FDA Approval Sought for Frontline Brentuximab Vedotin for Hodgkin Lymphoma

Clay Siegall, PhD

Clay Siegall, PhD

A supplemental new drug application has been submitted for brentuximab vedotin (Adcetris) in combination with Adriamycin, vinblastine, dacarbazine (AVD) as a frontline treatment for advanced classical Hodgkin lymphoma, according to a statement from the company developing the CD30-targeted antibody-drug conjugate, Seattle Genetics.

The application was based on findings from the phase III ECHELON-1 trial, which demonstrated superior progression-free survival (PFS) with brentuximab vedotin plus AVD compared with standard ABVD (AVD plus bleomycin). In the study, the brentuximab vedotin regimen reduced the risk of progression, death, or initiation of new therapy by 23% compared with ABVD. The 2-year modified PFS rate was 82.1% with brentuximab vedotin compared with 77.25% for standard chemotherapy (HR, 0.77; P = .035).

Full findings from the ECHELON-1 study have not yet been released and are scheduled to be presented during the 2017 ASH Annual Meeting. Although exact numbers are not yet available, Seattle Genetics noted that a statistical trend favoring the brentuximab vedotin arm was also seen for overall survival.

In October, Seattle Genetics announced that brentuximab vedotin had received a breakthrough therapy designation from the FDA as a frontline treatment for Hodgkin lymphoma, based on findings from the ECHELON-1 study. The trial was conducted under a special protocol assessment agreement with the FDA, which suggests that findings from the study will be sufficient for approval. Under the Prescription Drug User Fee Act, the FDA is scheduled to review the application within 60 days, at which point the agency will assign a review deadline.

“Results from the ECHELON-1 study demonstrated superior activity of an Adcetris-containing regimen over standard of care, and resulted in FDA breakthrough therapy designation for Adcetris in combination with chemotherapy for frontline advanced classical Hodgkin lymphoma," Clay Siegall, PhD, president and chief executive officer of Seattle Genetics, said in a statement. "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.”

The phase III ECHELON-1 trial enrolled 1334 patients with stage III/IV classical Hodgkin lymphoma. All patients had not received prior treatment with systemic chemotherapy or radiotherapy and had an ECOG performance status of ≤2. In both arms, treatment was given on days 1 and 15 of a 28-day cycle. Doxorubicin was given at 25 mg/m2, vinblastine was administered at 6 mg/m2, and patients received dacarbazine at 375 mg/m2. In the investigational arm, brentuximab vedotin was administered at 1.2 mg/kg and in the control group bleomycin was administered at 10 units/m2.

The primary endpoint of the study was modified PFS by independent review committee. Under the modified criteria, PFS was defined as time to progression, death, or receipt of additional therapy for those not in complete response. The modified endpoint was meant to eliminate the potential impact of consolidation treatment with chemotherapy or radiotherapy. Secondary endpoints included overall survival and safety.

In a prior phase I study exploring the frontline regimen of brentuximab vedotin and AVD, 24 of 25 patients (96%) experienced a complete response with the combination. In long-term findings, the 3-year failure-free survival rate was 96% and the overall survival rate at 3 years was 100%. The most common grade ≥3 adverse events were neutropenia (77%), anemia (12%), febrile neutropenia (8%), and syncope (8%).

“There have been no new treatment advances for frontline Hodgkin lymphoma in more than 40 years,” said Siegall. “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.”

Brentuximab vedotin is currently approved for patients with classical Hodgkin lymphoma following autologous hematopoietic stem cell transplantation (HSCT) or after failure of 2 prior regimens, if not candidates for HSCT. The agent is also approved as consolidation therapy for patients with Hodgkin lymphoma at high risk of relapse or progression following autologous HSCT.

Connors JM, Ansell S, Park SI, et al. Brentuximab vedotin combined with ABVD or AVD for patients with newly diagnosed advanced stage Hodgkin lymphoma: long term outcomes. Blood. 2014; 124:292.