FDA has accepted for filing a supplemental Biologics License Application for Adcetris (brentuximab vedotin) in combination with chemotherapy for the frontline treatment of patients with advanced classical Hodgkin lymphoma. The FDA granted Priority Review for the application, and the Prescription Drug User Fee Act target action date is May 1, 2018.
The submission of the supplemental BLA is based on positive results from a phase III clinical trial called ECHELON-1 that was designed to determine if Adcetris in combination with chemotherapy could extend modified progression-free survival in previously untreated advanced classical Hodgkin lymphoma patients.
Adcetris, sponsored by Seattle Genetics Inc., is an antibody-drug conjugate directed to CD30, a defining marker of classical Hodgkin lymphoma. Adcetris is being evaluated globally as the foundation of care for CD30-expressing lymphomas in more than 70 corporate- and investigator-sponsored clinical trials. Adcetris is currently not approved as a frontline therapy for Hodgkin lymphoma.
In October 2017, the FDA granted Adcetris Breakthrough Therapy Designation based on the ECHELON-1 study results. 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 in one or more clinically significant endpoints.
The ECHELON-1 study evaluated a combination of Adcetris plus Adriamycin, vinblastine, dacarbazine compared to a recognized standard of care chemotherapy regimen, ABVD (which includes bleomycin), in frontline advanced classical Hodgkin lymphoma.
The positive results from the phase III ECHELON-1 trial were featured in the Plenary Scientific Session of the 59th American Society of Hematology Annual Meeting with simultaneous publication in the New England Journal of Medicine in December 2017. Results from the ECHELON-1 trial in 1,334 Hodgkin lymphoma patients included:
The trial achieved its primary endpoint with the combination of Adcetris plus AVD resulting in a statistically significant improvement in modified PFS versus the control arm of ABVD as assessed by an Independent Review Facility (p-value=0.035). This corresponds to a 23 percent reduction in the risk of progression, death, or need for additional anticancer therapy. Per IRF assessment, the two-year modified PFS rate for patients in the Adcetris plus AVD arm was 82.1 percent compared to 77.2 percent in the control arm.
The investigator assessment of modified PFS also demonstrated a statistically significant advantage for Adcetris plus AVD versus the control arm of ABVD (p-value <0.01).
All secondary endpoints, including interim analysis of overall survival, trended in favor of the Adcetris plus AVD arm.
The safety profile of Adcetris plus AVD in the ECHELON-1 trial was generally consistent with that known for the single-agent components of the regimen.
ECHELON-1 is a randomized, open-label, phase 3 trial is investigating ECHELON-1 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. 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 was conducted under a Special Protocol Assessment agreement from the FDA and the trial also received EMA scientific advice.
ECHELON-1 is being evaluated broadly in more than 70 clinical trials, including three phase III studies: the completed ECHELON-1 trial in frontline classical Hodgkin lymphoma, the ongoing ECHELON-2 trial in frontline mature T-cell lymphomas, and the ongoing CHECKMATE 812 trial of ADCETRIS in combination with Opdivo (nivolumab) for relapsed/refractory Hodgkin lymphoma.
