Several new analysis of Phase III data from the AETHERA trial (NCT01100502) demonstrate that brentuximab vedotin (Adcetris®; Seattle Genetics) consolidation therapy significantly extends progression-free survival (PFS) in patients with primary-refractory hodgkin lymphoma. The data was presented at the 13th International Conference on Malignant Lymphoma (ICML) being held June 17 to 19, 2015, in Lugano, Switzerland. This year the meeting, organized in collaboration with the European School of Oncology (ESO), brought about 3’000 physicians and leading researchers involved in the study and treatment of lymphoid neoplasms to Lugano. 
Brentuximab vedotin is an antibody-drug conjugate or ADC directed to CD30, which is expressed in classical Hodgkin lymphoma (HL), systemic anaplastic large cell lymphoma (sALCL) and several other types of non-Hodgkin lymphoma (NHL). The drug comprises of an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to monomethyl auristatin E (MMAE), a microtubule disrupting agent, utilizing Seattle Genetics’ proprietary technology. The protease-cleavable linker system is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing tumor cells.
Brentuximab vedotin is being evaluated broadly in more than 30 ongoing clinical trials, including four phase III studies, in earlier lines of its approved HL and sALCL indications as well as in many additional types of CD30-positive malignancies, including cutaneous T-cell lymphoma, B-cell lymphomas and mature T-cell lymphomas.
Today, brentuximab vedotin, for intravenous injection, has received accelerated approval from the U.S. Food and Drug Administration (FDA) for relapsed HL and sALCL and approval, with conditions, from Health Canada for 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 the treatment of patients with sALCL after failure of at least one prior multi-agent chemotherapy regimen. These indications are approved under accelerated approval based on overall response rate. The drug was also granted conditional marketing authorization by the European Commission in October 2012 for relapsed or refractory HL and sALCL.
The AETHERA trial is a randomized, double-blind, phase III study of brentuximab vedotin and best supportive care (BSC) versus placebo and BSC in Hodgkin lymphoma (HL) patients at increased risk of relapse or progression post-autologous stem cell transplant (ASCT).
Early consolidation post-ASCT with brentuximab vedotin demonstrated improved progression-free survival (PFS) per independent review compared with placebo (median PFS 43 vs. 24 months; HR = 0.57, p = 0.001). The most common treatment-emergent grade ≥3 adverse events (AEs) were neutropenia (29% brentuximab vedotin vs 10% placebo), peripheral sensory neuropathy (10% vs. 1%), thrombocytopenia (4% vs. 3%), peripheral motor neuropathy (6% vs 1%) and anemia (4% vs. 2%). Treatment discontinuation due to AEs occurred in 33% vs 6% of patients, and 53 of participating patients died on study (17% vs 16%).
During the 13th International Conference on Malignant Lymphoma (ICML) seven oral presentations and one poster demonstrated the breadth of the clinical development program for brentuximab vedotin. Data include an additional analysis of the Phase III AETHERA clinical trial showing that up to 16 cycles (approximately one year) of brentuximab vedotin 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 brentuximab vedotin showed activity in a variety of HL and NHL treatment settings (see below: Additional presentations).
“Since the initial FDA approval of brentuximab vedotin in 2011 for the treatment of relapsed HL and sALCL, it has been approved in more than 55 countries, and our clinical development program has expanded to include more than 30 corporate and investigator-sponsored clinical trials in CD30-expressing malignancies,” explained Clay B. Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics. “The … data presented at ICML supports our broad development plans for brentuximab vedotin. In the near-term, we anticipate an FDA decision on its use in the AETHERA setting as a post-transplant consolidation therapy, and, ultimately, our goal is to move even earlier into the treatment paradigm and redefine frontline treatment of HL with the addition of brentuximab vedotin.”
Analysis of primary-refractory Hodgkin lymphoma
Data from an additional analysis of the phase III AETHERA clinical trial evaluated PFS by investigator in patients who were refractory to frontline treatment.  Previously published data has suggested that 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% and 50%, respectively. Of the 329 patients enrolled in the AETHERA trial, 60% (196 patients) were primary-refractory to frontline treatment.
The results of the analysis demonstrated a two-year PFS rates per investigator among primary-refractory patients on the brentuximab vedotin and placebo arms were 60% and 42%, respectively, consistent with the primary analysis in the full intent-to-treat population. A 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. The adverse events in primary-refractory patients who received brentuximab vedotin 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 brentuximab vedotin compared with placebo. 
Supplemental Biologics License Application
Brentuximab vedotin is currently not approved for use in the AETHERA treatment setting. Based on the positive results from the AETHERA trial, a supplemental Biologics License Application (BLA) for brentuximab vedotin in the post-ASCT consolidation treatment of HL patients at high risk of relapse or progression was accepted for filing by the FDA. The FDA granted Priority Review for the application and the Prescription Drug User Fee Act (PDUFA) target action date is August 18, 2015. 
- Treatment with a standard combination therapy including doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) + radiation produces a high cure rate in limited stage Hodgkin lymphoma (HL) but carries risks of bleomycin-lung injury and late radiation toxicity. Brentuximab vedotin is highly active in relapsed HL and has been combined with doxorubicin, vinblastine, and dacarbazine (AVD). In a phase II trial, researchers evaluated brentuximab vedotin + doxorubicin, vinblastine, and dacarbazine (AVD) without radiation as initial therapy for non-bulky stage I–II HL. This combination of (x4) produced a high complete response rate (CRR) but with more toxicity than expected from a treatment with doxorubicin, vinblastine, and dacarbazine alone, particularly peripheral sensory neuropathy (PSN) and neutropenic fever. Given the overlapping mechanism of action and toxicity profile between brentuximab vedotin and vinblastine, the researchers are now considering a new study in which they will combine brentuximab vedotin with doxorubicin and dacarbazine (AD) in combination with brentuximab vedotin. 
- Although the concurrent administration of brentuximab vedotin with AVD followed by radiotherapy has not been studied for frontline treatment of early stage Hodgkin lymphoma, investigators at the Memorial Sloan Kettering Cancer Center, New York, NY, USA, looked at this regimen (1.2 mg/kg with AVD q2weeks × 4 cycles followed by 30 Gy involved-site radiotherapy or ISRT) in a pilot study to assesses its safety and efficacy to treat early stage, unfavourable risk HL. Their results showed that this treatment option is generally well tolerated with no evidence of significant pulmonary toxicity. Most evaluable patients (≥88%) achieved negative interim PET scans after 2 and 4 cycles of brentuximab vedotin + AVD, suggesting this is a highly active treatment even in patients with substantial disease bulk. 
- Standard chemotherapeutic regimens elicit inferior survival and are associated with increased toxicity in older Hodgkin lymphoma patients. Investigators initiated a multicentre study examining brentuximab vedotin given sequentially before and after chemotherapy for this pt population (NCT01476410). Sequential treatment integrating brentuximab vedotin before and after doxorubicin, vinblastine, and dacarbazine (AVD) chemotherapy for newly diagnosed older HL patients is feasible and promising. The pre-planned interim analysis confirmed the requisite complete response rate needed for continuation to the second stage of a multicentre phase II study 
- In a phase I–II trial designed to evaluate the tolerability and activity of the potentially promising combination of brentuximab vedotin and bendamustine, investigators at the Princess Margaret Cancer Centre, Toronto, Canada, the BC Cancer Agency, Vancouver, Canada and the Center for Lymphoid Malignancies, Columbia University Medical Center, New York, NY, USA, noted that, in the heavily treated population of of patients with Hodgkin lymphoma and ALCL, this combination represents a very effective and tolerable regimen. Of the 28 patients who were enroled in the phase I part of the study, 18 were male, 27 had HL and 1 ALCL, the median number of prior systemic therapies was 5 (range 1–14), and with 17 patients having had prior ASCT and 11 prior radiation. The maximum tolerated dose of brentuximab vedotin was 1.8 mg/m2 and bendamustine 90 mg/m2. Four patients (15%) obtained complete response, and 13 (48%) had a partial response for an overall response rate of 63%. Four patients had stable disease. Among the 9 patients who had received a prior treatment with brentuximab vedotin, 4 responded (44%) (PR = 4, SD = 2, PD = 3), and of the 4 patients who had prior bendamustine, 2 responded (50%) (PR = 2, SD = 1, PD = 1). Based on these results, the Phase II part of this trial is now enrolling. The goal is to accrue an additional 37 patients. In addition, plasma and serum biomarkers are being prospectively collected for correlation with toxicity and response.
- While many patients with diffuse large B-cell lymphoma (DLBCL) have long-term remissions with frontline rituximab-chemotherapy, there is no standard therapy for relapsed DLBCL patients who are not candidates for, or relapse after, stem cell transplant. In a phase II, open-label study designed to assess brentuximab vedotin in relapsed/refractory CD30+ DLBCL and in DLBCL with undetectable CD30 (CD30u) (NCT01421667), treatment with brentuximab vedotin alone and brentuximab vedotin + rituximab-chemotherapy showed greater activity in CD30+ DLBCL patients compared to CD30u patients. Toxicity was similar across arms and aligns with the current brentuximab vedotin safety profile. Biomarker analyses are ongoing. Response rates and alternative methods of assessing CD30 appear to support the targeted mechanism of action for brentuximab vedotin. 
- Finally, updated results of a phase II trial of brentuximab vedotin combined with RCHOP, an immunochemotherapy regimen consisting of rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride (doxorubicin hydrochloride), vincristine and prednisone used to treat both indolent and aggressive forms of non-Hodgkin lymphoma, in frontline treatment of patients with high-intermediate/high-risk DLBCL, who generally have a relatively poor outcomes with RCHOP, confirm that single-agent this drug has shown activity in patients with relapsed or refractory DLBCL (CD30+ pts, 17% CR; CD30− pts, 10% CR). In this study, patients were randomized to 6 cycles of BV + RCHOP: 1.2 or 1.8 mg/kg brentuximab vedotin q3 weeks IV with standard RCHOP. The available data suggest that the complete response rate (CR) in CD30+ patients was higher than in CD30− patients. When combined with RCHOP, the investigators from a number of centers, including Mayo Clinic, Rochester, NY, the University of Utah Huntsman Cancer Institute, Salt Lake City, UT, and The University of Texas MD Anderson Cancer Center, Houston, TX, noted that brentuximab vedotin is better tolerated at 1.2 mg/kg than 1.8 mg/kg due to reduced neuropathy. The protocol of this trial has been amended to assess the safety and activity of 1.8 mg/kg BV + RCHP in CD30+ high-intermediate/high-risk DLBCL patients.