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Brentuximab vedotin showed very positive results in lymphoma patients in several early trials, prompting the FDA's Oncologic Drugs Advisory Committee to unanimously recommend accelerated approval for the drug.
While treatment options have improved in recent years for patients with Hodgkin lymphoma, the mortality and relapse rates have remained fairly constant. The American Cancer Society estimates that of the approximately 8800 cases of Hodgkin lymphoma expected to be diagnosed in 2011, about 30% of those patients will relapse, usually within the first 2 years after treatment. About 1300 patients are expected to die as a result of the disease.
Although not as deadly as other forms of cancer, Hodgkin lymphoma incidence, mortality, and survival statistics have not changed significantly for a number of years because there has not been a new treatment for this disease approved by the FDA since 1977. However, that has changed recently as a new therapeutic agent, brentuximab vedotin (Adcetris), was approved in August to treat Hodgkin lymphoma and another rarer type of lymphoma. The drug showed very positive results in lymphoma patients in several early trials, prompting the FDA’s Oncologic Drugs Advisory Committee to unanimously recommend accelerated approval for the drug.
Brentuximab vedotin is an antidrug conjugate containing an anti-CD30 monoclonal antibody. The drug selectively targets CD30, an important genetic marker in classic lymphoma and anaplastic large cell lymphoma (ALCL), while sparing nearby normal cells that do not express the marker.
The drug is being developed by 2 companies: Seattle Genetics in the United States and Millennium: The Takeda Oncology Company, which has offices in Japan and Massachusetts. According to Clay B. Siegall, PhD, president and CEO of Seattle Genetics, the company did not necessarily set out to develop a drug to treat lymphoma, but identifying CD30 as a target genetic marker made lymphomas a natural course in the drug’s development.
“We felt that we had a target that was superb in treating unmet medical needs,” Siegall said.
The FDA has approved the drug for Hodgkin lymphoma patients who have relapsed after autologous stem cell transplantation, or after 2 prior rounds of chemotherapy. Brentuximab vedotin has also been approved as a second-line treatment for patients with ALCL who have relapsed after at least 1 prior round of chemotherapy.
The intravenous drug was tested in 2 different dosages: one arm tested a weekly dosage, and another study arm tested delivering a dose every 3 weeks. Michelle A. Fanale, MD, assistant professor in the Department of Lymphoma/ Myeloma in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston, was lead author of the weekly dosage study. Fanale said that the study did not show enough of a difference in the response rate to justify continuing the pursuit of a weekly dosage.
“By delivering the medicine every 3 weeks, it’s much less of a burden on the patient,” Fanale said.
I’m hoping that many patients have access to this drug. In patients with Hodgkin lymphoma, I believe it’s going to become a standard of therapy. ”
—Robert W. Chen, MD
The approval of brentuximab vedotin was based on a number of encouraging studies. At the American Society of Hematology’s annual meeting in 2010, Robert W. Chen, MD, assistant professor of hematology and hematopoietic cell transplantation at City of Hope in Duarte, California, presented the results of a study involving patients with relapsed or refractory Hodgkin lymphoma who had previously undergone autologous stem cell transplantation.
Of the 102 patients enrolled in the study, 75% experienced a significant shrinkage in their tumors by 50% or more. Complete remission was achieved in 34% of patients in the study. Overall, 94% of patients experienced some form of tumor regression. On average, patients in the study responded to the drug for 6.7 months.
“We were surprised by just how well patients responded to brentuximab,” Chen said. “Suddenly…nearly every patient was having positive results.”
Side effects included peripheral sensory neuropathy, fatigue, nausea, upper respiratory tract infection, and diarrhea. The most common adverse events of at least grade 3 were neutropenia, peripheral sensory neuropathy, thrombocytopenia, and anemia. Twenty percent of patients in the study discontinued brentuximab vedotin because of treatment-related adverse affects, which, according to Chen, was similar to the rates seen in other trials. He said that none of the deaths of patients enrolled in the study were attributable to brentuximab vedotin.
With the results of the study, Chen said he believes that brentuximab vedotin will eventually get approved as a first-line treatment and become available to all patients with Hodgkin lymphoma, not just those who have relapsed after another treatment.
“I’m hoping that many patients have access to this drug,” Chen said. “In patients with Hodgkin lymphoma, I believe it’s going to become a standard of therapy.”
Further studies confirmed brentuximab vedotin’s effectiveness, including 2 that were presented at the European Hematology Association’s annual meeting in June. In a single-arm study of 58 patients with ALCL, patients were treated only with brentuximab vedotin. In this study, 86% of patients showed a complete or partial response and responded to therapy for an average of 12.6 months.
The other study focused on cutaneous lesions, an uncomfortable and cosmetically displeasing side effect associated with lymphoma. In this retrospective study of 58 patients with relapsed or refractory ALCL, 15 patients had cutaneous involvement of their disease at the time of enrollment. The phase II study found that 14 of the 15 patients (93%) achieved complete remission of their cutaneous lesions after a median of 14.9 weeks of treatment with brentuximab vedotin. An independent central review further revealed that all 15 patients achieved objective response to their systemic disease, and 13 of the 15 patients achieved complete remission. The remaining 2 patients achieved partial remission.
“Not only were patients having really good outcomes, but they were really having a better quality of life after treatment,” Fanale said. “I had young patients who had full heads of hair, who looked like any other kids their age, able to do normal things. You couldn’t even tell they had dealt with this disease.”
According to Fanale and Chen, patients have been clamoring to get into clinical trials of brentuximab vedotin for months. With the approval from the FDA, many patients will have access to the drug as a second- or third-line therapy. However, not all Hodgkin lymphoma patients can currently take advantage of the drug.
Seattle Genetics said the company is currently exploring a number of applications for other cancers by exploring how effective the CD30 target is in the treatment of leukemia, myeloma, melanoma, and sarcoma.
Finally, Siegall said the company is looking into clinical trials to test the drug’s effectiveness in patients with cutaneous T-cell lymphoma, as well as exploring the possibility of making brentuximab vedotin a first-line treatment for Hodgkin lymphoma and T-cell lymphoma.
“We see a broad range of opportunities for this agent,” Siegall said. “The sooner we get the data, the better.”