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Trial Suggests New Treatment Option for Hodgkin Lymphoma

Posted Dec 14 2010 12:00am

Trial Suggests New Treatment Option for Hodgkin Lymphoma

An illustration showing the mechanism of action of brentuximab vedotin, an antibody-drug conjugate The antibody-drug conjugate (ADC) brentuximab vedotin works by binding to CD30 proteins on the surface of Hodgkin lymphoma cells. The ADC then forms a complex with CD30 and enters the cell. Inside the cell, the ADC’s chemotherapy component is released and kills the cancer cell. [ Enlarge ]

Intermediate results from a phase II clinical trial indicate that an investigational agent called brentuximab vedotin may be an effective alternative for some patients with Hodgkin lymphoma who have few viable treatment options. The results are promising enough that the drug’s manufacturer, Seattle Genetics, will submit the agent to the Food and Drug Administration (FDA) for approval in early 2011. The trial results were presented last week at the American Society of Hematology (ASH) annual meeting in Orlando, FL.

In the 102-patient clinical trial, 75 percent of patients saw their tumors shrink to at least half their original size (an objective response), and one-third of patients had complete tumor regressions (a complete response). Overall, the estimated 1-year survival rate was 88 percent.

The antitumor effect is particularly impressive, according to trial investigator Dr. Robert Chen of City of Hope Comprehensive Cancer Center, because most of the patients in the trial were high risk: they had never achieved a complete response to standard first- and second-line therapies such as chemotherapy or hematopoietic stem cell transplantation . Brentuximab is “very active for a single-agent therapy in this setting,” Dr. Chen said during a press briefing.

Hodgkin lymphoma most often occurs in younger patients, and the median age of trial participants was 31. The prognosis is generally poor for patients whose disease doesn’t respond to therapy or returns after an autologous hematopoietic stem cell transplant, explained Dr. Ginna Laport of Stanford University Medical Center, during the briefing. “There is usually not much to offer them,” she said. So the results with brentuximab represent “a big breakthrough for this [patient] population.”

Although other therapies can be somewhat effective in such patients, if the FDA does approve brentuximab, it should fill an important clinical niche, said Dr. Wyndham Wilson, head of the Lymphoma Therapeutics Section in NCI’s Center for Cancer Research (CCR). “Certainly as a salvage regimen, it may become the first drug to turn to in the post-transplant setting,” he said.

Patients in the trial received brentuximab—also known as SGN-35—once every 3 weeks during a 30-minute infusion for as many as 16 cycles of therapy. Side effects were limited, mostly low-grade nausea, fatigue, and peripheral neuropathy . About 10 percent of patients had to halt treatment because of peripheral neuropathy, which often consists of intense tingling, burning, or pain in the extremities. But, in most patients, the symptoms could be managed and many could resume treatment, Dr. Chen said.

The Technology behind the Results

Brentuximab is an antibody-drug conjugate (ADC) in which an antibody directed against the protein CD30 is chemically linked to a potent chemotherapy drug called MMAE. The CD30 protein frequently is found on the surface of cancer cells in Hodgkin lymphoma but is present on less than 1 percent of healthy cells.

Also in the News: Panobinostat Shows Promise for Hodgkin Lymphoma

Brentuximab is not the only investigational agent that has shown promise for the treatment of relapsed/refractory Hodgkin lymphoma. Results from a 129-patient phase II trial of the drug panobinostat , part of a class of drugs known as HDAC inhibitors , showed strong antitumor activity in this same patient population, including 30 objective responses and five complete responses.

Those results were also presented at the ASH meeting. The most problematic side effect was a dangerous drop in blood platelets, reported the trial’s lead investigator, Dr. Anna Sureda of the Hospital of the Holy Cross and Saint Paul in Barcelona. However, this could be reversed by temporarily withholding treatment or modifying the dose.

Unlike some other antibodies currently approved for treating cancer, the antibody component of brentuximab does not have any anticancer effect in Hodgkin lymphoma, explained the trial’s lead investigator, Dr. Anas Younes of the University of Texas M. D. Anderson Cancer Center. Rather, Dr. Chen explained, “the antibody allows for selective delivery of the chemotherapy agent directly into Hodgkin lymphoma cells.”

The chemical that tethers the antibody to the chemotherapy drug is also extremely important, explained Dr. Helen Chen of the Cancer Therapy Evaluation Program in NCI’s Division of Cancer Treatment and Diagnosis. “The first critical requirement is that the linker has to be very stable in the blood,” she said. “You don’t want it to release the drug before getting to the cell.”

The linker also determines whether the conjugate only kills cancer cells to which it has attached through the antibody component, or whether the drug component can be released back out of the cell to kill surrounding cancer cells (but also, potentially, healthy cells), a so-called bystander effect, Dr. Helen Chen noted. Brentuximab is designed to have a bystander effect.

In addition to the design and selection of the linker, she continued, the safety and efficacy of ADCs also depend on the chosen antibody target and the “cytotoxic payload” to which the antibody is attached.

One of the first ADCs to receive FDA approval was gemtuzumab (Mylotarg) for the treatment of acute myeloid leukemia. Gemtuzumab is composed of a CD33-targeted antibody linked to the chemotherapy drug ozogamicin. But gemtuzumab was withdrawn earlier this year after a post-approval clinical trial required by the FDA found that, in combination with chemotherapy, it was no more effective than chemotherapy alone and was associated with serious liver complications and a greater risk of death. Gemtuzumab, Dr. Helen Chen noted, used an older generation linker and a different class of chemotherapy drug than brentuximab, in addition to targeting a different cell-surface antigen, all of which may have contributed to its failure in the confirmatory trial.

A number of ADCs are under investigation. Trastuzumab-DM1, for example, an ADC that couples the HER2-targeted antibody trastuzumab (Herceptin) with the chemotherapy drug DM1, is being tested in multiple breast cancer clinical trials. And at NCI, Dr. Ira Pastan’s lab in CCR has developed numerous ADCs that link an antibody to a bacterial toxin, including a conjugate called HA22, which has shown promise in patients with hairy cell leukemia and is now being developed by MedImmune.

Already Thinking Ahead

Dr. Philip Bierman of the University of Nebraska Medical Center called the results exciting. “There’s no question that this is an advance, and there’s no question that this is a drug that will get used,” he said. What these results mean for the future is of even more intense interest among oncologists, he continued.

“I think people are even more enthusiastic about possibly using this drug in the upfront setting,” he said, in combination with a four-drug chemotherapy regimen called ABVD that is the standard first-line therapy for Hodgkin lymphoma. The ABVD regimen has been used since the 1970s and leads to complete remissions in approximately 70 to 80 percent of patients. “So, this could become the new rituximab ,” Dr. Bierman said, referring to the CD30-targeted monoclonal antibody used to treat non-Hodgkin lymphoma. (Rituximab initially showed efficacy as a third-line treatment but eventually became a first-line treatment in combination with chemotherapy.) A phase I trial of brentuximab in combination with ABVD is already under way.

“The goal in Hodgkin lymphoma is to cure,” Dr. Wilson stressed. So, testing brentuximab with chemotherapy as an initial therapy makes perfect sense, he continued, “to see if you can improve the cure rate.”

Also presented at the ASH meeting were the results from a smaller phase II clinical trial of brentuximab against a subtype of non-Hodgkin lymphoma called anaplastic large cell lymphoma . The findings were similar, with 87 percent of patients—all of whom had relapsed/refractory disease—achieving an objective response and 57 percent achieving a complete response. Seattle Genetics will also apply for FDA approval of brentuximab for use in this patient population.

Carmen Phillips


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