Researchers Refine Anti-CD30 Approach in Lymphoma

Owen A. O’Connor, MD, PhD

The CD30-directed antibody-drug conjugate brentuximab vedotin (Adcetris) has shown promise in several studies.

An ongoing phase II trial examining patients with advanced diffuse large B-cell lymphoma (DLBCL) found that brentuximab vedotin with standard R-CHOP yielded objective responses in 80% of patients.

In the study, patients were randomized in a 1:1 ratio to standard R-CHOP plus brentuximab vedotin at a dose of either 1.2 mg/kg (n = 30) or 1.8 mg/kg (n = 23). Brentuximab vedotin was administered on day 1 of each 21-day cycle, for a maximum of 6 cycles. Upon review, the higher dose was eliminated after the first 10 patients in each arm completed treatment, due to safety concerns.

Forty-one patients (80%) in the trial achieved an objective response, including 34 (67%) complete remissions and 7 (14%) partial remissions. Five patients (10%) had progressive disease.

Another recent multicenter phase II study investigated the use of brentuximab vedotin in place of bleomycin, in the standard ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) regimen for nonbulky stage I/II Hodgkin lymphoma.

Thirty-four patients received a lead-in cycle of brentuximab monotherapy 1.2 mg/kg on days 1 and 15, followed by a PET scan. Patients then received 4 to 6 cycles of brentuximab plus AVD. By the end of treatment, 88% of patients (n = 30) had a complete response, 2 had progressive disease, and 2 discontinued due to toxicity. At a median follow-up of 14 months, progression-free survival (PFS) and overall survival were 90% and 97%, respectively.

To better understand the future of brentuximab vedotin in lymphoma and the importance of properly identifying CD30-expression, OncLive spoke with Owen A. O’Connor, MD, PhD, professor of Medicine and Experiment Therapies, co-program director, Lymphoid Development and Malignancy Program, Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center.

OncLive: Please discuss the role of CD30 expression in lymphoma?

Dr O’Connor: The development of novel targeted drugs against discrete cell surface proteins, such as CD30, has really opened up a new way of thinking about targeted cancer biology. One recent example of a drug that has been developed as a target against many lymphoma cells is brentuximab vedotin (Adcetris), which is an antibody-drug conjugate that targets CD30. CD30 is a defining protein expressed on the surface of anaplastic large cell lymphoma and to a very high extent in patients with Hodgkin lymphoma. It is variably expressed in other types of lymphomas, such as cutaneous T-cell lymphoma, peripheral T-cell lymphoma, and diffuse large B-cell lymphoma.

Early on, there was a sentiment that the amount of CD30 that was expressed on the surface of anaplastic large cell lymphoma turned out not to be an important determinant of response to brentuximab vedotin. Patients with relatively low levels of CD30 were found to respond in a fashion that was very similar to patients that we saw with relatively high levels.

What we are seeing now, as brentuximab vedotin migrates away from its original FDA approvals in anaplastic large cell lymphoma and Hodgkin disease, is that there are variable response rates across those diseases, and that the level of CD30 expression can span from zero all the way to up to in excess of 90%. There is some recently presented data that suggests that patients who had CD30-negative diffuse large B-cell lymphoma responded to brentuximab vedotin and had some duration of benefit.

Overall, those benefits were found to be much less than what we saw in patients that had CD30-positive disease. This raises two questions. First, do those patients even respond if they don’t have the target? Second, should we be measuring the drug in a more reliable way, so we can target the drug and try and improve the outcome?

What studies have been done to investigate this?

A number of studies have been done that now seem to suggest that, outside of the context of anaplastic large cell lymphoma and Hodgkin lymphoma, there may be a threshold effect. Some recent data from Stanford University examined patients with mycosis fungoides and cutaneous T-cell lymphoma seem to suggest that patients with expression on less than 5% malignant lymphoma cells seem to have a very low likelihood of responding to brentuximab vedotin, while patients with greater than 5% malignant lymphoma cells seem to have a reasonably good probability of responding.

What can we learn from these findings?

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,).