Brentuximab Shows "Amazing" Responses in Refractory Lymphoma

Zosia Chustecka

December 08, 2010

December 8, 2010 (Orlando, Florida) — The experimental agent brentuximab vedotin has shown "amazing responses" in patients with resistant and refractory Hodgkin's lymphoma, researchers reported here at the American Society of Hematology (ASH) 52nd Annual Meeting. It offers hope for patients who have no other options and a poor prognosis, they said.

Brentuximab represents "a big breakthrough for this patient population," said Ginna Laport, MD, associate professor of medicine at Stanford University Medical Center, California.

"This is a very exciting drug for Hodgkin's lymphoma," she told journalists at an ASH press briefing.

Lymphoma expert Andre Goy, MD, from the John Thuerer Cancer Center at Hackensack University in New Jersey, agreed.

Dr. Goy told Medscape Medical News that the responses that have been seen in refractory patients have been "very impressive," and he predicted that even better responses will be seen with the drug in less advanced patients. In the future, he said, it could be used up front in combination with chemotherapy, which could be "phenomenal."

The drug is being developed by Seattle Genetics and Millennium/Takeda, and the companies plan to apply for approval in early 2011.

Dr. Goy praised the researchers for their persistence in developing the drug; there have been several previous frustrating failed attempts.

The product is an antibody–drug conjugate. The antibody targets CD30, a protein expressed on cancer cells in Hodgkin's lymphoma. It is also expressed in anaplastic large cell lymphoma, an aggressive type of T cell non-Hodgkin's lymphoma, which also responds to treatment with this drug.

The antibody latches onto the CD30 expressed on the cancer cell surface, and then delivers the attached drug (monomethyl auristatin E), which is toxic to the cell. It is this double action that led to success; previous attempts using just antibodies had been unsuccessful.

New Hope for Patients

The indication of refractory and resistant Hodgkin's lymphoma has been allocated fast-track approval by the US Food and Drug Administration (FDA), because these patients have no other treatment options.

These patients tend to be young; average age at diagnosis is about 30 years. Once they have failed autologous stem cell transplantation and several lines of chemotherapy, there is really little else that remains, and survival then is only about 2 and a half years, explained Anas Younes, MD, from the University of Texas M.D. Anderson Cancer Center in Houston. He was involved in the clinical trials of brentuximab, and headed a recently published phase 1 study (N Engl J Med. 2010;363:1812-1821).

This new drug offers hope for these patients, he said. Hodgkin's lymphoma is a highly curable disease, he noted, but about 20% of patients become refractory or resistant to further treatment.

The responses to brentuximab that have been reported "are amazing with a single agent in such a refractory patient population," Dr. Younes told Medscape Medical News.

New details from 2 phase 2 clinical trials, which will be used for the approval application, were presented at the ASH meeting and highlighted in the final Best of ASH session. Top-line results were released last month, and reported by Medscape Medical News at the time.

Dramatic Response Rates

Dr. Robert Chen

The results in refractory and resistant Hodgkin's lymphoma were reported by Robert Chen, MD, assistant professor at the City of Hope National Medical Center in Duarte, California.

They come from a single-group multicenter study of 102 patients, all of whom had failed autologous stem cell transplantation and a median of 4 chemotherapy regimens (range, 1 to 13). The median age of patients was 31 years (range, 15 to 77 years).

Brentuximab 1.8 mg/kg was administered as a 30-minute outpatient intravenous infusion once every 3 weeks, up to 16 cycles of therapy (median, 9 cycles).

Responses were "dramatic," Dr. Chen said. The objective response rate was 75%, and tumor reduction was demonstrated in 94 patients (96%). Around one third of patients (34%) achieved complete remission; the median duration for complete remission has not yet been reached.

Adverse effects were "very manageable," Dr. Chen said. The most common were peripheral sensory neuropathy (reported by 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.

Kristie Blum, MD, from Ohio State University in Columbus, highlighted these brentuximab data in an educational session on future treatments for Hodgkin's lymphoma, alongside other new agents that are being investigated in this disease. These include the experimental agent panobinostat (Novartis), everolimus, and lenalidomide.

"Brentuximab is the one that is furthest along and it has shown the highest response rates so far," she told Medscape Medical News. Some of the other new drugs have responses that are not as high but are very durable, with patients remaining in remission for 2 to 3 years so far.

Dr. Blum highlighted the problem of peripheral neuropathy with brentuximab, and said that she has had patients who have had to discontinue the drug because of this adverse effect.

Results in Anaplastic Large Cell Lymphoma

Results in refractory and resistant anaplastic large cell lymphoma were presented at the meeting by Andrei Shustov, MD, from the Fred Hutchinson Cancer Research Center, University of Washington, Seattle. They come from a phase 2 study of 58 patients who had failed on a median of 2 chemotherapy regimens (range, 1 to 6); 44% of patients had also undergone radiation.

Dr. Shustov noted that the only FDA-approved therapy for these patients is pralatrexate (Folotyn), which has shown an objective response rate of 27% and complete remission in 8% of patients.

In this trial, brentuximab treatment resulted in an objective response rate of 86% and complete remission in 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.

"All but 1 patient had shrinkage of their tumor," Dr. Shustov reported, adding that this result (in 57 of 58 patients) was confirmed by an independent review. The median duration of response has not been reached, he added.

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.

All the brentuximab studies were funded by the manufacturer.

American Society of Hematology (ASH) 52nd Annual Meeting: Abstract 283, presented December 6, 2010; Abstract 961, presented December 7, 2010.

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