Data reported today demonstrating that prolonged treatment with Brentuximab Vedotin (SGN-35; Adcetris™, Seattle Genetics) beyond 16 cycles of therapy was associated with clinically meaningful durations of response with a manageable safety profile. In addition, data were presented showing that Brentuximab Vedotin is a viable option for reducing tumor burden prior to allogeneic stem cell transplant. The data were presented at the 53rd Annual Meeting of the American Society of Hematology being held December 10-13, 2011 in San Diego, CA.

Brentuximab Vedotin is an antibody-drug conjugate (ADC) existing of an ant-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent called monomethyl auristatin E or MMAE. The drug is stable in the bloodstream but, being directed to CD30, it will release MMAE upon internalization into CD30-expressing tumor cells

“Through both corporate and investigator trials, we are continuing to increase our knowledge about the activity and tolerability of ADCETRIS in patients with relapsed Hodgkin lymphoma or systemic anaplastic large cell lymphoma (sALCL),” said Thomas C. Reynolds, M.D., Ph.D., Chief Medical Officer at Seattle Genetics. “These ASH presentations describe data from patients receiving extended treatment with Adcetris, as well as the use of ADCETRIS prior to allogeneic transplant. There is also a preclinical report on the activity of Adcetris in primary effusion lymphoma, an aggressive type of non-Hodgkin lymphoma. We look forward to two other presentations that will take place at the ASH meeting, including one that will describe data from longer follow-up in our pivotal trial in systemic ALCL and another that will be the first report of data from our phase I front-line trial in Hodgkin lymphoma.”

Prolonged Treatment in Patients with HL or sALCL
Andres Forero-Torres, MD, University of Alabama at Birmingham, Birmingham, AL, presented data from a retrospective analysis of relapsed Hodgkin lymphoma and sALCL patients who received greater than 16 cycles of Brentuximab Vedotin in a treatment extension study. Seventeen patients were included in the analysis, and median duration of treatment was 17.3 months (approximately 24 cycles of every three week dosing). The trial drug was approved for treatment until a maximum of 16 cycles, disease progression or unacceptable toxicity.

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Brentuximab vedotin 1.2 or 1.8 mg/kg was administered every 3 weeks as a 30-minute outpatient IV infusion for up to 16 cycles of treatment in 1 of 4 preceding studies. Consecutive cycles of treatment were then administered in the extension study until disease progression, unacceptable toxicity, or withdrawal of consent. Antitumor activity in this case series was based on objective response assessments per the investigator according to the Revised Response Criteria for Malignant Lymphoma

The trial results show an overall objective response rate of 88%, including 76% complete remissions and 12% partial remissions with a median time to objective response of 2.5 months. At presentation of the data, the median duration of objective response has not been reached (range 8.3 to 23.2+ months).
Brentuximab Vedotin was generally well-tolerated, with the most common adverse events being peripheral neuropathy (71%), upper respiratory infection (53%) and fatigue (47%). In this study, prolonged treatment with brentuximab vedotin was associated with clinically meaningful durations of response without worsening of toxicity over time.

Allogeneic Transplant + Brentuximab Vedotin in Patients with Relapsed or Refractory CD30+ Lymphomas
An unrelated study described the outcome of 15 patients with relapsed Hodgkin lymphoma or sALCL who underwent an allogeneic stem cell transplant (allo-SCT) as their first subsequent therapy after participation in a pivotal trial of Brentuximab Vedotin. The drug is not indicated to enable a subsequent allogeneic stem cell transplant.

Allogeneic stem cell transplant for relapsed or refractory lymphoma is often limited by the amount of residual tumor burden following cytoreductive therapy. However, in recent phase II trials, brentuximab vedotin induced objective responses in 75% of patients with Hodgkin lymphoma (HL) and 86% of patients with systemic ALCL (sALCL). Fifteen of 160 patients (9%) who participated in these two phase II studies received an allo-SCT as their first subsequent antitumor therapy after treatment with brentuximab vedotin.

Brentuximab vedotin 1.8 mg/kg was administered every 3 weeks as a 30-minute outpatient IV infusion for up to 16 cycles of treatment. After discontinuing brentuximab vedotin, patients were followed for survival/disease status and information regarding subsequent therapy, including allo-SCT, was collected. Treatment with brentuximab vedotin provided cytoreduction in patients with relapsed or refractory HL and sALCL, many of whom had failed a prior autologous SCT.

Fifteen patients who achieved an objective response with brentuximab vedotin (12 patients with a complete remission and three patients with a partial remission) subsequently received an allogeneic transplant. Ten of 15 patients (67%) remained in remission following subsequent allogeneic transplant. Three patients progressed and two died. At the time of the data analysis, the median progression-free survival and overall survival had not been reached after a median duration of follow-up of approximately 20 months (range 8 to 24 months). However, the data demonstrates that brentuximab vedotin may be an option for reducing tumor burden in advance of an allogeneic stem cell transplant.

Preclinical Activity in Primary Effusion Lymphoma (PEL)
In a poster session, Shruti Bhatt from the University of Miami Miller School of Medicine described preclinical data on the expression of CD30 in primary effusion lymphoma (PEL). PEL is an aggressive subtype of non-Hodgkin lymphoma (NHL) that is commonly diagnosed patients with underlying immunodeficiency such as in the case of HIV-positive patients.  In patients that are not HIV-positive, almost all cases are related to their being immunosuppressed for other reasons, such as post-organ transplant. It is caused by Kaposi’s sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV-8). In most cases, the lymphoma cells are also infected with Epstein Barr virus (EBV). PEL was recognized as a a distinct subtype of NHL until the discovery of HHV-8 in 1994.

HIV-related lymphoma is not unusual. It occurs in between 5 – 20% of HIV-positive patients and is generally considered an AIDS-defining illness. However, most HIV-related lymphomas are of the diffuse large B-cell or Burkitt’s type. Hence, even in the setting of HIV-related NHL, primary effusion lymphoma is rare. The general outlook for patients with PEL is limited and very poor.  This type of NHL is usually resistant to currently available chemotherapy drugs and most patients only survive an average of six months from the time of diagnosis, and only one-third of patients live a year.

While patients who are HIV-positive are initiated or continued on anti-viral therapy for their HIV,  most treatment plans for patients PEL are modeled after treatment for diffuse large B-cell lymphoma, which is the most common type of aggressive NHL. First-line treatment with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) has been reported to result in a response rate of 40 to 50%.

The preclinical trial data for brentuximab vedotin demonstrate the expression of CD30 on PEL cell lines and primary tumor samples. In this trial, brentuximab vedotin induced apoptosis in PEL cell lines and extended survival in a preclinical PEL model. In contrast, control IgG conjugated with MMAE failed to induce apoptosis and cell death of PEL cell lines confirming specific brentuximab vedotin cytotoxicity. The results in this study demonstrate, for the first time, that brentuximab vedotin may be a potent anti-PEL therapy and support the need to further evaluate brentuximab vedotin in patients with PEL.

Accelerated approval
Brentuximab Vedotin was granted accelerated approval by the U.S. Food and Drug Administration in August 2011 for two indications the treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplant (ASCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates, and the treatment of patients with sALCL after failure of at least one prior multi-agent chemotherapy regimen. These indications are based on response rate. Today, there is no data available demonstrating improvement in patient-reported outcomes or survival with Brentuximab Vedotin. The drug is not approved for use outside the United States.

For more information:
Program: Oral and Poster Abstracts
Abstract: 3711 Prolonged Treatment with Brentuximab Vedotin (SGN-35) in Patients with Relapsed or Refractory Hodgkin Lymphoma (HL) or Systemic Anaplastic Large Cell Lymphoma (sALCL)
Session: 624. Lymphoma – Therapy with Biologic Agents, excluding Pre-Clinical Models: Poster III
When: Monday, December 12, 2011, 6:00 PM-8:00 PM
Where: Hall GH (San Diego Convention Center)

Program: Oral and Poster Abstracts
Abstract: 3091 Allogeneic Transplant Following Brentuximab Vedotin Treatment in Patients with Relapsed or Refractory CD30+ Lymphomas
Session: 731. Clinical Allogeneic and Autologous Transplantation – Results: Poster II
When: Sunday, December 11, 2011, 6:00 PM-8:00 PM
Where: Hall GH (San Diego Convention Center)

Program: Oral and Poster Abstracts
Abstract: 3728 Preclinical Activity of Brentuximab Vedotin (SGN-35) in Primary Effusion Lymphoma (PEL)
Session: 625. Lymphoma – Pre-Clinical – Chemotherapy and Biologic Agents: Poster III
When: Monday, December 12, 2011, 6:00 PM-8:00 PM
Where: Hall GH (San Diego Convention Center)

Also read:
Updated Data for Brentuximab Vedotin Shows Durable Complete Remission and Manageable Toxicity.

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