FDA Expands Brentuximab Vedotin's Hodgkin Lymphoma Label

Craig H. Moskowitz, MD

The FDA has approved the antibody-drug conjugate (ADC) brentuximab vedotin (Adcetris) as a consolidation therapy following autologous stem cell transplantation (ASCT) in patients with Hodgkin lymphoma at risk of relapse or progression, based on the phase III AETHERA trial.

In the study, treatment with the anti-CD30 ADC reduced the risk of disease progression by 43% compared with placebo. The median progression-free survival (PFS) with brentuximab vedotin was 42.9 versus 24.1 months (HR, 0.57; 95% CI, 0.40-0.81; P = .0013). Results from the study were presented at the 2014 ASH Annual Meeting and subsequently published in The Lancet.

“The FDA approval of brentuximab vedotin for post-autologous hematopoietic transplantation consolidation treatment in classical Hodgkin lymphoma patients with high risk of relapse or progression is a significant milestone for patients and physicians,” lead investigator on the trial Craig Moskowitz, MD, Clinical Director, Division of Hematologic Oncology, Memorial Sloan Kettering Cancer Center, said in a statement. “Approximately half of all Hodgkin lymphoma patients who undergo an autologous hematopoietic stem cell transplant will relapse, representing a significant need for additional treatment options to improve progression free survival.”

In the phase III study, 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. 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.

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.

“With this FDA approval, Adcetris is the first and only consolidation treatment option available to high risk classical Hodgkin lymphoma patients who undergo a transplant to preserve their post-auto-HSCT remissions,” Clay Siegall, PhD, president and chief executive officer of Seattle Genetics, said in a statement. “This represents a meaningful advance for cancer patients and an important milestone for the Adcetris development program.”

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.

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 moves treatment with the drug forward, as a therapy for patients who are at high risk of relapse following ASCT. Additionally, the approval converts the accelerated approval to a full approval for patients with Hodgkin lymphoma.

A number of phase III clinical trials continue to assess brentuximab vedotin 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.

"Together with our three ongoing phase II trials and more than 30 additional clinical trials, this approval supports our goal to broadly establish Adcetris as the foundation of therapy for classical Hodgkin lymphoma and CD30-expressing malignancies,” Siegall said.

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.