FDA Expands Adcetris' Label in Hodgkin Lymphoma

The FDA has approved Adcetris (brentuximab vedotin) 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 3 AETHERA trial.

In the study, treatment with the drug reduced the risk of disease progression by 43 percent compared with placebo. The median progression-free survival (PFS) with Adcetris was 42.9 versus 24.1 months. Results from the study were presented at the 2014 American Society of Hematology Annual Meeting and subsequently published in The Lancet.

“The FDA approval of [Adcetris] 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, 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 3 study, 329 patients were randomized to receive Adcetris (165 patients) or placebo (164 patients). Adcetris was administered at 1.8 mg/kg intravenously every three weeks for a median of 15 cycles. A majority (60 percent) 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 two (ranging from two to eight), with 47 percent of patients receiving greater than two prior therapies. Overall, 42 percent of patients had experienced a prior CR with salvage therapy, a PR for 34 percent, and SD in 24 percent. The primary endpoint of the study was PFS, with secondary endpoints focused on overall survival (OS) and safety.

The two-year PFS rate for patients treated with Adcetris following ASCT was 54 percent. For patients with primary-refractory disease, the two-year PFS rate was 60 percent with Adcetris compared with 42 percent for placebo.

The estimated two-year OS rates with Adcetris and placebo were both 88 percent. This endpoint was potentially confounded by crossover, as 85 percent of patients in the placebo arm received Adcetris when the trial was unblinded in September 2014.

The most common all-grade adverse events with Adcetris versus placebo were peripheral sensory neuropathy (56 vs 16 percent) and neutropenia (35 vs 12 percent). A majority (85 percent) of patients who experienced peripheral neuropathy with Adcetris 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, 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.”

Adcetris 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.

Adcetris 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 3 clinical trials continue to assess Adcetris 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, Adcetris is being explored in combination with chemotherapy for younger patients with newly diagnosed Hodgkin lymphoma.

"Together with our three ongoing phase 2 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.