ECHELON-1, a randomized, multicenter, phase III clinical trial evaluating brentiximab vedotin (Adcetris®) as part of a combination chemotherapy regimen in 1,334 patients with advanced Hodgkin Lymphoma, met primary endpoint, demonstrating a statistically significant improvement in modified progression-free survival (PFS) per Independent Review Facility assessment using the Revised Response Criteria for Malignant Lymphoma versus control.[1]

This endpoint was chosen as it provides a clearer picture of the efficacy of frontline chemotherapy and eliminates the confounding impact of salvage and consolidation chemotherapies and radiotherapy. Secondary endpoints include overall survival, complete remission and safety.

The study, conducted in North America, Europe, South America, Australia, Asia and Africa, enrolled 1,334 patients who had a histologically-confirmed diagnosis of Stage III or IV classical Hodgkin lymphoma and had not been previously treated with systemic chemotherapy or radiotherapy.

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. Classical Hodgkin lymphoma is distinguished from other types of lymphoma by the presence of one characteristic type of cell, known as the Reed-Sternberg cell. The Reed-Sternberg cell expresses CD30.

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Based on these results, Seattle Genetics and Takeda plan to submit an abstract for presentation during the 2017 annual meeting of the American Society of Hematology, to be held in Atlanta, GA, December 9-12, 2017. The companies are also planning to submit these results to regulatory authorities for approval in their respective territories.

Diagram 1.o: The ECHELON 1 clinical trial (NCT01712490) is an open-label, randomized, 2-arm, multicenter, phase III study has the primary objective of comparing the modified progression-free survival (mPFS) obtained with brentuximab vedotin (Adcetris®) plus AVD (doxorubicin [Adriamycin], vinblastine, and dacarbazine; abbreviated A+AVD) versus that obtained with ABVD (doxorubicin [Adriamycin],bleomycin, vinblastine, and dacarbazine) for the frontline treatment of advanced classical Hodgkin lymphoma(HL).
Brentuximab vedotin is an antibody-drug conjugate (ADC) directed to CD30, a defining marker of classical Hodgkin lymphoma.

The drug is currently not approved as a frontline therapy for Hodgkin lymphoma.

Patients in ECHELON-1 were randomized to receive either a combination of brentuximab vedotin + AVD (Adriamycin, vinblastine, dacarbazine) or ABVD (Adriamycin, bleomycin, vinblastine, dacarbazine), a recognized standard of care for frontline Hodgkin lymphoma.

Study results
The results of the ECHELON-1 trial demonstrated that combination treatment with brentuximab vedotin resulted in a statistically significant improvement in modified PFS versus the control arm as assessed by an Independent Review Facility (hazard ratio=0.770; p-value=0.035).

The two-year modified PFS rate for patients in the brentuximab vedotin arm was 82.1 percent compared to 77.2% in the control arm. Interim analysis of overall survival (OS), the key secondary endpoint, also trended in favor of the brentuximab vedotin + AVD arm.

Photo 1.0: Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics. Courtesy: © 2017. Seattle Genetics. Used with permission.

Safety profile
The safety profile of brentuximab vedotin + AVD in the ECHELON-1 trial was consistent with that known for the single-agent components of the regimen.

The researchers observed an increased incidence of febrile neutropenia and peripheral neuropathy in the brentuximab vedotin + AVD arm. Febrile neutropenia was reduced through the use of prophylactic growth factors in a subset of patients, and peripheral neuropathy was managed through dose modifications. The control arm had an increased rate and severity of pulmonary toxicity.

Positive results
“We are excited about the positive result which shows a statistically significant improvement in the primary endpoint of modified PFS,” said Dirk Huebner, MD., Executive Medical Director, Oncology Therapeutic Area Unit, Takeda Pharmaceutical Company. “The results of this trial signify an important step forward in the development of brentuximab vedotin and have the potential to change the treatment approach of frontline advanced Hodgkin lymphoma.”

“The outcome of the Phase III ECHELON-1 trial represents a significant milestone for the Hodgkin lymphoma community,” said Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics. “Seattle Genetics’ goal is to establish brentuximab vedotin as the foundation of care for CD30-expressing lymphomas, including Hodgkin lymphoma. Notably, this is the first clinical trial in frontline advanced Hodgkin lymphoma to show superior efficacy of a regimen that eliminates bleomycin.”

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