U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation to brentuximab vedotin (Adcetris®; Seattle Genetics) in combination with chemotherapy for the frontline treatment of patients with advanced classical Hodgkin lymphoma.
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.
“The decision by the FDA to grant this designation recognizes the need for new options that can change the care of people with newly diagnosed advanced Hodgkin lymphoma”
The positive topline results of the phase III ECHELON-1 clinical trial were announced in June 2017 and full data will be presented at the upcoming American Society of Hematology (ASH) annual meeting, December 9-12, 2017 in Atlanta, Georgia.
Brentuximab vedotin is an antibody-drug conjugate (ADC) directed to CD30, a defining marker of classical Hodgkin lymphoma. The drug includes 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 drug employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-positive tumor cells.
Breakthrough Therapy Designation
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.
“The phase III ECHELON-1 study that supports the Breakthrough Therapy Designation for brentuximab vedotin in combination with chemotherapy showed superior activity versus the standard of care chemotherapy regimen in the treatment of frontline advanced classical Hodgkin lymphoma patients,” said Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics.
“The decision by the FDA to grant this designation recognizes the need for new options that can change the care of people with newly diagnosed advanced Hodgkin lymphoma. The designation supports our goal to make brentuximab vedotin available to patients in this setting as soon as possible. We look forward to presenting the data from our phase III ECHELON-1 trial at the upcoming ASH annual meeting and intend to submit a supplemental Biologics License Application to the FDA before the end of 2017,” Siegall added.
The Breakthrough Therapy Designation was based on data from the ECHELON-1 clinical trial, a randomized, open-label, phase III trial investigating a combination of brentuximab vedotin plus AVD (Adriamycin, vinblastine, dacarbazine) versus ABVD (Adriamycin, bleomycin, vinblastine, dacarbazine), a recognized standard of care chemotherapy regimen in previously untreated advanced classical Hodgkin lymphoma, as frontline therapy in patients with 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+AVD in the ECHELON-1 trial was consistent with that known for the single-agent components of the regimen.
The primary endpoint of the ECHELON-1 study 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. The endpoint was chosen since 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.
Clinical trial program
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.
These trials include the ECHELON-1 trial in frontline classical Hodgkin lymphoma from which positive topline results were recently reported, 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 Opdivo (nivolumab) for relapsed/refractory Hodgkin lymphoma.
Submission of Supplemental Biologics License Application for brentuximab vedotin in Frontline Advanced Hodgkin Lymphoma Planned Before the End of 2017.