On April 20, 2015 Seattle Genetics reported that the U.S. Food and Drug Administration (FDA) has accepted for filing a supplemental Biologics License Application (BLA) for ADCETRIS (brentuximab vedotin) in the AETHERA setting for the post-transplant consolidation treatment of Hodgkin lymphoma (HL) patients at high risk of relapse or progression (Press release, Seattle Genetics, APR 20, 2015, View Source [SID:1234503088]). 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 is based on positive results from a phase 3 clinical trial called AETHERA that was designed to determine if 16 cycles of ADCETRIS 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. ADCETRIS is an antibody-drug conjugate (ADC) directed to CD30, which is expressed in classical HL and systemic anaplastic large cell lymphoma (sALCL), as well as other lymphoma subtypes. ADCETRIS is approved in relapsed HL and sALCL but is currently not approved for consolidation therapy in HL patients immediately after ASCT. Schedule your 30 min Free 1stOncology Demo! 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 percent 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.
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"The FDA’s filing of our supplemental BLA and priority review designation for ADCETRIS as consolidation therapy represents a significant milestone towards our goal of making ADCETRIS available to high risk HL patients immediately following an autologous stem cell transplant who currently have no therapeutic options to prevent progression," said Clay B. Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics. "The phase 3 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."
The positive results from the phase 3 AETHERA trial were published in The Lancet in March 2015 and were presented at the 56th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in December 2014. Results from the AETHERA trial in 329 HL patients at high risk of relapse following ASCT included:
The trial 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 percent in the ADCETRIS arm compared to 51 percent 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.
ADCETRIS-treated patients received a median of 15 treatment cycles and 48 percent received the maximum of 16 cycles, indicating generally acceptable tolerability and a manageable adverse reaction profile.
The most common adverse events in the ADCETRIS arm were peripheral sensory neuropathy (56 percent), neutropenia (35 percent), upper respiratory tract infection (26 percent), fatigue (24 percent) and peripheral motor neuropathy (23 percent). The most common adverse events in the placebo arm were upper respiratory tract infection (23 percent), fatigue (18 percent) peripheral sensory neuropathy (16 percent), cough (16 percent) and neutropenia (12 percent). Eighty-five percent of patients with peripheral neuropathy on the ADCETRIS arm had resolution or improvement in symptoms with a median time to improvement of 23.4 weeks.
Submission of safety data from the AETHERA trial to the FDA is a post-marketing requirement.
About ADCETRIS
ADCETRIS is being evaluated broadly in more than 30 ongoing clinical trials, including four phase 3 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.
ADCETRIS (brentuximab vedotin) is an ADC comprising 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 ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing tumor cells.
ADCETRIS for intravenous injection received accelerated approval from the FDA and approval with conditions from Health Canada for two indications: (1) 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, and (2) the treatment of patients with sALCL after failure of at least one prior multi-agent chemotherapy regimen. The indications for ADCETRIS are approved under accelerated approval based on overall response rate. An improvement in patient-reported outcomes or survival has not been established. Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials.
ADCETRIS was granted conditional marketing authorization by the European Commission in October 2012 for two indications: (1) for the treatment of adult patients with relapsed or refractory CD30-positive HL following ASCT, or following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option, and (2) the treatment of adult patients with relapsed or refractory sALCL. ADCETRIS has received marketing authorization by regulatory authorities in more than 50 countries. See important safety information below.
Seattle Genetics and Takeda are jointly developing ADCETRIS. Under the terms of the collaboration agreement, Seattle Genetics has U.S. and Canadian commercialization rights and Takeda has rights to commercialize ADCETRIS in the rest of the world. Seattle Genetics and Takeda are funding joint development costs for ADCETRIS on a 50:50 basis, except in Japan where Takeda will be solely responsible for development costs.
About Hodgkin Lymphoma
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 HL will be diagnosed in the United States during 2015 and more than 1,150 will die from the disease.