NEW DRUG FOR REFRACTORY HODGKIN LYMPHOMA APPROVED

July 14, 2011 — The Oncologic Drugs Advisory Committee to the US Food and Drug Administration (FDA) voted 10-0 today to recommend that the FDA grant accelerated approval of brentuximab vedotin (Adcetris, Seattle Genetics/Millenium-Takeda Oncology) for the treatment of relapsed or refractory Hodgkin's lymphoma. The committee also voted likewise for brentuximab for the treatment of relapsed or refractory systemic anaplastic large-cell lymphoma (ALCL).
The new product is an antibody–drug conjugate that targets CD30, a protein expressed on the surface of cells in Hodgkin's lymphoma and ALCL, an aggressive type of T-cell non-Hodgkin's lymphoma.
Patient responses to brentuximab have been called "remarkable" and "amazing" by experts.
With the committee's comments in hand, the FDA now will proceed to its final decision on the 2 Biologics License Applications (BLAs) for brentuximab; the target date for the decision on the 2 indications is August 30, 2011.
Before the FDA grants accelerated approval, the pharmaceutical company is typically required to commit to a confirmatory trial protocol submission date, a trial completion date, and a study report submission. If a confirmatory study does not show a similar benefit as earlier, small studies, an agent that received accelerated approval can be denied full regular approval, which is a rare event.
The BLAs for brentuximab vedotin are based on results from a pivotal phase 2 trial in relapsed or refractory Hodgkin's lymphoma and another phase 2 trial in relapsed or refractory systemic ALCL.
The Hodgkin's lymphoma trial is a single-group multicenter study of 102 patients; in all patients, autologous stem cell transplantation and a median of 4 chemotherapy regimens (range, 1 - 13) had failed. The median age of patients was 31 years (range, 15 - 77 years).
Brentuximab, 1.8 mg/kg, was administered as a 30-minute outpatient intravenous infusion once every 3 weeks, for up to 16 cycles of therapy (median, 9 cycles).
Responses were "dramatic," according to investigator Robert Chen, MD, from the City of Hope National Medical Center in Duarte, California, at the 2010 annual meeting of the American Society of Hematology (ASH), as reported by Medscape Medical News.
The objective response rate was 75%, and tumor reduction was demonstrated in 94 patients (96%). Around one third of patients (34%) achieved complete remission.
Adverse effects were "very manageable," Dr. Chen said at the time. The most common were peripheral sensory neuropathy (43% of patients), fatigue (40%), nausea (35%), neutropenia (19%), diarrhea (18%), and pyrexia (16%). Most were grade 1 or 2. The neuropathy resolved once the drug was discontinued in most patients, he said. It was discontinued in 10% of patients because of neuropathy, and another 9% had a dose reduction because of this adverse effect.
Hodgkin's lymphoma is a highly curable disease, but about 20% of patients become refractory or resistant to further treatment, explained another expert at the ASH meeting. There are no other treatment options for this refractory, resistant disease, and thus brentuximab has been on a fast track for approval from the FDA.
With regard to ALCL, the pivotal trial is a study of 58 patients in whom a median of 2 chemotherapy regimens (range, 1 - 6) had previously failed; 44% of patients had also unsuccessfully undergone radiation. Treatment with brentuximab resulted in an objective response rate of 86% and a complete remission rate of 54%.
This complete remission rate is "remarkable," said Robert Hromas, MD, from the University of New Mexico, Albuquerque, who highlighted these results in the "Best of ASH" session at the end of the meeting.
The effectiveness of brentuximab is a strong contrast to that of the only FDA-approved therapy for these patients. Pralatrexate (Folotyn, Allos Therapeutics) has shown an objective response rate of 27% and complete remission in 8% of patients, said one of the brentuximab investigators, Andrei Shustov, MD, from the Fred Hutchinson Cancer Research Center, University of Washington, Seattle, during his presentation at the ASH meeting.
In contrast, in this trial of brentuximab in 58 patients with ALCL, "all but 1 patient had shrinkage of their tumor," Dr. Shustov reported at the time. The adverse effects were manageable, he said. The median time to onset of peripheral neuropathy was 16 weeks, and the neuropathy was reversible in about half of patients, he said.