FDA Grants Priority Review for Brentuximab Vedotin in the Post-Transplant Consolidation Treatment of Hodgkin Lymphoma Patients at High Risk of Relapse (AETHERA Setting)
Published on 20th April
The U.S. Food and Drug Administration (FDA) has accepted a supplemental Biologics License Application (BLA) for brentuximab vedotin (Adcetris®; Seattle Genetics)
in the AETHERA setting for the post-transplant consolidation treatment of Hodgkin lymphoma (HL) patients at high risk of relapse or progression. The FDA granted Priority Review for the application and the Prescription Drug User Fee Act (PDUFA) target action date is August 18, 2015.
The submission of the supplemental BLA in February 2015 was based on positive results from a Phase III clinical trial called AETHERA that was designed to determine if 16 cycles of brentuximab vedotin as consolidation therapy immediately following an autologous stem cell transplant (ASCT) could extend progression-free survival (PFS) in HL patients at high risk of relapse or progression.
Brentuximab vedotin is an antibody-drug conjugate (ADC) for intravenous injection comprising of an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), utilizing Seattle Genetics’ proprietary technology. The antibody-drug conjugate employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing tumor cells.
CD30, de drug’s target, is expressed in classical Hodgkin Lymphoma (HL) and systemic anaplastic large cell lymphoma (sALCL), as well as other lymphoma subtypes. The drug is approved in relapsed HL and sALCL but is currently not approved for consolidation therapy in HL patients immediately after ASCT.
Lymphoma is a general term for a group of cancers that originate in the lymphatic system and is the most common type of blood cancer. There are two major categories of lymphoma: HL and non-Hodgkin lymphoma. HL is distinguished from other types of lymphoma by the presence of one characteristic type of cell, known as the Reed-Sternberg cell. The Reed-Sternberg cell generally expresses CD30.
According to the American Cancer Society, approximately 9,050 cases of Hodgkin lymphoma will be diagnosed in the United States during 2015 and more than 1,150 will die from the disease. However, globally, there are more than 65,000 cases of HL diagnosed each year. Although frontline combination chemotherapy can result in durable responses, up to 30% of these patients relapse or are refractory to frontline treatment. The standard for these patients is to proceed to an ASCT but approximately half of all HL patients who undergo an ASCT experience subsequent disease relapse.
Ongoing clinical trials
While the drug is approved for the treatment of patients with HL after failure of ASCT or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates, as well as the treatment of patients with sALCL after failure of at least one prior multi-agent chemotherapy regimen, brentuximab vedotin is being evaluated broadly in more than 30 ongoing clinical trials. These trials including four phase III studies, in earlier lines of its approved HL and sALCL indications as well as in many additional types of CD30-positive malignancies, including cutaneous T-cell lymphoma, B-cell lymphomas and mature T-cell lymphomas.
“The FDA’s filing of our supplemental BLA and priority review designation for brentuximab vedotin as consolidation therapy represents a significant milestone towards our goal of making brentuximab vedotin available to high risk HL patients immediately following an autologous stem cell transplant who currently have no therapeutic options to prevent progression,” noted Clay B. Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics. “The Phase III AETHERA trial demonstrated that using brentuximab vedotin 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 brentuximab vedotin.”
The positive results from the Phase III AETHERA trial were published in March 20154 edition of The Lancet and were presented at the 56th Annual Meeting of the American Society of Hematology (ASH) in San Francisco in December 2014. In short, the trial results from AETHERA trial in 329 HL patients at high risk of relapse following ASCT achieved its primary endpoint and demonstrated a significant increase in PFS per independent review facility, with a hazard ratio of 0.57 and a p-value of 0.001. Median PFS was 43 months for patients who received ADCETRIS versus 24 months for patients who received placebo. The two-year PFS rate was 63% in the brentuximab vedotin arm compared to 51% in the placebo arm.
The PFS benefit was consistent across all pre-specified subgroups, including primary refractory patients, patients who relapsed within twelve months of frontline therapy and patients who relapsed after twelve months with extranodal disease.
Patients treated with brentuximab vedotin received a median of 15 treatment cycles and 48% received the maximum of 16 cycles, indicating generally acceptable tolerability and a manageable adverse reaction profile.
The most common adverse events in the brentuximab vedotin arm were peripheral sensory neuropathy (56%), neutropenia (35%), upper respiratory tract infection (26%), fatigue (24%) and peripheral motor neuropathy (23%). The most common adverse events in the placebo arm were upper respiratory tract infection (23%), fatigue (18%) peripheral sensory neuropathy (16%), cough (16%) and neutropenia (12%). Eighty-five percent of patients with peripheral neuropathy on the brentuximab vedotin arm had resolution or improvement in symptoms with a median time to improvement of 23.4 weeks.
The submission of safety data from the brentuximab vedotintrial to the FDA is a post-marketing requirement.
Photo: Brentuximab vedotin (Adcetris®; Seattle Genetics). Photo Courtesy: Seattle Genetics.
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