The European Commission has approved brentuximab vedotin in combination with doxorubicin, vinblastine, and dacarbazine for the treatment of adult patients with previously untreated, CD30-positive, stage III Hodgkin lymphoma.
The European Commission (EC) has approved brentuximab vedotin (Adcetris) in combination with doxorubicin, vinblastine, and dacarbazine (AVD) for the treatment of adult patients with previously untreated, CD30-positive, stage III Hodgkin lymphoma.1
The regulatory decision followed a recommendation from the European Medicine Agency’s Committee for Medicinal Products for Human Use and was supported by data from the phase 3 ECHELON-1 trial (NCT01712490), which met its primary end point of modified progression-free survival (mPFS) and a key secondary end point of overall survival (OS) in patients with stage III or IV Hodgkin lymphoma treated with brentuximab vedotin plus AVD compared with those treated with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD).1,2
Findings showed that at a median follow-up of 24.6 months (range, 0-49.0), patients treated with brentuximab vedotin plus AVD (n = 664) experienced a 2-year mPFS rate of 82.1% (95% CI, 78.8%-85.0%) compared with 77.2% (95% CI, 73.7%-80.4%) for those treated with ABVD (n = 670; HR, 0.77; 95% CI, 0.60-0.98; P = .04).3 The interim 2-year OS rates were 96.6% (95% CI, 94.8%-97.7%) for brentuximab vedotin plus AVD and 94.2% (95% CI, 92.0%-95.9%) for ABVD (HR, 0.73; 95% CI, 0.45-1.18; P = .20).
Updated findings at a median follow-up of 73.0 months (95% CI, 72.3-73.6; range, 0.0-100.6) showed that treatment with brentuximab vedotin plus AVD led to a statistically significant and clinically meaningful improvement in OS compared with ABVD (HR, 0.59; 95% CI, 0.40-0.88; P = .009).4 Patients treated with brentuximab vedotin plus AVD achieved a 6-year estimated OS rate of 93.9% (95% CI, 91.6%-95.5%) vs 89.4% (95% CI, 86.6%-91.7%) for those given ABVD. A subgroup analysis showed that patients with stage III disease treated with brentuximab vedotin (n = 237) experienced a numerical benefit in OS compared with those given ABVD (n = 246; HR, 0.86; 95% CI, 0.45-1.65).
“We are thrilled with the decision of the EC to approve [brentuximab vedotin] in combination with chemotherapy as a treatment for adult patients with previously untreated, CD30-positive, stage III Hodgkin lymphoma, particularly as up to one third of patients with stage III and IV disease are at risk of experiencing treatment failure with current regimens,” Awny Farajallah, MD, head of global medical affairs oncology at Takeda, stated in a news release.1 “These patients now have [brentuximab vedotin] as a treatment option, and the significant improvement in survival outcomes that [brentuximab vedotin] may provide when added to a frontline treatment regimen, as evidenced by the ECHELON-1 clinical trial data.”
In February 2019, the EC approved the combination of brentuximab vedotin and AVD for the frontline treatment of patients with CD30-positive, stage IV Hodgkin lymphoma, based on data from ECHELON-1.5 Additionally, the FDA approved brentuximab vedotin plus chemotherapy for use as a first-line treatment in patients with stage III or IV classical Hodgkin lymphoma in March 2018, based on data from the same phase 3 study.6
The open-label, randomized ECHELON-1 trial enrolled patients at least 18 years of age with histologically confirmed advanced classical Hodgkin lymphoma per the World Health Organization classification system who had Ann Arbor stage III or IV disease and did not receive prior treatment with systemic chemotherapy or radiotherapy.3 Patients were also required to have an ECOG performance status of 0 to 2, adequate absolute neutrophil and platelet counts, adequate hemoglobin levels, and acceptable liver and kidney function.
Key exclusion criteria included nodular lymphocyte–predominant Hodgkin lymphoma; peripheral sensory or motor neuropathy; known cerebral or meningeal disease; any evidence of residual disease from another cancer; diagnosis of another cancer within 3 years before the first dose of study treatment; or any clinically relevant cardiovascular conditions.
Patients were randomly assigned 1:1 to receive 1.2 mg/kg of brentuximab vedotin plus 25 mg/m2 of doxorubicin, 6 mg/m2 of vinblastine and 375 mg/m2 of dacarbazine; or 25 mg/m2 of doxorubicin, 10 units/m2 of bleomycin, 6 mg/m2 of vinblastine, and 375 mg/m2 of dacarbazine. Treatment in both arms was given on days 1 and 15 of each 28-day cycle for up to 6 cycles.
Findings showed that 89.3% of patients in the brentuximab vedotin plus AVD group and 90.7% of patients in the ABVD group completed all 6 cycles of treatment.4
The safety population consisted of 662 patients in the brentuximab vedotin plus AVD arm and 659 patients in the ABVD arm.3 Any-grade adverse effects (AEs) occurred in 99% of patients in the investigative arm vs 98% of those in the control arm. The rates of grade 3 or higher AEs were 83% and 66%, respectively. Serious toxicities were reported in 43% and 27% of patients, respectively.
The most common AEs reported in the brentuximab vedotin plus AVD and ABVD arms, respectively, included neutropenia (any-grade, 58% vs 45%; grade ≥3, 54% vs 39%), constipation (42% vs 37%; 2% vs <1%), vomiting (33% vs 28%; 3% vs 1%), fatigue (32% vs 32%; 3% vs 1%), peripheral sensory neuropathy (29% vs 17%; 5% vs <1%), diarrhea (27% vs 18%; 3% vs <1%), pyrexia (27% vs 22%; 3% vs 2%), peripheral neuropathy (26% vs 13%; 4% vs <1%), abdominal pain (21% vs 10%; 3% vs <1%), and stomatitis (21% vs 16%; 2% <1%).