A BREAKTHROUG TREATMENT FOR RELAPSED HODGKIN LYMPHOMA

November 3, 2010 — A new drug for relapsed or refractory Hodgkin's lymphoma and anaplastic large-cell lymphoma — brentuximab vedotin (developed by Seattle Genetics and Millennium/Takeda) — is close to market.

"I never use the term breakthrough, but this is definitely a major step forward in the treatment of both of those types of lymphoma," Joseph Connors, MD, director of the Centre for Lymphoid Cancer in Vancouver, British Columbia, told Medscape Medical News. He was involved in 2 pivotal clinical trials that will be used for approval applications for brentuximab in both the United States and Europe, expected to be filed early next year.

Both studies are due to be presented next month at the American Society of Hematology annual meeting, but top-line results showing "very high response rates" were announced in press releases from the manufacturer.

Brentuximab used alone in patients with relapsed or refractory Hodgkin's lymphoma (n = 102) showed a 75% objective response rate; in patients with relapsed or refractory anaplastic large-cell lymphoma (n = 58), the drug produced an 86% objective response rate.

"These sorts of response rates are unheard of," said Anas Younes, MD, from the University of Texas M.D. Anderson Cancer Center in Houston.

"This is remarkable single-agent activity," Dr. Younes told Medscape Medical News, and it confirms results seen in an earlier phase 1 trial that he conducted, which has just been published in the November 4 issue of the New England Journal of Medicine.

These are patients who have no other therapeutic options, Dr. Younes said. They have failed on first-line chemotherapy, and then they have failed on second-line chemotherapy with an autologous stem-cell transplant, he explained.

"We can try other chemotherapies and even radiation, but these don't really work, and the average life-span for such a patient is about 2 and a half years," he said.

"Keep in mind that these are young patients," Dr. Younes added, pointing out that the average age of a patient diagnosed with Hodgkin's lymphoma is about 30 years.

Brentuximab will offer a new option for these patients, and "creates hope for these young men and women," he said. "They have been neglected in terms of drug development for more than 4 decades," Dr. Younes said, because "they represent a very small market."

Hodgkin's lymphoma affects about 8500 people annually in the United States, he noted, adding that "we expect to cure about 80% of all new comers. It's a highly curable disease." But the patients who fail on standard therapies have had, until now, no other hope, he said.

Antibody With Toxin Attached

The new product is an antibody–drug conjugate that targets CD30, which is expressed on the surface of cells in Hodgkin's lymphoma and anaplastic large-cell lymphoma, an aggressive type of T cell non-Hodgkin's lymphoma.

In both of these diseases, all of the cancer cells express CD30, so this protein represents an obvious target for therapy. However, previous attempts with antibodies directed against CD30 were unsuccessful. Even the antibody in this latest product, when used alone, showed little clinical activity, explained Dr. Younes — it was combining it with a toxin that did the trick.

The toxin in brentuximab is the antitubulin agent monomethyl auristatin E, and it is attached to anti-CD30-specific monoclonal antibody cAC10. The antibody acts as a delivery system to get the "cargo" into the cell, Dr. Younes explained.

The resultant product is "very well tolerated," he said, especially compared with chemotherapy. In the phase 1 trial that he headed, there were reports of fatigue, fever, diarrhea, some neutropenia, and cumulative neuropathy, he said.

That just-published phase 1 study involved 45 patients with relapsed or refractory Hodgkin's lymphoma or anaplastic large-cell lymphoma. Patients received brentuximab as a single agent, once every 3 weeks (as they did in the 2 pivotal phase 2 studies). The results showed objective responses in 17 patients, with complete remission in 11 patients; median duration of response was 9.7 months. In addition, 36 of 42 evaluable patients (86%) showed a tumor response.

"These sorts of responses are amazing with a single agent in such a refractory patient population," Dr. Younes noted. These initial results have since been confirmed by another phase 1 trial (presented recently at the 8th International Symposium on Hodgkin Lymphoma in Cologne, Germany [abstract 74]) and by the 2 larger pivotal phase 2 trials.

Having been involved in both of those pivotal trials, Dr. Connors predicts that brentuximab will "have a major role to play" in the management of both Hodgkin's lymphoma and anaplastic large-cell lymphoma.

"First, it will be useful all by itself for patients with no other good alternative," he said.

The 2 studies will be used as the basis for approval applications in both the United States and in Europe, which the manufacturer plans to file in early 2011. The product has been granted fast-track status by the US Food and Drug Administration for Hodgkin's lymphoma, which means review within 6 months, so brentuximab could be on the market before the end of next year.

The product has also been granted orphan drug status in both the United States and Europe, because relapsed and refractory Hodgkin's lymphoma represents a substantial unmet medical need, according to the company. Worldwide, almost one third of the 30,000 newly diagnosed patients relapse or become refractory to front-line therapy each year.

However, this use in relapsed/refractory patients might be just the beginning. Dr. Connors notes that "in future studies, it should be possible to include brentuximab in addition to standard treatments for both of those lymphomas in a way that boosts their cure rates without adding much to the toxicity of the treatments."

Further trials are already under way, the manufacturers note in a press release. A phase 3 clinical trial (known as AETHERA) is being conducted in patients at high risk for residual Hodgkin's lymphoma after autologous stem-cell transplant, a phase 2 trial is exploring retreatment in relapsed patients who have previously responded to brentuximab, and a phase 1 trial is investigating front-line combination treatment of Hodgkin's lymphoma.

All of the clinical trials with brentuximab have been/are being funded by the manufacturers, Seattle Genetics and Millennium/Takeda.

N Engl J Med. 2010;363:1812-1821.