Data presented at the 2014 Annual Bone Marrow Transplant (BMT) Tandem Meetings organized by The American Society for Blood and Marrow Transplantation and the Center for International Blood & Marrow Transplant Research being held in Grapevine (Dallas), Texas, February 26 – March 2, 2014, highlights the benefits of brentuximab vedotin (Adcetris®; Seattle Genetics) in various treatment schedules for hard to treat cancers.
Brentuximab vedotin is an antibody-drug conjugate or ADC comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), utilizing Seattle Genetics’ proprietary technology. Antibody-drug conjugates employ a linker system that designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing tumor cells, which are expressed in classical HL and systemic anaplastic large cell lymphoma (sALCL).
Presentations included the first report from an ongoing phase I/II clinical trial evaluating the combination of brentuximab vedotin and bendamustine in the treatment of salvage Hodgkin lymphoma (HL). In addition, a poster presentation summarized the clinical trial design and pooled patient demographics from the phase III AETHERA trial in patients with increased risk factors for HL progression following autologous stem cell transplant (ASCT).
“We are focused on exploring the potential to improve outcomes in earlier lines of HL by incorporating ADCETRIS in novel settings, and the data presented at the 2014 BMT Tandem Meetings illustrate this goal,” said Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development, at Seattle Genetics. “The interim data presented today evaluating brentuximab vedotin and bendamustine combination therapy in the salvage HL setting are encouraging, showing a complete remission rate of 77%, with another 15% of patients, who currently remain on treatment, achieving early partial remissions. In addition, a pooled analysis for the overall population in the AETHERA phase III clinical trial was presented, including demographic data, baseline disease characteristics and treatment exposure. We look forward to presenting efficacy and safety data from the AETHERA trial in the second half of 2014.”
First salvage setting
The interim results from another ongoing phase I/II clinical trial were reported from 23 patients with HL after first relapse. The multi-phase study was divided into two cohorts to determine the recommended dose and tolerability of brentuximab vedotin in combination with bendamustine and to assess the complete remission rate associated with combination use.
Bendamustine is an alkylating agent used in the treatment of chronic lymphocytic leukemias and lymphomas. In this trial, patients are eligible to receive up to six cycles of brentuximab vedotin in combination with bendamustine followed by additional single-agent brentuximab vedotin for a total of 16 cycles. As a part of the trial design, after patients receive brentuximab vedotin plus bendamustine combination therapy, they have the option to pause therapy to receive an ASCT and then resume treatment with single-agent brentuximab vedotin as consolidation. The median age of patients enrolled in the trial was 43 years. At the time of data analysis, 23 patients were evaluable for safety and 13 were evaluable for response. Key findings of the study included:
- After a median of two cycles of therapy, 92% of patients evaluable for response (12 of 13 patients) achieved an objective response, including 77% (ten patients) with complete remissions and 15% (two patients) with partial remissions. At the time of analysis, the two patients with partial remissions had each received two cycles of therapy and treatment was ongoing.
- At the time of the analysis, seven patients had undergone an ASCT and three had restarted ADCETRIS as monotherapy.
- The most common adverse events were nausea (57%), rash (39%), fever (35%), fatigue (30%) and vomiting (30%).
Grade 3 or 4 adverse events
The most common Grade 3 or 4 adverse event was lymphopenia (13% Grade 3 and 9%Grade 4).
Infusion reactions considered related to combination therapy were reported as serious adverse events in six patients and led to treatment discontinuation for three patients. Symptoms included rash, hives, itching, shortness of breath, wheezing, throat tightness, fever, chills and hypotension. As a result, the protocol is being amended to require premedication with corticosteroids and antihistamines.
High Risk of Residual Hodgkin Lymphoma Following Autologous Stem Cell Transplant
During the annual meeting, results of a different trial – the AETHERA Trial – were also presented. The AETHERA trial is a randomized, double-blind, placebo-controlled phase II study designed to evaluate the potential of brentuximab vedotin in the treatment of patients at high risk of residual hodgkin lymphoma following autologous stem cell transplant. The investigators looked at patients with at least one risk factor for lymphoma progression and the potential of brentuximab vedotin to prevent progression post-ASCT.
The primary endpoint is progression-free survival. Randomization was stratified by risk factors at the time of initiating salvage therapy (refractory, relapsed within 12 months or relapsed after 12 months with extranodal involvement) and by response to salvage therapy (complete remission, partial remission or stable disease). The presentation reviewed the demographics and baseline disease characteristics of the 329 patients who enrolled in the study. Key findings for the pooled, blinded data include:
- Response to frontline therapy, 196 patients (60%) were refractory, 107 patients (33%) relapsed in less than 12 months and 26 patients (8%) relapsed after more than 12 months with extranodal disease.
- Response to salvage treatment pre-ASCT, 125 patients (38%) had a complete remission, 111 patients (34%) had a partial remission and 93 patients (28%) had stable disease.
- The median number of treatment cycles was 15 (range, 1-16), and approximately half of all patients (49%) received the maximum 16 cycles of study treatment.
- All patients had completed or discontinued treatment as of August 2013; 61 patients (19%) discontinued treatment due to an adverse event.
- Forty-two patients (13%) are known to have died, including 37 deaths that occurred after disease progression and one death that occurred within 30 days of the last dose and was considered not disease related.