The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval of brentuximab vedotin (Adcetris) for use in combination with chemotherapy as a frontline treatment for adult patients with CD30+ stage IV Hodgkin lymphoma.
The CHMP recommendation is based on findings from the phase III ECHELON-1 trial, which demonstrated superior progression-free survival (PFS) with brentuximab vedotin plus Adriamycin, vinblastine, and dacarbazine (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; 95% CI, 0.60-0.98; P
Among patients with stage IV disease, the use of brentuximab vedotin resulted in a 29% reduction in the risk of progression, death, or need for new therapy (HR, 0.71; P
= .023). The European Commission will now review the submission for a final approval decision.
“For a large number of previously untreated Hodgkin lymphoma patients diagnosed with stage IV disease, progression will occur with current treatments, highlighting a true unmet need in this population,” Anna Sureda, MD, PhD, head of the Hematology Department and Hematopoietic Stem Cell Transplant Programme, Institut Català d'Oncologia - Hospital Duran i Reynals, said in a statement.
“In the ECHELON-1 clinical trial, Adcetris in combination with AVD reduced the risk of progression, death, or need for subsequent anticancer therapy in patients with stage IV disease by 29% versus ABVD, a standard of care. If approved in this indication, Adcetris may offer an important novel treatment option for previously untreated patients with stage IV Hodgkin lymphoma in Europe,” added Sureda.
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. Patients ranged in age from 18 to 83, the median age was 36 years, and 58% were men.
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 (CR). The modified endpoint was meant to eliminate the potential impact of consolidation treatment with chemotherapy or radiotherapy. Secondary endpoints included overall survival and safety.
PFS was met with 117 events in the brentuximab vedotin arm and 146 events in the AVBD arm. At a median follow-up of 24.9 months, the 2 year modified PFS was 82.1% (95% CI, 78.7-85.0) with the brentuximab vedotin regimen compared with 77.2% (95% CI, 73.7-80.4) with ABVD.
The CR rate was 73% for the brentuximab vedotin arm and 70% for the ABVD arm. In addition, researchers found that 33% fewer patients treated with the brentuximab vedotin regimen received subsequent chemotherapy or high-dose chemotherapy and transplant compared with the patients treated with ABVD.
Safety profiles were consistent with known toxicities of the single agents. Grade ≥3 infections were more common in the brentuximab vedotin group (18%) than the ABVD arm (10%).
Neutropenia was reported in 58% of patients who received the brentuximab vedotin regimen compared with 45% who received ABVD. In the brentuximab vedotin arm, the rate of febrile neutropenia was lower among the 83 patients who received primary prophylaxis with GCSF than among those who did not (11% vs 21%).
Peripheral neuropathy occurred in 67% of patients receiving brentuximab vedotin plus AVD and 43% of patients receiving ABVD.
There were 28 deaths in the brentuximab vedotin cohort and 39 in the ABVD arm (HR for interim overall survival, 0.72; 95% CI, 0.44-1.17; P
= 0.19). Among the deaths that occurred during treatment, 7 of 9 in the brentuximab vedotin group were associated with neutropenia and 11 of 13 in the ABVD group were associated with pulmonary-related toxicity.
According to the co-developers of brentuximab vedotin, Takeda Pharmaceutical Company and Seattle Genetics, the CD30-targeted antibody-drug conjugate currently has approved EU indications for the treatment of adult patients with relapsed/refractory CD30-positive Hodgkin lymphoma following autologous stem cell transplant (ASCT), or following at least 2 prior therapies when ASCT or multi-agent chemotherapy is not a treatment option; adult patients with relapsed or refractory systemic anaplastic large cell lymphoma; adult patients with CD30-positive Hodgkin lymphoma at increased risk of relapse or progression following ASCT; and adult patients with CD30-positive cutaneous T-cell lymphoma after at least 1 prior systemic therapy.
Connors J, Jurczak W, Straus D J., et al. Brentuximab vedotin plus doxorubicin, vinblastine, dacarbazine (A+AVD) as frontline therapy demonstrates superior modified progression-free survival versus ABVD in patients with previously untreated stage III or IV hodgkin lymphoma (HL): the phase 3 echelon-1 study. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta. Abstract 6.