Drugs Xagena
The FDA ( Food and Drug Administration ) has approved Adcetris ( Brentuximab vedotin ) for the treatment of patients with classical Hodgkin lymphoma ( HL ) at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation ( auto-HSCT ) consolidation.
The approval is based on a phase 3 clinical trial called AETHERA that was designed to compare up to 16 cycles ( approximately one year ) of therapy with Brentuximab vedotin administered every three weeks following auto-HSCT to placebo.
The primary endpoint was met with a significant improvement in median progression-free survival ( PFS ) of 42.9 months ( 95% CI: 30.4, 42.9 ) for patients who received Brentuximab vedotin versus 24.1 months ( 95% CI: 11.5, not estimable ) for patients who received placebo, an improvement of 18.8 months ( hazard ratio, HR=0.57 [ 95% CI: 0.40, 0.81 ]; p-value=0.001 ).
Brentuximab vedotin 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.
This is the third indication for Adcetris, which was granted accelerated FDA approval in August 2011 for two other indications: (1) treatment of Hodgkin lymphoma patients who fail autologous transplant or who fail at least two prior multi-agent chemotherapy regimens and are not autologous transplant candidates, and (2) treatment of systemic ALCL patients who fail at least one prior multi-agent chemotherapy regimen.
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 fail frontline treatment. The standard for these patients is salvage therapy, followed by auto-HSCT; approximately half of all HL patients who undergo an auto-HSCT experience subsequent disease relapse.
The positive results from the phase 3 AETHERA trial were published in The Lancet in March 2015. A total of 329 HL patients at risk of relapse or progression were enrolled, including 165 on the Brentuximab vedotin arm and 164 on the placebo arm. Patients eligible for enrollment in the AETHERA trial must have had a history of primary 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-auto-HSCT relapse.
The trial achieved its primary endpoint and demonstrated a significant increase in progression-free survival per independent review facility, with a hazard ratio of 0.57 ( 95% CI: 0.40, 0.81 ) and a p-value of 0.001. Median progression-free survival was 43 months ( 95% CI: 30.4, 42.9 ) for patients who received Brentuximab vedotin versus 24 months ( 95% CI: 11.5, not estimable ) for patients who received placebo.
The most common adverse events ( greater than or equal to 20% ), of any grade and regardless of causality, in the Brentuximab vedotin arm were neutropenia ( 78% ), peripheral sensory neuropathy ( 56% ), thrombocytopenia ( 41% ), anemia ( 27% ), upper respiratory tract infection ( 26% ), fatigue ( 24% ), peripheral motor neuropathy ( 23% ), nausea ( 22% ), cough ( 21% ) and diarrhea ( 20% ).
The most common adverse events ( greater than or equal to 20% ), of any grade and regardless of causality, in the placebo arm were neutropenia ( 34% ), upper respiratory tract infection ( 23% ) and thrombocytopenia ( 20% ).
Sixty-seven percent of patients on the Brentuximab vedotin arm experienced peripheral neuropathy. Of those patients, 85% had resolution ( 59% ) or partial improvement ( 26% ) in symptoms at the time of their last evaluation, with a median time to improvement of 23 weeks ( range 0.1-138 ). ( Xagena )
Source: Seattle Genetics, 2015
XagenaMedicine_2015
