ASH 2013: Brentuximab Vedotin Shows Promising Activity in Non-Hodgkin Lymphoma
The antibody-drug conjugate brentuximab vedotin (Adcetris) has shown “compelling” antitumor activity in patients with non-Hodgkin lymphomas who were no longer responding to treatment, in a study presented at the American Society of Hematology (ASH) Annual Meeting and Exposition (Abstract 848). The ongoing open-label phase II study was designed to test the activity of brentuximab vedotin in relapsed or refractory non-Hodgkin lymphoma (NHL) including B-cell cancers such as diffuse large B-cell lymphoma.
Brentuximab vedotin has been approved by the U.S. Food and Drug Administration for the treatment of relapsed or refractory Hodgkin lymphoma and anaplastic T-cell lymphoma, and its success prompted the trial in NHL, said senior author Eric Jacobsen, MD, of Dana-Farber Cancer Center in Boston.
Study Details
To date, the trial has enrolled 62 patients with B-cell lymphomas, including 44 diagnosed with diffuse large B-cell lymphoma. Most of the patients were no longer responding to previous therapy, and 23% had never responded to any treatment.
Forty percent of the 43 evaluable patients with diffuse large B-cell lymphoma had an objective response to the drug with a median duration of 36 weeks, including some responses of more than 8 months. Seven patients had complete remissions, and 10 had partial remissions. Among the other B-cell lymphoma patients, 22 had an objective response.
"In this interim analysis of 62 patients with highly refractory B-cell lymphomas, compelling antitumor activity has been observed with brentuximab vedotin," the authors wrote.
"It was more active than many expected," noted Dr. Jacobsen. "In my opinion, these results are encouraging enough to take the drug forward in diffuse large B-cell lymphoma."
Puzzling Finding
Brentuximab is a monoclonal antibody that binds to CD30, a molecule found on cells in Hodgkin lymphoma and anaplastic T-cell lymphoma. The frequency of CD30 expression varies in other subtypes of lymphoma but is estimated to be present in one-quarter to one-third of B-cell NHL cells. In brentuximab vedotin, the targeted antibody is linked to a potent toxin that interferes with cell division and blocks cell growth.
Some of the patients' lymphoma cells strongly expressed the CD30 molecule, but in others the expression was less, and in some patients CD30 expression wasn't detected at all.
Surprisingly, the strength of CD30 expression by the patients' cancer bore no relationship to how they responded to the drug. "In fact, although the trend was not statistically significant, there was almost an inverse correlation. Some patients with the weakest CD30 expression had the most positive responses," said Dr. Jacobsen.
Dr. Jacobsen admitted that this finding is puzzling: How did the antibody recognize and bind to the lymphoma cells that lacked the CD30 molecule? Possibilities include binding to another target, although preclinical tests suggested this was not the case. Other possibilities are that brentuximab vedotin binds more effectively to CD30 than the antibody used to detect CD30 in the lab or that different cells have differing abilities to ingest brentuximab once the antibody binds to the cell. There is no clear answer from the study, but further laboratory tests are ongoing. Dr. Jacobsen said the trial is beginning to evaluate the drug's activity in a cohort of patients whose lymphomas have no measurable CD30 expression.
The drug caused an array of adverse events, leading to discontinuation in six patients. Among the toxicities were fatigue, nausea, low white blood counts, fever, diarrhea, peripheral sensory neuropathy, vomiting, anemia, and constipation. The researchers said this profile was consistent with that seen previously with brentuximab vedotin.
This study was supported by Seattle Genetics. For full disclosures of the study authors, view the study abstract on the ASH website.
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