Drug-antibody pair has promising activity in non-Hodgkin lymphoma
A toxin linked to a targeted monoclonal antibody has shown compelling antitumor activity in patients with non-Hodgkin lymphomas (NHLs) who were no longer responding to treatment, according to a new report. This ongoing open-label, phase 2 study was presented at the American Society of Hematology (ASH) meeting, held December 7-10, 2013, in New Orleans, Louisiana. It was designed to test the activity of brentuximab vedotin (Adcetris) in relapsed or refractory non-Hodgkin lymphoma including B-cell cancers such as diffuse large B cell lymphoma (DLBCL).
The antibody-toxin compound has been approved for 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 Institute in Boston, Massachusetts.
To date, the trial has enrolled 62 patients with B-cell lymphomas, including 44 diagnosed with DLBCL. Most of whom were no longer responding to previous therapy, and 23% had never responded to any treatment.
Forty percent of the 43 evaluable DLBCL patients had an objective response to the drug with a median duration of 36 weeks, including some of more than 8 months. Seven had complete remissions and 10 had partial remissions. In 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 Jacobsen. "In my opinion, these results are encouraging enough to take the drug forward in DLBCL."
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 the compound brentuximab vedotin, the targeted antibody is linked to a potent toxin that interferes with cell division and blocks cell growth. Like a chemical Trojan horse, the antibody-toxin compound is swallowed by cancer cells that carry the CD30 molecule on their surface. Once inside the cell, the poisonous cargo separates from the antibody and disables the cell.
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 Jacobsen.
The drug caused an array of adverse events, leading to discontinuation in six patients. Among the toxicities were fatigue, nausea, low white blood cell counts, fever, diarrhea, peripheral sensory neuropathy, vomiting, anemia, and constipation. The researchers said this profile was consistent with that seen previously with brentuximab vedotin.