FDA Grants Priority Review to Brentuximab Vedotin Consolidation in Hodgkin Lymphoma

Clay B. Siegall, PhD

The FDA has granted a priority review to the antibody-drug conjugate brentuximab vedotin (Adcetris) as a consolidation therapy following autologous stem cell transplantation (ASCT) in patients with Hodgkin's lymphoma at risk of relapse or progression, based on findings from the phase III AETHERA trial. The FDA is scheduled to review the drug by August 18, 2015.

In the AETHERA study, treatment with brentuximab vedotin improved progression-free survival (PFS) by 43% compared with placebo in patients at high-risk of relapse or with primary refractory Hodgkin's lymphoma immediately following ASCT. Results from the study were presented at the 2014 ASH Annual Meeting and subsequently published in The Lancet.

“The FDA’s filing of our supplemental BLA [Biologics License Application] and priority review designation for Adcetris as consolidation therapy represents a significant milestone towards our goal of making Adcetris available to high risk Hodgkin's lymphoma patients immediately following an autologous stem cell transplant who currently have no therapeutic options to prevent progression,” said Clay B. Siegall, PhD, president and chief executive officer of Seattle Genetics, the company marketing the drug.

Brentuximab vedotin was granted an accelerated approval in August 2011 as a treatment for patients with Hodgkin lymphoma after failure of ASCT or after failure of at least two prior chemotherapy regimens in patients who were not candidates for ASCT. The new indication for brentuximab, based on the AETHERA trial, would move treatment with the drug forward, as a therapy for patients who are at high risk of relapse following ASCT.

In AETHERA, 329 patients were randomized to receive brentuximab (n = 165) or placebo (n = 164). Brentuximab was administered at 1.8 mg/kg intravenously every 3 weeks for a median of 15 cycles. In the study, 48% of patients received the maximum intended dose of 16 cycles. The primary endpoint of the study was PFS.

The median PFS with brentuximab was 42.9 versus 24.1 months (HR = 0.57; 95% CI, 0.40-0.81; P = .0013). The hazard ratio for PFS was consistently below 1.00 across all subgroups analyzed in the study, including patients with primary refractory disease. At the time of the analysis, 17% of patients had died in the brentuximab arm compared with 16% of patients in the placebo arm.

“The phase III AETHERA trial demonstrated that using Adcetris in this setting significantly improved progression-free survival with a manageable safety profile. We look forward to working with the FDA during their review of our application for approval of this additional indication for Adcetris,” Siegall said.

The most common all-grade adverse events with brentuximab 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 had resolution of this adverse event within a median of 23.4 months.

“This is the first study in lymphoma to demonstrate that the addition of a maintenance drug after transplant can markedly improve patient outcomes,” lead investigator Craig Moskowitz, MD, of Memorial Sloan Kettering Cancer Center, said when the results were presented at ASH. “Given these extremely positive results, we predict that brentuximab vedotin will soon become the standard of care for Hodgkin lymphoma patients who undergo an autologous stem cell transplant.”

Brentuximab 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.

Brentuximab continues to be explored in a number of phase III clinical trials for patients with hematologic malignancies. The drug is being compared with physician's choice as a treatment for patients with CD30-positive cutaneous T-cell lymphoma. Additionally, brentuximab is being explored in combination with chemotherapy for younger patients with newly diagnosed Hodgkin's lymphoma.