Seattle Genetics Announces FDA Approval of ADCETRIS (Brentuximab Vedotin)

On Mar 23, 2018

Seattle Genetics announced that the U.S. Food and Drug Administration (FDA) has approved ADCETRIS (brentuximab vedotin) in combination with chemotherapy in adult patients with previously untreated Stage III or IV classical Hodgkin lymphoma. The approval is based on the successful outcome of the phase 3 ECHELON-1 clinical trial that compared ADCETRIS plus AVD (Adriamycin, vinblastine and dacarbazine) to ABVD (Adriamycin, bleomycin, vinblastine and dacarbazine). In addition, data from the ECHELON-1 trial converted the U.S. accelerated approval of ADCETRIS for the treatment of adults with systemic anaplastic large cell lymphoma (sALCL) after failure of at least one multi-agent chemotherapy regimen to regular approval. In October 2017, the FDA granted Breakthrough Therapy Designation (BTD) to ADCETRIS in combination with chemotherapy for the frontline treatment of patients with advanced classical Hodgkin lymphoma. The FDA also granted Priority Review for the supplemental Biologics License Application (BLA), and the Prescription Drug User Fee Act (PDUFA) target action date was May 1, 2018.

“The standard of care for treating newly diagnosed advanced Hodgkin lymphoma has not changed in more than four decades. For years, the physician community has been conducting clinical trials to identify improved regimens that are both less toxic and more effective to no avail,” said Joseph M. Connors, M.D., FRCPC, Clinical Director, Center for Lymphoid Cancer at BC Cancer in Vancouver, Canada. “The ECHELON-1 study results demonstrated superior efficacy of the ADCETRIS plus chemotherapy regimen when compared to the standard of care while removing bleomycin, an agent that can cause unpredictable and sometimes fatal lung toxicity, completely from the regimen. This represents a meaningful advance for this often younger patient population.”

This is the fifth FDA-approved indication for ADCETRIS, which also has regular approval for adult patients with: (1) classical Hodgkin lymphoma (cHL) at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-HSCT) consolidation, (2) cHL after failure of auto-HSCT or failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates, (3) sALCL after failure of at least one prior multi-agent chemotherapy regimen, and (4) primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) who have received prior systemic therapy.

“Currently, up to 30 percent of newly diagnosed advanced-stage classical Hodgkin lymphoma patients will experience disease progression after treatment with the current standard of care, representing a significant need for improved treatment options for these often younger patients,” said Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics. “The ECHELON-1 trial was a bold, five-year effort to redefine the frontline treatment of Stage III/IV classical Hodgkin lymphoma and provide patients with a more effective treatment regimen. In the ECHELON-1 study, ADCETRIS plus AVD was shown to have superior efficacy to ABVD. With today’s FDA approval, the physician and patient community have a new treatment option for previously untreated Stage III or IV Hodgkin lymphoma patients. We want to thank all of the patients, physicians and their staff who participated in the ECHELON-1 trial which supported the FDA approval of this novel regimen.”

The FDA approval is based on positive results from a phase 3 trial called ECHELON-1 that were presented at the 59^th American Society of Hematology (ASH) annual meeting in December 2017 with simultaneous publication in the New England Journal of Medicine. Results from the ECHELON-1 trial in 1,334 Stage III or IV classical 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 progression-free survival (PFS) versus the control arm of ABVD as assessed by an Independent Review Facility (IRF) (HR 0.77; 95% CI, 0.60-0.98; p-value=0.035). This corresponds to a 23 percent reduction in the risk of progression, death or need for additional anticancer therapy in patients not in complete response (CR) after frontline treatment.
Overall survival (OS) was a key secondary endpoint and the rate of CR per IRF assessment at the end of the randomized regimen was a secondary endpoint. At the time of the modified PFS analysis, an interim OS analysis trended in favor or the ADCETRIS plus AVD arm, but did not demonstrate significant difference (HR 0.72; 95% CI, 0.44-1.17; p-value=0.19). The CR rate was 73 percent on the ADCETRIS plus AVD arm and 70 percent on the ABVD 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.
The most common adverse events of any grade that occurred in at least 10 percent of patients in the ADCETRIS plus AVD arm were: anemia, neutropenia, peripheral sensory neuropathy, constipation, vomiting, diarrhea, pyrexia, decreased weight, stomatitis, abdominal pain, febrile neutropenia, bone pain, insomnia, decreased appetite, back pain, rashes/eruptions/exanthemas, dyspnea, peripheral motor neuropathy, and increased alanine aminotransferase. In both the ADCETRIS plus AVD and ABVD arms, the most common Grade 3 or 4 events were neutropenia, febrile neutropenia, and anemia.
Based on ECHELON-1 clinical trial results, prophylactic growth factors (G-CSF) should be administered starting at cycle one for Stage III or IV classical Hodgkin lymphoma patients receiving ADCETRIS plus AVD.