The EMA's Committee for Medicinal Products for Human Use has granted a positive opinion to brentuximab vedotin (Adcetris) for use as a consolidation therapy following autologous stem cell transplantation in patients with CD30-positive Hodgkin lymphoma at risk of relapse or progression.
The EMA's Committee for Medicinal Products for Human Use (CHMP) has granted a positive opinion to brentuximab vedotin (Adcetris) for use as a consolidation therapy following autologous stem cell transplantation (ASCT) in patients with CD30-positive Hodgkin lymphoma at risk of relapse or progression.
The recommendation is based on the phase III AETHERA trial, in which brentuximab vedotin reduced the risk of disease progression by 43% compared with placebo. The median progression-free survival (PFS) with brentuximab vedotin was 42.9 months versus 24.1 months with placebo (HR, 0.57; 95% CI, 0.40-0.81; P = .0013).
Receiving the positive opinion from the CHMP suggests brentuximab vedotin is likely to be approved for this indication when the European Commission issues its final decision.
“While ASCT is the standard of care following failure of frontline chemotherapy in Hodgkin lymphoma, we know that many patients will unfortunately see their disease return. Early eradication of residual disease through treatment with Adcetris has the highest chance of preventing the disease from returning in these patients,” Dirk Huebner, MD, Executive Medical Director of the Oncology Therapeutic Area Unit at Takeda, which is codeveloping the antibody-drug conjugate with Seattle Genetics, said in a statement.
“This opinion, in addition to the recent 5-year overall survival data in relapsed or refractory Hodgkin lymphoma, further establishes the role of Adcetris in improving outcomes for patients. We look forward to the European Commission’s authorization of this new indication and bringing this medicine to physicians and patients in the European Union.”
In the phase III AETHERA study, 329 patients were randomized to receive brentuximab vedotin (n = 165) or placebo (n = 164). Brentuximab vedotin was administered at 1.8 mg/kg IV every 3 weeks for a median of 15 cycles. A majority (60%) of patients treated in the study were refractory to frontline therapy. All patients were required to have obtained a complete remission (CR), partial remission (PR), or stable disease (SD) to salvage therapy prior to ASCT.
The median age of patients enrolled in the trial was 32 years. The median number of prior therapies was 2 (range, 2-8), with 47% of patients receiving >2 prior therapies. Overall, 42% of patients had experienced a prior CR with salvage therapy, a PR for 34%, and SD in 24%. The primary endpoint of the study was PFS, with secondary endpoints focused on overall survival (OS) and safety.
The 2-year PFS rate for patients treated with brentuximab vedotin following ASCT was 54%. The hazard ratio for PFS was consistently below 1.00 across all subgroups analyzed in the study, including patients with primary refractory disease. For patients with primary-refractory disease, the 2-year PFS rate was 60% with brentuximab vedotin compared with 42% for placebo.
Data from a 3-year follow-up upheld the PFS benefit observed at the 2-year analysis (HR, 0.58; 95% CI, 0.41-0.81).
The estimated 2-year OS rates with brentuximab vedotin and placebo were both 88%. This endpoint was potentially confounded by crossover, as 85% of patients in the placebo arm received brentuximab vedotin when the trial was unblinded in September 2014.
The most common all-grade adverse events with brentuximab vedotin versus placebo were peripheral sensory neuropathy (56% vs 16%) and neutropenia (35% vs 12%). A majority (85%) of patients who experienced peripheral neuropathy with brentuximab vedotin had resolution of this adverse event within a median of 23.4 months. The primary cause of treatment discontinuation was progression.
Brentuximab vedotin consists of the anti-CD30 monoclonal antibody SGN-30 conjugated to the cytotoxic agent monomethyl auristatin E (MMAE) via a valine-citrulline peptide linker. The treatment is internalized by CD30 expressing tumor cells, causing the release of MMAE into the cytosol through the enzymatic cleavage of the linker.
The European Commission previously granted brentuximab vedotin marketing authorization for two indications. The first was for patients with relapsed/refractory CD30-positive Hodgkin lymphoma after ASCT, or after at least 2 prior therapies in patients not eligible for ASCT or multiagent chemotherapy. The second was for patients with relapsed/refractory systemic anaplastic large cell lymphoma (sALCL). Following these approvals, the EC later approved a Type II variation to add data on the retreatment of patients with Hodgkin lymphoma or sALCL who relapse after previously responding to brentuximab vedotin.
In addition to recommending a new indication for the antibody-drug conjugate, today’s CHMP action also included a positive opinion for the extension of these current conditional approvals of brentuximab vedotin.
Moskowitz CH, Nadamanee A, Masszi T, et al. The Aethera trial: results of a randomized, double-blind, placebo-controlled phase 3 study of brentuximab vedotin in the treatment of patients at risk of progression following autologous stem cell transplant for Hodgkin lymphoma. Presented at: 2014 ASH Annual Meeting; December 6-9, 2014; San Francisco, CA. Abstract 673.