In Hodgkin's Lymphoma, Brentuximab vs Placebo for First Time

Veronica Hackethal, MD

March 19, 2015

Brentuximab vedotin (BV) (Adcetris, Seattle Genetics, Inc) given early after stem cell transplant significantly improves progression-free survival compared with placebo in patients with hard-to-treat Hodgkin's lymphoma, according to results from the AETHERA trial, published online on March 19 in the Lancet.

"This is the first placebo-controlled study ever done [of BV] in Hodgkin's lymphoma," commented first author Craig Moskowitz, MD, of the Memorial Sloan Kettering Cancer Center, in New York City.

"There is a 20% improvement in progression-free survival for the patients receiving BV, and it will become standard of care for patients that have not received BV," he predicted.

The trial did not include patients who had previously received BV, which could have limited the study.

"In patients who have previously received BV, there are no data to determine if post-ASCT [autologous stem cell transplant] treatment should be given," Dr Moskowitz explained. "However, if a patient responded to BV prior to ASCT, it is reasonable to give it post ASCT for consolidation."

The standard of care for patients with Hodkgin's lymphoma that relapses or does not respond to initial therapy is high-dose chemotherapy followed by ASCT. This regimen cures only about 50% of such patients. Most of those who progress after ASCT will likely die from the disease, according to background information in the article.

BV is a novel targeted therapy: it consists of an anti-CD30 antibody conjugated to a microtubule-disrupting agent. Because Hodgkin's and Reed-Sternberg cells overexpress CD30, the anti-CD30 antibody on BV allows it to target these cells and deliver chemotherapy directly into them. BV has been approved for relapsed or refractory lymphoma in more than 40 countries; the product was approved in the United States in 2011.

Trial Details

Dr Moskowitz and colleagues looked at the effect on progression-free survival after giving BV early after ASCT in patients with risk factors for progression (relapsed disease, failure to respond completely to initial therapy, or extranodal involvement when starting pretransplant chemotherapy). The trial took place at 78 sites in North America and Europe between April 2010 and September 2012. Researchers randomly assigned participants to 16 cycles of 1.8 mg/kg BV (n = 165) or placebo (n = 164) intravenously for 3 weeks, beginning 30 to 45 days after transplant. Both patients and investigators remained masked to treatment assignment.

Results showed that the BV group had significantly better progression-free survival than the placebo group (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.40 - 0.81; P = .0013). The BV group also had longer median progression-free survival than the placebo group (42.9 months [95% CI, 30.4 - 42.9] vs 24.1 months [95% CI, 11.5 - not estimable], respectively). On independent review, 63% of patients in the BV group remained progression-free by 24 months, compared with 51% of patients in the placebo group.

Nearly half of all participants in the BV group completed all 16 cycles of treatment. About one third of the BV group discontinued treatment because of adverse effects.

Among participants in the BV group, the most frequently experienced adverse effects included peripheral sensory neuropathy (94/167 [56%] BV vs 25/160 [16%] placebo) and neutropenia (58/167 [35%] BV vs 19/160 [12%] placebo).

Both groups had similar overall survival: 28/167 (17%]) patients in the BV group died, compared with 25/160 [16%] patients in the placebo group. Two patients in the BV group died from treatment-related events.

"What is very clear from the AETHERA study is that nearly 90% of patients had multiple risk factors [for progression], and the benefit of BV in these cohorts was further increased," Dr Moskowitz emphasized. "BV was well tolerated in this study, and most importantly, the patients need to be commended for staying on treatment for a year."

"AETHERA is a positive study establishing a promising new treatment approach for patients with Hodgkin's lymphoma at high risk for relapse," Andreas Engert, MD, from the University Hospital of Cologne, in Germany, wrote in a linked comment.

He emphasized the roughly 50% progression-free survival at 24 months in the placebo group, which he says points to the need for more research to determine which patients are at high risk for relapse and who could benefit most from BV.

"An international consortium is currently reassessing the effect of risk factors in patients with relapsed Hodgkin's lymphoma to define a high-risk patient population in need of consolidation treatment," he wrote. "We look forward to a better definition of patients with relapsed Hodgkin's lymphoma who should receive consolidation treatment with brentuximab vedotin."

The study was funded by Seattle Genetics Inc and Takeda Pharmaceuticals International Co. The relevant financial relationships of the authors of the study are listed in the original article. Dr Engert reports research funding and consultancy/presentation fees from Takeda Millenium.

Lancet. Published online March 19, 2015. Abstract, Commentary

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