For patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who are ineligible for transplant or fail to respond to salvage regimens, treatment with brentuximab vedotin – alone or in combination with rituximab – was associated with significant activity and reduction in tumor volume. According to the report published in Blood, responses also occurred across a range of CD30 expression.
There is no standard therapy for DLBCL patients resistant to frontline treatment and who fail to respond to salvage regimens or who are ineligible for transplant, lead author Eric Jacobsen, MD, from the Dana-Farber Cancer Institute in Boston, and co-authors noted. “Response rates are poor in this setting and novel approaches are needed.”
Brentuximab vedotin is a CD30-directed antibody-drug conjugate (ADC); data have suggested that, after binding to CD30 on the tumor cell surface, the ADC internalizes, leading to induction of cell-cycle arrest and apoptosis. CD30 is expressed on a variety of malignancies and is present in 14 to 25 percent of DLBCL cases – making the antigen, and the tumor cells that express it, appropriate targets for treatments.
In this phase 2 study, brentuximab vedotin was administered to 49 patients with DLBCL and 19 patients with other B-cell lymphomas. Most patients had Stage III or IV disease, more than half had received three or more prior systemic therapies, and nearly all had received prior rituximab.
Of 48 efficacy-evaluable DLBCL patients, eight (17%) achieved a complete remission (CR) and 13 (27%) a partial remission (PR), for an objective response rate of 44 percent at a median follow-up of 4.6 months from the first dose. Of the 19 patients with other B-cell lymphomas, five (26%) had either a CR or PR.
Objective responses were also durable: 5.6 months in all responders and 16.6 months in patients with a CR.
Thirteen percent of patients required dose modifications, primarily due to episodes of neutropenia and peripheral sensory neuropathy.
To explore the safety of combining brentuximab vedotin and rituximab, researchers amended the study protocol in January 2013 to include 15 patients with histologically confirmed DLBCL. Patients in this cohort experienced a similar number of treatment-emergent adverse events as patients in the monotherapy cohort, though these patients did have a shorter duration of drug exposure (13% received >5 cycles versus 43% on monotherapy). For the 13 efficacy-evaluable patients, the ORR was 46 percent, including two with a CR and four with a PR.
In one “unanticipated” finding of the study, there was no statistical correlation between response and level of CD30 expression, the investigators noted. “Neither the degree of surface expression of CD30 nor sCD30 levels correlated with the likelihood of response,” the investigators observed. “However, all responding DLBCL patients had elevated sCD30 at baseline and also proved to have a quantifiable level of CD30 expression by computer-assisted methods, even if the visual assessment by immunohistochemistry on central review did not suggest CD30 expression.”
Patients with primary mediastinal B-cell lymphoma also experienced a relatively low response rate (one CR out of six patients; 17% ORR), though reasons for this poor response are unclear. “Mediastinal DLBCL does not respond as well as other DLBCL subtypes to salvage therapy in general, so it may just represent the inherent drug resistance of this subtype,” Dr. Jacobsen told ASH Clinical News.
“Future studies of combination therapy are warranted,” he added. “The lack of correlation between CD30 expression and response is puzzling and requires further investigation.”
- Jacobsen ED, Sharman JP, Oki Y, et al. Brentuximab vedotin demonstrates objective responses in a phase 2 study of relapsed/refractory DLBCL with variable CD30 expression. Blood. 2015 January 8. [Epub ahead of print]