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?