New, updated, data from a phase II clinical trial of brentuximab vedotin (Adcetris®; Seattle Genetics) in patients with diffuse large B-cell lymphoma or DLBCL and other B-cell non-Hodgkin lymphomas, demonstrated an encouraging activity and tolerability profile in the relapsed and refractory setting. The results were presented at the 55th annual meeting of ASH®, the American Society of Hematology, held in New Orleans, Louisiana, USA, from December 7 – 10, 2013.
Brentuximab vedotin is an antibody-drug conjugate or ADC directed to the protein CD30 which is expressed in classical Hodgkin lymphoma and systemic anaplastic large cell lymphoma. The anti-CD30 monoclonal antibody is attached by a protease-cleavable linker to the microtubule disrupting agent monomethyl auristatin E or MMAE. The drug employs a linker system that is designed to be stable in the bloodstream but releases MMAE upon internalization into CD30-expressing tumor cells. Brentuximab vedotin is currently not approved for the treatment of DLBCL or other B-cell lymphomas.
Lymphoma is a general term for a group of cancers that originate in the lymphatic system. There are two major categories of lymphoma: Hodgkin lymphoma and non-Hodgkin lymphoma. Non-Hodgkin lymphoma represents a diverse group of cancers that develop in the lymphatic system and are characterized by uncontrolled growth and accumulation of abnormal lymphocytes. Lymphocytes are a type of blood cells that are responsible for defending the body against infection. The most common forms of non-Hodgkin lymphoma are diffuse large B-cell lymphoma (an aggressive subtype) and follicular lymphoma (an indolent subtype).
Better therapeutic approaches
“In DLBCL, patients with relapsed or refractory disease have poor outcomes, and there is a significant need for better therapeutic approaches to treat this aggressive non-Hodgkin lymphoma subtype,” said Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics. “We are encouraged by the interim Phase II results which demonstrated that single-agent brentuximab vedotin induced a 42% objective response rate and manageable safety profile among advanced DLBCL patients, including a high percentage whose disease was refractory to their prior therapy. Based on these data, we have expanded our clinical program for brentuximab vedotin in DLBCL both as a single-agent and in combination with standard regimens for both relapsed and newly diagnosed patients.”
Interim data from an ongoing Phase II clinical trial were reported from 50 patients with DLBCL and 18 patients with other B-cell lymphomas. Among the DLBCL patients, the median age was 63 years, 74% were refractory to frontline therapy and 82% were refractory to their most recent prior therapy. Patients were treated with single-agent brentuximab vedotin every three weeks. The trial was designed to assess the anti-tumor activity, duration of response and safety profile of brentuximab vedotin in these patients. Key findings presented by Nancy Bartlett, MD from the Washington University, Siteman Cancer Center in St. Louis, MO, included:
- Of the 50 patients with DLBCL, 42% achieved an objective response, including 16% complete remissions and 26% partial remissions;
- At the time of data analysis, the median duration of response for DLBCL was 5.8 months. For DLBCL patients who achieved a complete remission, the median duration of response was 11.5 months;
- Objective responses were observed across a broad range of CD30 expression, from DLBCL patients with undetectable CD30 by standard immunohistochemistry testing to those with CD30 expression up to 90%;
- The most common treatment-emergent adverse events of any grade in patients with DLBCL and other B-cell lymphomas occurring in more than 25% of all patients enrolled were fatigue (49%), neutropenia (40%), nausea (38%), diarrhea (37%) and fever (29%).
- The most common Grade 3 treatment-emergent adverse events in patients with DLBCL and other B-cell lymphomas were neutropenia and anemia. The only Grade 4 treatment-emergent event was neutropenia. Serious adverse events considered related to treatment and occurring in more than one patient were pneumonia (three patients) and anemia, febrile neutropenia, neutropenia and thrombocytopenia (two patients each).
These encouraging findings support ongoing evaluation of brentuximab vedotin as a treatment for DLBCL. The Phase II clinical trial presented at the Annual Meeting of the American Society of Hematology has been expanded to include a treatment arm to assess the activity and tolerability of brentuximab vedotin in combination with rituximab (Rituxan®’ Genentech/Biogen Idec) as well as an arm to evaluate single-agent brentuximab vedotin in patients with undetectable CD30 expression using standard immunohistochemistry methods. In addition, a Phase II trial was recently initiated to evaluate brentuximab vedotin plus R-CHOP in newly diagnosed, high-risk DLBCL patients, regardless of CD30 expression level.