Results from the randomized phase III AETHERA trial (NCT01100502) shows a statistically significant improvement in progression-free survival in Hodgkin lymphoma (HL) patients at risk of relapse following an autologous stem cell transplant (ASCT) who received brentuximab vedotin (Adcetris®; Seattle Genetics/Takeda oncology) as consolidation therapy immediately after ASCT. The results show that these patients had significant improvement in progression-free survival (PFS) compared to patients who received placebo (median of 43 months versus 24 months, respectively; hazard ratio=0.57; p-value=0.001). The data from the AETHERA trial will be featured in an Oral Session on Monday, December 8, 2014 during the 56th Annual Meeting of the American Society of Hematology (ASH), being held in San Francisco, December 6 – 9, 2014.
Lymphoma is a general term for a group of cancers that originate in the lymphatic system. There are two major categories of lymphoma: HL or Hodgkin lymphoma 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 9,200 cases of HL will be diagnosed in the United States during 2014 and more than 1,200 will die from the disease. Globally, there are more than 62,000 cases of HL diagnosed each year.
Although frontline combination chemotherapy can result in durable response rates, up to 30 percent of these patients relapse or are refractory to frontline treatment and have few therapeutic options beyond ASCT. Brentuximab vedotin, which is jointly developed by Seattle Genetics and Takeda, is an antibody-drug conjugate or ADC directed to CD30, a defining marker of classical HL. The drug comprises an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E or 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.
Brentuximab vedotin has been approved in more than 45 countries for the treatment of relapsed or refractory HL and systemic anaplastic large cell lymphoma (sALCL). The drug 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,” Moskowitz further explained. “The outcome of the AETHERA trial is an important milestone. It demonstrates that early consolidation treatment with brentuximab vedotin in Hodgkin lymphoma patients at risk of relapse following an autologous transplant can result in a substantial improvement in PFS versus placebo,” noted Clay 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 brentuximab vedotin 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 brentuximab vedotin in frontline disease through our ongoing Phase III ECHELON-1 and ECHELON-2 trials in HL and mature T-cell lymphomas.”
The AETHERA Trial The Phase III AETHERA trial was designed to evaluate the potential of single agent brentuximab vedotin 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 brentuximab vedotin 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 brentuximab vedotin 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 brentuximab vedotin arm and 11 cycles on the placebo arm. Key findings, to be highlighted by 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 brentuximab vedotin versus 24 months for patients who received placebo. The two-year PFS rate per IRF was 63 percent in the brentuximab vedotin 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 brentuximab vedotin arm compared to 45 percent in the placebo arm. The median PFS per investigator has not yet been reached for patients who received rentuximab vedotin 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 brentuximab vedotin arm, only eight of 51 patients (16% receiving subsequent therapy were treated with rentuximab vedotin following relapse. In the placebo arm, 72 of 85 patients (85% receiving subsequent therapy were treated with single agent bentuximab vedotin. Twenty-four patients in the placebo arm and 13 patients in the brentuximab vedotin 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 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 t 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.
- Grade 3 or higher adverse events in the brentuximab vedotin 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 brentuximab vedotin treatment from treatment-related acute respiratory distress syndrome (ARDS) associated with pneumonitis. One death occurred on the brentuximab vedotin arm at Day 40 from ARDS following an episode of treatment-related acute pancreatitis, which had resolved at the time of death.