Clinical Trials

Date: 2015-06-17

Type of information: Presentation of results at a congress

phase: 3

Announcement: presentation of results at the 13th International Conference on Malignant Lymphoma (ICML) being held June 17 to 19, 2015, in Lugano, Switzerland

Company: Seattle Genetics (USA - WA)

Product: Adcetris® (brentuximab vedotin)

Action mechanism:

• monoclonal antibody/antibody drug conjugate (ADC). Adcetris® (brentuximab vedotin) is an antibody-drug conjugate (ADC) comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE). The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalisation into CD30-expressing tumor cells. The CD30 antibody part of the product acts as a carrier for the cytotoxic substance. When the antibody attached by the linker to the cytotoxin attaches to the CTCL cells, it is taken up by the cells. Once inside the cancer cells, the linker is cut and the cytotoxic molecule, monomethyl auristatin E, gets released and stops cell division. The cancer cells are then expected to undergo programmed cell death. The anti-tumour activity of brentuximab-vedotin has been established in the HL and sALCL study populations as well as in the relapsed or refractory HL patients ineligible for ASCT/multidrug chemotherapy. The different clinical endpoints demonstrated clinical benefit in terms of disease control, resolution of B-symptoms and in terms of enabling further potentially curative treatment options.

Disease: consolidation therapy immediately following an autologous stem cell transplant (ASCT) in Hodgkin lymphoma (HL) patients at high risk of relapse

Therapeutic area: Cancer - Oncology

Country: Bulgaria, Czech Republic, France, Germany, Hungary, Italy, Poland, Romania, Russian Federation, Serbia, Spain, UK, USA

Trial details:

• The AETHERA trial is a randomized, double-blind, placebo-controlled phase 3 study designed to evaluate the potential of 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, safety and tolerability. Patients must have risk factors for residual HL, defined as a history of refractory HL, those who relapse or progress within one year from receiving frontline chemotherapy and/or those who have disease outside of the lymph nodes at the time of pre-ASCT relapse. Patients received ADCETRIS or placebo every three weeks for up to approximately one year. This international multi-center trial is being conducted in the United States, Eastern and Western Europe and Russia. (NCT01100502)

Latest news:

• • On June 17, 2015, Seattle Genetics announced several Adcetris® (brentuximab vedotin) data presentations at the 13th International Conference on Malignant Lymphoma (ICML) being held June 17 to 19, 2015, in Lugano, Switzerland. Seven oral presentations and one poster at ICML demonstrate the breadth of the clinical development program for Adcetris®. Data include an additional analysis of the phase 3 AETHERA clinical trial showing that up to 16 cycles (approximately one year) of Adcetris® consolidation therapy following autologous stem cell transplant (ASCT) significantly extended progression-free survival (PFS) versus placebo for those patients with primary-refractory HL. In addition, data from several corporate and investigator-sponsored trials with ADCETRIS showed activity in a variety of HL and NHL treatment settings.
• Analysis of primary-refractory Hodgkin lymphoma patients in a randomized, placebo-controlled study of brentuximab vedotin consolidation after autologous stem cell transplant (Seattle Genetics and Takeda; Abstract #120, oral presentation Friday, June 19, 2015, at 11:50 a.m. CEST): Data were reported from an additional analysis of the phase 3 AETHERA clinical trial evaluating PFS by investigator in patients who were refractory to frontline treatment. Previously published data suggest primary-refractory HL patients have poor outcomes following ASCT, as demonstrated by the historical two-year PFS and three-year overall survival rates of less than 40 percent and 50 percent, respectively. Of the 329 patients enrolled in the AETHERA trial, 60 percent (196 patients) were primary-refractory to frontline treatment.
• Results of the analysis demonstrated: Two-year PFS rates per investigator among primary-refractory patients on the Adcetris® and placebo arms were 60 percent and 42 percent, respectively, consistent with the primary analysis in the full intent-to-treat population. Subgroup analyses of patients by disease characteristics as well as number of risk factors showed that PFS was improved broadly across subgroups, including patients with B-symptoms, extranodal involvement and those who received more than two systemic anticancer treatments pre-ASCT. Adverse events in primary-refractory patients who received Adcetris® were consistent with the known safety profile. Additional AETHERA data were included in a poster presentation reporting the frequency of healthcare resource utilization (HRU) among patients on the two treatment arms of the trial. Preliminary reports suggest a trend toward lower HRU in patients treated with Adcetris® compared with placebo.
• • On June 1, 2015, Seattle Genetics announced several Adcetris® (brentuximab vedotin) data presentations in the AETHERA post-transplant consolidation setting for Hodgkin lymphoma (HL) and in frontline diffuse large B-cell lymphoma (DLBCL) at the American Society of Clinical Oncology (ASCO) 50th Annual Meeting being held May 29 to June 2, 2015, in Chicago, IL.
• Multivariate analysis of PFS from the AETHERA trial: A phase 3 study of brentuximab vedotin consolidation after autologous stem cell transplant for HL (Abstract #8519, poster presentation Sunday, May 31, 2015): Data were reported from a multivariate analysis of the effects of demographics, baseline disease characteristics and other risk factors on progression-free survival (PFS) from the phase 3 AETHERA clinical trial. After adjusting for several clinical factors in a multivariate regression analysis, consolidation treatment with Adcetris® was significantly associated with improved PFS compared with placebo (hazard ratio of 0.44) and was more important, or as important, as all evaluated clinical factors. Results show consistent PFS benefit of Adcetris® consolidation therapy, regardless of the clinical factors, further supporting Adcetris® use as consolidation in HL patients following autologous stem cell transplant (ASCT). Based on the positive results from the AETHERA trial, a supplemental Biologics License Application (BLA) for Adcetris® in the AETHERA setting for the post-ASCT consolidation treatment of HL patients at high risk of relapse or progression was accepted for filing by the FDA.
• • On December 6, 2014, Seattle Genetics and Takeda Pharmaceutical reported data demonstrating that Hodgkin lymphoma (HL) patients at risk of relapse following an autologous stem cell transplant (ASCT) who received Adcetris® (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 . 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 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.
• 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)
• • On September 29, 2014, Seattle Genetics and Takeda Pharmaceutical announced that patients with Hodgkin lymphoma  who received Adcetris® (brentuximab vedotin) as consolidation therapy immediately following an autologous stem cell transplantation (ASCT) lived significantly longer without disease progression compared to patients who received placebo. The  AETHERA trial compared the use of single agent Adcetris® to placebo in 329 patients with HL who were at risk of relapse.  The trial met its primary endpoint with Adcetris® treatment resulting in a statistically significant improvement in progression-free survival versus placebo as assessed by an independent central review committee (hazard ratio=0.57; p-value=0.001), which equates to a 75 percent improvement in PFS. PFS was assessed after a minimum of two years post initiation of treatment for all study patients. A pre-specified interim analysis of overall survival showed no statistically significant difference between the treatment arms. Patients on both study arms with progression of HL received a variety of subsequent therapies. Notably, most patients on the placebo arm received Adcetris® after progression. A further analysis of overall survival is planned in 2016.

Is general: Yes