ASH: New data demonstrates Hodgkin lymphoma (HL) patients at risk of relapse following an autologous stem cell transplant (ASCT) who received brentuximab vedotin as consolidation therapy immediately after ASCT 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 were featured at the 56th American Society of Hematology (ASH) Annual Meeting 2014. Brentuximab is an antibody-drug conjugate (ADC) directed to CD30, a defining marker of classical HL.
Brentuximab has been approved in more than 45 countries for the treatment of relapsed or refractory HL and systemic anaplastic large cell lymphoma (sALCL), but 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.”
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 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 arm and 11 cycles on the placebo arm.
Key findings, which were highlighted by Dr. Moskowitz at the ASH meeting, 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 versus 24 months for patients who received placebo. The two-year PFS rate per IRF was 63 percent in the brentuximab 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 arm compared to 45 percent in the placebo arm. The median PFS per investigator has not yet been reached for patients who received brentuximab 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 arm, only eight of 51 patients (16 percent) receiving subsequent therapy were treated with brentuximab following relapse. In the placebo arm, 72 of 85 patients (85 percent) receiving subsequent therapy were treated with single agent brentuximab. Twenty-four patients in the placebo arm and 13 patients in the brentuximab 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 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 brentuximab 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 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 treatment from treatment-related acute respiratory distress syndrome (ARDS) associated with pneumonitis. One death occurred on the brentuximab arm at Day 40 from ARDS following an episode of treatment-related acute pancreatitis, which had resolved at the time of death.