% and 66%, respectively, and the incidence of serious AEs was 43% and 27%, respectively.
Common AEs (in the A+AVD and ABVD arms, respectively) included neutropenia (58% and 45%), constipation (42% and 37%), vomiting (33% and 28%), fatigue (both 32%), diarrhea (27% and 18%), pyrexia (27% and 22%), abdominal pain (21% and 10%), and stomatitis (21% and 16%).
Peripheral neuropathy events were observed in 67% of patients in the A+AVD arm and 43% in the ABVD arm. Grade 3 or higher peripheral neuropathy was reported in 11% and 2%, respectively.
Febrile neutropenia occurred in 19% of patients in the A+AVD arm and 8% of those in the ABVD arm. However, prophylaxis with granulocyte colony-stimulating factor (G-CSF) was able to reduce the incidence of febrile neutropenia. In the A+AVD arm, the rate of febrile neutropenia was 11% among patients who received G-CSF and 21% among patients who did not.
Pulmonary toxicity occurred in 2% of patients in the A+AVD arm and 7% of those in the ABVD arm. Grade 3 or higher pulmonary toxicity was reported in 0.76% and 3%, respectively.
There were 9 deaths during treatment in the A+AVD arm. Seven were due to neutropenia or associated complications, and 2 were due to myocardial infarction. One of the patients who died of neutropenia had the condition prior to trial enrollment. The remaining 6 patients did not receive G-CSF prophylaxis.
In the ABVD arm, there were 13 deaths during treatment. Eleven were due to or associated with pulmonary-related toxicity, 1 was due to cardiopulmonary failure, and 1 death had an unknown cause.
