It is interesting that it doesn’t look like it is a continuous variable. It doesn’t appear that patients with 20% or 30% expression do any worse than those with 80% or 90% expression. However, there may be an important threshold effect. It really comes down to how we measure CD30 on these cells. There is a lot of inter-laboratory and inter-institutional variation. How it is measured, in terms of the details of the assays that people use to measure, really varies.What is being done to combat the problem of variation in CD30 measurement?
The FDA has asked Seattle Genetics to develop a companion diagnostic to get a better, more quantitated, more reproducible handle on measuring CD30 across different lymphomas so that we can better understand the relative importance of CD30 express as a detriment for response to brentuximab vedotin.What are the next steps in the investigation of brentuximab vedotin within lymphoma?
You will begin to see two lines of clinical research. One will focus on trying to integrate brentuximab vedotin into some classic chemotherapy regimens. Most of the research right now is focused on therapies used in Hodgkin lymphoma with ABVD.
There was data presented that asked the question, “Is it possible to eliminate one of the drugs in the ABVD backbone?” The suggested drug was bleomycin, which has a lot of associated pulmonary toxicities. It was suggested to replace it with a novel active agent, such as brentuximab vedotin, and reshape that backbone for Hodgkin lymphoma. Early data suggest that eliminating bleomycin and replacing it with brentuximab vedotin could produce responses and PFS that are right in line with what we would expect with standard chemotherapy.
The second strategy looks at adding brentuximab vedotin to a standard backbone like R-CHOP chemotherapy for diffuse large B-cell lymphoma as a way to improve the response rates of R-CHOP chemotherapy.
One study investigated two different doses of brentuximab vedotin and stratified patients by high and low levels of CD30. It was not a randomized study; therefore, it was difficult to see if the addition of brentuximab vedotin added any benefit to R-CHOP. However, it seemed to suggest that adding it was safe and produced fairly high complete response and overall response rates. However, the data showed that those who were CD30-negative did not do as well as those who were CD30-positive, which reinforces that we need to develop better companion diagnostics and better assays that will allow us to more precisely quantitate the relative expression of CD30 on an individual cell and the expression of CD30 across all the cells in a particular tumor.
Abramson J, Arnason J, LaCasce A, et al. Brentuximab vedotin plus AVD for non-bulky limited stage Hodgkin lymphoma: a phase II trial. J Clin Oncol. 2015;33 (suppl; abstr 8505,).