Multiple presentations at the 56th American Society of Hematology (ASH) Annual Meeting and Exposition taking place in San Francisco, CA, December 6-9, 2014, highlighted brentuximab vedotin (Adcetris ; Seattle Genetics/Takeda) in frontline and salvage Hodgkin lymphoma or HL.
Brentuximab vedotin is an antibody-drug conjugate or ADC directed to CD30, in which a monoclonal antibody is attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E or MMAE. The drug is based on Seattle Genetics’ proprietary technology. The antibody-drug conjugate employs a linker system that is designed to be stable in the bloodstream and release MMAE upon internalization into CD30-expressing tumor cells.
CD30 or Ki-1 is a marker expressed in classical HL and systemic anaplastic large cell lymphoma (sALCL), an aggressive type of non-Hodgkin lymphoma that is usually of the T-cell type. The marker may appear in the lymph nodes, skin, bones, soft tissues, lungs, or liver.
Hodgkin lymphoma, also called Hodgkin disease, is a cancer of the immune system that is marked by the presence of a type of cell called the Reed-Sternberg cell. The two major types of Hodgkin lymphoma are classical Hodgkin lymphoma and nodular lymphocyte-predominant Hodgkin lymphoma. Symptoms include the painless enlargement of lymph nodes, spleen, or other immune tissue. Other symptoms include fever, weight loss, fatigue, or night sweats.
The American Cancer Society estimates aproximately 9,100 new cases and 1,180 deaths from HL in the United States in 2014. More than 75% of all newly diagnosed patients with adult HL can be cured with combination chemotherapy and/or radiation therapy. 
Starting in the 1960’s with breakthroughs in combination chemotherapy the prognosis for patients have been steadily improving. Trends in long-term survival shows rapidly falling mortality – more rapidly than for any other malignancy 
Foundation of therapy
Data highlighted in oral sessions include encouraging long-term outcomes from a phase I trial evaluating brentuximab vedotin in combination with AVD chemotherapy in frontline HL, as well as strong activity evaluating brentuximab vedotin combination therapy in second-line HL and brentuximab vedotin monotherapy or combination therapy in frontline HL patients age 60 and older. In addition, encouraging data from multiple investigator-sponsored trials were featured in oral and poster sessions evaluating brentuximab vedotin in frontline and salvage HL and in non-Hodgkin lymphoma settings.
“Our goal is to establish brentuximab vedotin as the foundation of therapy for CD30-positive malignancies. The multiple data sets presented at this year’s annual meeting of the American Society of Hematology support that vision, showing encouraging activity associated with brentuximab vedotin treatment both as a single-agent and in combination with other agents for frontline and salvage Hodgkin lymphoma,” explained Clay B. Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics. “Of note, the oral presentation on the three-year long term follow-up from the phase I frontline Hodgkin lymphoma trial, demonstrating a failure-free survival rate of 92% and overall survival rate of 100% with a manageable safety profile, supports our goal to redefine frontline treatment of Hodgkin lymphoma with the addition of brentuximab vedotin. The phase III ECHELON-1 trial is evaluating brentuximab vedotin in this setting.”
Combined therapy in newly diagnosed advanced stage HL patients
This phase I trial was conducted to evaluate brentuximab vedotin plus the chemotherapy regimen ABVD (= doxorubicin hydrochloride or Adriamycin®, bleomycin or Blenoxane®, vinblastine sulfate or Velban® and dacarbazine or DTIC-Dome®) or brentuximab vedotin plus AVD, which removes bleomycin, for the treatment of newly diagnosed advanced stage HL patients.
Data previously presented from this trial demonstrated that 24 of 25 patients (96%) who received brentuximab vedotin plus AVD achieved a complete remission and 21 of 22 patients (95%) who completed therapy with brentuximab vedotin plus ABVD achieved a complete remission. The most common adverse events of any grade occurring in more than 30% of patients across both treatment regimens were hair loss, constipation, diarrhea, fatigue, insomnia, nausea, neutropenia, peripheral sensory neuropathy, fever and vomiting. As previously reported, pulmonary toxicity was seen in the brentuximab vedotin plus ABVD cohorts, resulting in a contraindication for the concomitant administration of brentuximab vedotin and bleomycin. No pulmonary toxicity was observed in the brentuximab vedotin plus AVD cohort.
The long-term data presented by Joseph Connors, M.D., BC Cancer Agency, includes:
- In the brentuximab vedotin plus AVD arm, three-year overall survival was 100 percent and three-year failure-free survival was 92%. In the brentuximab vedotin plus ABVD arm, three-year overall survival was 92% and three-year failure-free survival was 79%.
- Patients were followed for a median of 36 months in the brentuximab vedotin plus AVD arm and 45 months in the brentuximab vedotin plus ABVD arm. The longest time to relapse in either arm was 23 months.
Based on the phase I results, the global phase III ECHELON-I trial was initiated and is currently enrolling patients. This randomized trial is comparing progression-free survival in patients receiving brentuximab vedotin in combination with AVD to patients receiving ABVD alone. 
In combination with Bendamustine for HL Patients relapsed/refractory to Frontline Therapy
Interim data were presented from an ongoing phase 1/2 single-arm, open-label clinical trial evaluating the efficacy and tolerability of brentuximab vedotin in combination with bendamustine in HL patients who have relapsed or were refractory to frontline therapy. Current treatment options in this setting include salvage chemotherapy regimens that historically have resulted in variable complete remission rates of 19 to 60% and are associated with significant toxicities. 
The phase I study determined the dosing level of bendamustine combined with brentuximab vedotin, and assessed safety and tolerability. The phase II expansion cohort is evaluating combination treatment of brentuximab vedotin and bendamustine to assess best response, duration of response and progression-free survival. In the trial, brentuximab vedotin in combination with bendamustine is administered every three weeks, for up to six cycles, followed by additional treatment with single-agent brentuximab vedotin for up to a total of 16 cycles of therapy. After patients receive at least two cycles of combination therapy, they have the option to pause treatment to receive an autologous stem cell transplant or ASCT and then resume treatment with single-agent brentuximab vedotin as consolidation.
Data were reported from 54 patients with a median age of 37 years. The majority of patients (54%) had stage III/IV disease at the time of initial diagnosis and 37 patients (69%) had either primary refractory disease or had relapsed within one year of frontline therapy. Interim data from this phase 1/2 trial to be highlighted in an oral presentation by Ann LaCasce, M.D., Dana-Farber Cancer Institute, include:
- Of 48 patients evaluable for response, 46 patients (96%) had an objective response, including 40 patients (83%) with a complete remission and six patients (13%) with a partial remission. One patient had stable disease and one patient had progressive disease. The majority of complete remissions (34 of 40 patients) were achieved after two cycles of combination therapy.
- Median duration of response, progression-free survival and overall survival had not yet been reached.
- No adverse impact on stem cell mobilization or engraftment was observed. Thirty-two patients had received an ASCT to date.
- The most common adverse events from combination treatment were infusion-related reactions (IRRs) which were seen in approximately 50% of patients. Approximately 20% of IRRs were Grade 3 or higher. The majority of IRRs occurred within 24 hours of the second cycle of combination treatment and were considered related to both therapies. Symptoms associated with IRRs were dyspnea (15%), chills (13%) and flushing (13%). The trial protocol was amended to require premedication with corticosteroids and antihistamines, which decreased the severity of IRRs.
Phase II study of monotherapy and in combination with dacarbazine in Frontline Treatment
Data were presented from an ongoing phase II clinical trial evaluating brentuximab vedotin as a single-agent or in combination with dacarbazine as frontline therapy for HL patients age 60 or older. Interim data were reported from 27 patients treated with single-agent brentuximab vedotin and 18 patients treated with the combination of brentuximab vedotin and dacarbazine. The median age of patients was 78 years in the single-agent brentuximab vedotin arm and 72.5 years in the dacarbazine combination arm. A majority of patients in each arm had stage III/IV disease at the time of diagnosis. The data will be highlighted in an oral presentation by Andres Forero-Torres, MD, University of Alabama at Birmingham.
Data from the single-agent brentuximab vedotin arm include:
- Of 27 evaluable patients, 25 patients (93%) had an objective response, including 19 patients (70%) with a complete remission and six patients (22%) with a partial remission. Two patients (7%) had stable disease.
- All 27 patients (100%) achieved tumor reduction.
- After a median follow-up time of 8.7 months, the median duration of response was 9.1 months and the median PFS was 10.5 months.
- The median number of treatment cycles was eight.
- The most common adverse events of any grade occurring in 20% or more of patients were peripheral sensory neuropathy, fatigue, nausea, swelling, diarrhea, decreased appetite and constipation.
The only Grade 3 adverse events occurring in more than one patient were peripheral sensory neuropathy (7 patients) and peripheral motor neuropathy and rash (two patients each). No Grade 4 adverse events occurred.
Preliminary key findings in the ongoing trial evaluating combination brentuximab vedotin and dacarbazine include:
- Of 14 evaluable patients, 13 patients (93%) had an objective response, including four patients (29%) with a complete remission and nine patients (64%) with a partial remission.
- All 14 evaluable patients (100%) achieved tumor reduction.
- Fifteen of 18 patients (83%) were still on treatment at the time of the analysis.
- The most common Grade 1 and 2 adverse events were peripheral sensory neuropathy and nausea (33% each); diarrhea and constipation (28% each); fatigue, hair loss, joint pain and headache (22%each).
- Grade 3 or serious adverse events occurring in one patient each were colitis and vomiting, hypotension and hyperglycemia.
- The trial is currently enrolling patients to evaluate the combination of brentuximab vedotin and bendamustine.