Seattle Genetics, Takeda report phase III AETHERA clinical trial data from ADCETRIS

The data from the AETHERA trial were featured at the 56th American Society of Hematology (ASH) Annual Meeting press program today and will be presented in an oral session on December 8, 2014. ADCETRIS is an antibody-drug conjugate (ADC) directed to CD30, a defining marker of classical HL.

ADCETRIS has been approved in more than 45 countries for the treatment of relapsed or refractory HL and systemic anaplastic large cell lymphoma (sALCL). ADCETRIS is currently not approved in the AETHERA treatment setting.

"Over the past 20 years, no improvement has been shown in the outcomes of patients treated with autologous stem cell transplant regimens for aggressive lymphomas, including Hodgkin lymphoma," said Craig Moskowitz, M.D. Clinical Director, Division of Hematologic Oncology, Memorial Sloan Kettering Cancer Center.

"Approximately half of the patients who undergo an autologous stem cell transplant will relapse, demonstrating a significant need to identify regimens that improve patient outcomes. Data from the AETHERA clinical trial demonstrate that the addition of brentuximab vedotin use in the immediate post-transplant setting resulted in a statistically significant improvement in PFS with a manageable safety profile."

"The outcome of the AETHERA trial is an important milestone. It demonstrates that early consolidation treatment with ADCETRIS in Hodgkin lymphoma patients at risk of relapse following an autologous transplant can result in a substantial improvement in PFS versus placebo," said Clay B. Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics.

"We are pleased to share these data with the physician community at ASH. We will be meeting with the FDA soon to discuss the submission of a supplemental Biologics License Application in the first half of 2015 seeking approval in this consolidation setting."

"The AETHERA data provide compelling evidence regarding the potential utility of ADCETRIS as consolidation therapy post-transplant in these Hodgkin lymphoma patients, and we look forward to submitting these data to health authorities around the world," said Michael Vasconcelles, M.D., Global Head, Oncology Therapeutic Area Unit, Takeda Pharmaceutical Company Limited.

"Going forward, we are conducting a robust clinical development program to more fully understand the potential of CD30 targeting with ADCETRIS in frontline disease through our ongoing Phase 3 ECHELON-1 and ECHELON-2 trials in HL and mature T-cell lymphomas."

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 (Abstract #673, oral presentation at 4:30 p.m. PT on December 8, 2014 at the Moscone Center West Building, 3001-3003-3014-3016)

The Phase 3 AETHERA trial was designed to evaluate the potential of single agent ADCETRIS to extend PFS post-ASCT in patients with HL who have at least one risk factor for progression. In addition to the primary endpoint of PFS, secondary endpoints included overall survival (OS), safety and tolerability. Eligible patients must have had a history of refractory HL, have relapsed within one year from receiving frontline chemotherapy and/or have had disease outside of the lymph nodes at the time of pre-ASCT relapse.

These factors are consistently reported to be associated with poor prognosis after transplant. Patients received ADCETRIS or placebo every three weeks for up to approximately one year. This international multi-center trial was conducted at 78 sites in the United States, Eastern and Western Europe and Russia.

A total of 329 HL patients at risk of relapse were enrolled, including 165 on the ADCETRIS arm and 164 on the placebo arm. Patients received a median of 15 cycles of treatment on both arms, with an average of 12 cycles on the ADCETRIS arm and 11 cycles on the placebo arm. Key findings, which were highlighted by Dr. Moskowitz, include:

• The trial achieved its primary endpoint and demonstrated a significant increase in PFS per independent review facility (IRF), with a hazard ratio of 0.57 and a p-value of 0.001. Median PFS per IRF was 43 months for patients who received ADCETRIS versus 24 months for patients who received placebo. The two-year PFS rate per IRF was 63 percent in the ADCETRIS arm compared to 51 percent in the placebo arm.
• Per investigator, the hazard ratio was 0.50. The two-year PFS rate per investigator was 65 percent in the ADCETRIS arm compared to 45 percent in the placebo arm. The median PFS per investigator has not yet been reached for patients who received ADCETRIS versus 16 months for patients who received placebo. Very few progression events have been observed beyond two years.
• 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 in both arms of the study who experienced disease progression received a variety of subsequent therapies. In the ADCETRIS arm, only eight of 51 patients (16 percent) receiving subsequent therapy were treated with ADCETRIS following relapse. In the placebo arm, 72 of 85 patients (85 percent) receiving subsequent therapy were treated with single agent ADCETRIS. Twenty-four patients in the placebo arm and 13 patients in the ADCETRIS arm received stem cell transplant as subsequent therapy, the majority of which were allogeneic transplants.
• OS data are immature, and no statistically significant difference in OS has been observed between the treatment arms (hazard ratio 1.15; p-value=0.62). A further analysis of overall survival is planned in 2016.
• 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.
• Grade 3 or higher adverse events in the ADCETRIS arm included neutropenia, peripheral sensory neuropathy, peripheral motor neuropathy, nausea, fatigue and diarrhea. Grade 3 or higher adverse events in the placebo arm included neutropenia, fatigue, peripheral motor neuropathy, diarrhea and peripheral sensory neuropathy. No Grade 4 peripheral neuropathy events occurred.
• One death occurred within 30 days of ADCETRIS treatment from treatment-related acute respiratory distress syndrome (ARDS) associated with pneumonitis. One death occurred on the ADCETRIS arm at Day 40 from ARDS following an episode of treatment-related acute pancreatitis, which had resolved at the time of death.

Submission of safety data from the AETHERA trial to the FDA is a post-marketing requirement that Seattle Genetics will fulfill in its planned supplemental BLA. Takeda plans to submit data from the AETHERA trial to regulatory agencies in its territories.

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 U.S. Food and Drug Administration 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 based on response rate. There are no data available demonstrating improvement in patient-reported outcomes or survival with ADCETRIS.

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 45 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.