Based on positive results from the Phase III ECHELON-1 Clinical Trial evaluating brentuximab vedotin (Adcetris®; Seattle Genetics) in combination with chemotherapy for the frontline treatment of patients with advanced classical Hodgkin lymphoma, Seattle Genetics has submitted a supplemental Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA)

Brentuximab vedotin is an antibody-drug conjugate or ADC directed to CD30, a defining marker of classical Hodgkin lymphoma. The drug comprises an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), utilizing Seattle Genetics’ proprietary technology. The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing tumor cells.

“…ECHELON-1 study demonstrated superior activity of an brentuximab vedotin-containing regimen over standard of care… [this] resulted in FDA Breakthrough Therapy Designation for brentuximab vedotin in combination with chemotherapy for frontline advanced classical Hodgkin lymphoma…”

Foundation of Care
Brentuximab vedotin is being evaluated globally as the foundation of care for CD30-expressing lymphomas in more than 70 corporate- and investigator-sponsored clinical trials, including four phase III studies: the ECHELON-1 trial in frontline classical Hodgkin lymphoma from which positive top-line results were recently reported and the FDA granted Breakthrough Therapy

Phase III Frontline Therapy Trial in Patients With Advanced Classical Hodgkin Lymphoma (NCT01712490)

Designation in this setting, the ongoing ECHELON-2 trial in frontline mature T-cell lymphomas, the completed ALCANZA trial in cutaneous T-cell lymphoma that supported the supplemental BLA with a Prescription Drug User Fee Act (PDUFA) target action date of December 16, 2017, and the recently initiated CHECKMATE 812 trial of brentuximab vedotin in combination with nivolumab (Opdivo®; Bristol-Myers Squibb Company) for relapsed/refractory Hodgkin lymphoma.

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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.

According to the American Cancer Society, approximately 8,260 cases of Hodgkin lymphoma will be diagnosed in the United States during 2017 and more than 1,000 will die from the disease. According to the Lymphoma Coalition, over 62,000 people worldwide are diagnosed with Hodgkin lymphoma each year and approximately 25,000 people die each year from this cancer.

Brentuximab vedotin is currently not approved as a frontline therapy for Hodgkin lymphoma.

Advances in frontline therapy
“There have been no new treatment advances for frontline Hodgkin lymphoma in more than 40 years. Up to 30% of the patients diagnosed with advanced disease will experience disease progression after frontline treatment with the current standard of care chemotherapy regimen, representing a significant unmet need to improve the treatment outcome of these patients who are often young adults,” said Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics.

“Results from the ECHELON-1 study demonstrated superior activity of an brentuximab vedotin-containing regimen over standard of care, and resulted in FDA Breakthrough Therapy Designation for brentuximab vedotin in combination with chemotherapy for frontline advanced classical Hodgkin lymphoma. We believe these data represent a significant advance for the patient and physician community and look forward to working with the FDA to complete the review of this new treatment regimen as quickly as possible.”

Clinical trials
About 70-80% of all patients with advanced stage of Hodgkin’s lymphoma are cured with various first-line and second-line treatments, including ABVD  (Adriamycin, Bleomycin, Vinblastine, and Dacarbazine) , BEACOPP, and stem-cell transplantation. Since brentuximab vedotin has shown significant clinical activity, with a manageable safety profile, in patients with relapsed or refractory Hodgkin’s lymphoma.[1]

The ECHELON-1 study evaluated a combination of brentuximab vedotin plus AVD (Adriamycin, Vinblastine, Dacarbazine) compared to a recognized standard of care chemotherapy regimen, ABVD (which also includes Bleomycin), in previously untreated advanced classical Hodgkin lymphoma. The ECHELON-1 study met its primary endpoint of a statistically significant improvement in modified progression-free survival (PFS) of the brentuximab vedotin-containing regimen 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% compared to 77.2% in the control arm. Interim analysis of overall survival, the key secondary endpoint, also trended in favor of the brentuximab vedotin plus AVD arm. The safety profile of brentuximab vedotin plus AVD in the ECHELON-1 trial was consistent with that known for the single-agent components of the regimen.

Brentuximab vedotin was recently granted Breakthrough Therapy Designation by the FDA based on data from the phase III ECHELON-1 clinical trial. The FDA’s Breakthrough Therapy Designation is intended to expedite the development and review of promising drug candidates for serious or life-threatening conditions. It is based upon clinical evidence of substantial improvement over existing therapies on one or more clinically significant endpoints.

Trial Design
The randomized, open-label, phase 3 trial is investigating brentuximab vedotin plus AVD versus ABVD as frontline therapy in patients with advanced classical Hodgkin lymphoma. The primary endpoint is modified PFS per Independent Review Facility assessment using the Revised Response Criteria for Malignant Lymphoma. Modified PFS is defined as the time to progression, death or receipt of additional anticancer therapy for patients who are not in complete response after completion of frontline therapy per Independent Review Facility.

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 multi-center trial was conducted in North America, Europe, South America, Australia, Asia and Africa. The study 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. The ECHELON-1 trial is being conducted under a Special Protocol Assessment (SPA) agreement from the FDA and the trial also received European Medicines Agency (EMA) scientific advice.

American Society of Hematology
In a statement, Seattle Genetics confirmed that full data from the ECHELON-1 study will be presented in the Plenary Scientific Session at the annual meeting of the American Society of Hematology (ASH) on Sunday, December 10, 2017 from 2:00 – 4:00 p.m. ET in Atlanta, Georgia.

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