Brentuximab Vedotin Active Regardless of CD30 Expression in DLBCL

Nancy Bartlett, MD

Brentuximab vedotin, an anti-CD30 monoclonal antibody, has demonstrated antitumor activity in the setting of relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and has generated responses across a broad range of CD30 expression, including low or undetectable CD30 expression. Data from an ongoing phase II study were presented by Nancy Bartlett, MD, at the 55th annual meeting of the American Society of Hematology (ASH).

Patients with relapsed or refractory DLBCL have poor outcomes. Autologous transplant is of limited efficacy, with a 3-year event-free survival of only 21%. There is currently no standard of care for patients ineligible for transplant.

CD30 expression is observed in up to 25% of patients with B-cell lymphomas. In two recent series of >1300 patients with newly diagnosed DLBCL, CD30 expression was shown to be a potentially favorable prognostic factor. In one of these series, “They looked at gene expression profiling and saw that the CD30-positive subset of DLBCL did appear to have a unique gene expression profile,” said Bartlett.

Brentuximab vedotin is a CD30-directed monoclonal antibody conjugated to a tubulin-disrupting agent, monomethyl auristatin E. It has produced durable responses with a manageable safety profile in pivotal phase II trials of relapsed/refractory Hodgkin lymphoma and anaplastic large-cell lymphoma, “with a substantial number of complete remissions,” Bartlett said. The ongoing open-label, single-arm phase II study she described at ASH is enrolling patients with CD30-positive B-cell non-Hodgkin lymphoma with variable CD30 expression who have relapsed or have been refractory to at least one prior systemic therapy. Any level of CD30-positive expression, as determined by immunohistochemistry per local laboratory, is permitted.

Dosing of brentuximab is 1.8 mg/kg every 3 weeks by intravenous infusion. Patients who achieve at least stable disease are eligible to receive continued treatment until disease progression or unacceptable toxicity.

Results from 68 evaluable patients were presented at ASH, with the primary endpoint being the overall response rate (ORR). Fifty of the patients had a diagnosis of DLBCL and 18 had other B-cell lymphomas at enrollment. Patients are being followed every 3 months for the first 2 years. The median age is 63 years in the DLBCL cohort and 36 years in the B-cell lymphoma cohort. The median percentage of CD30-positive malignant cells was 25% in the DLBCL cohort and 45% in the other B-cell histologies.

After a median of four treatment cycles (range, 1 to 19), the ORR was 42% in the patients with DLBCL and 22% in those with other B-cell histologies. Twenty percent of the patients with DLBCL and 50% with other B-cell neoplasms achieved stable disease. The median duration of objective response was 5.8 months and 5.0 months in patients with DLBCL and patients with other B-cell histologies, respectively. Sixteen percent and 11%, respectively, achieved complete remission, with a median duration of complete remission of 11.5 months in the DLBCL patients. The median duration of complete remission in patients with other B-cell lymphomas has not yet been reached. Eight patients remain on treatment.

Eighty-one percent of patients have achieved tumor reduction (10 patients were not included in this analysis because of incomplete data; when factoring these patients into the denominator, 69% of the entire study group achieved tumor reduction). Remissions have occurred in patients with undetectable, and up to 90%, CD30 expression by central laboratory.

Correlation between antitumor activity and quantitative CD30 expression is also being explored, and no statistical correlation between CD30 expression and response rate has been discovered thus far, according to Bartlett. Among patients with relapsed disease, activity has been observed across all levels of CD30 expression: the ORRs were 57% among those with CD30 expression of 0% to 9% (n = 14), 40% among those with CD30 expression of 10% to 90% (n = 30), and 17% in those for whom CD30 expression has not been determined (n = 6).

The most common treatment-emergent adverse events have been fatigue (49%), neutropenia (40%), nausea (38%), diarrhea (37%), pyrexia (29%), anemia (24%), decreased appetite (24%), peripheral sensory neuropathy (24%), constipation (22%), cough (21%), vomiting (21%), and dyspnea (16%).

Of the 60 patients who have discontinued treatment, 63% have done so for progressive disease and 10% for adverse events.

A frontline study of brentuximab plus R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone) in high-risk patients with DLBCL regardless of CD30 expression is currently enrolling patients, according to Bartlett.

Bartlett NL, Sharman JP, Oki Y, et al. A phase 2 study of brentuximab vedotin in patients with relapsed or refractory CD30-positive non-Hodgkin lymphomas: interim results in patients with DLBCL and other B-cell lymphomas. Presented at: 55th ASH Annual Meeting; December 7-10, 2013; New Orleans, LA.  Abstract 848.

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