The European Medicine Agency’s Committee for Medicinal Products for Human Use has recommended the approval of brentuximab vedotin in combination with doxorubicin, vinblastine, and dacarbazine in adult patients with previously untreated, CD30-positive, stage III Hodgkin lymphoma.
The European Medicine Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended the approval of brentuximab vedotin (Adcetris) in combination with doxorubicin, vinblastine, and dacarbazine (AVD; A+AVD) in adult patients with previously untreated, CD30-positive, stage III Hodgkin lymphoma.1
The positive opinion was supported by data from the phase 3 ECHELON-1 trial (NCT01712490), in which A+AVD significantly improved progression-free survival (PFS) and overall survival (OS) vs doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in this population.
Earlier data showed that at a median follow-up of 24.6 months (range, 0-49.0), the 2-year PFS rate with A+AVD (n = 664) was 82.1% (95% CI, 78.8%-85.0%) vs 77.2% (95% CI, 73.7%-80.4%) with ABVD (n = 670), translating to a 23% reduction in the risk of disease progression or death (HR, 0.77; 95% CI, 0.60-0.98; P = .04).2 The interim 2-year OS rates were 96.6% (95% CI, 94.8%-97.7%) and 94.2% (95% CI, 92.0%-95.9%), respectively (HR, 0.73; 95% CI, 0.45-1.18; P = .20).
With a longer follow-up of 73.0 months (95% CI, 72.3-73.6), the OS analysis significantly favored the A+AVD regimen vs ABVD (HR, 0.59; 95% CI, 0.40-0.88; P = .009).3 The estimated 6-year OS rate with A+AVD was 93.9% (95% CI, 91.6%-95.5%) vs 89.4% (95% CI, 86.6%-91.7%) with ABVD.
The European Commission will now review the submission for brentuximab vedotin.1
In March 2018, the FDA approved brentuximab vedotin plus chemotherapy for use as a first-line treatment in patients with stage III or IV classical Hodgkin lymphoma.4 The decision was based on earlier findings from ECHELON-1.
The open-label, multicenter, phase 3 ECHELON-1 trial enrolled patients with histologically confirmed advanced classical Hodgkin lymphoma by the World Health Organization classification system who were at least 18 years of age and who have Ann Arbor stage III or IV disease.2 To participate, patients needed to have an ECOG performance status ranging from 0 to 2; acceptable absolute neutrophil and platelet counts, as well as hemoglobin levels; and satisfactory liver and kidney function.
Exclusion criteria included having nodular lymphocyte-predominant Hodgkin lymphoma, peripheral sensory or motor neuropathy, cerebral or meningeal disease, residual disease from another cancer, another cancer diagnosis within 3 years before the first dose of treatment on study, or other relevant cardiovascular conditions.
Study participants were randomly assigned in a 1:1 fashion to A+AVD or ABVD. Those in the investigative arm were given brentuximab vedotin at 1.2 mg/kg in combination with doxorubicin at 25 mg/m2, vinblastine at 6 mg/m2, and dacarbazine at 375 mg/m2. Patients in the control arm were given doxorubicin at 25 mg/m2, bleomycin at 10 units/m2, vinblastine at 6 mg/m2, and dacarbazine at 375 mg/m2.
Stratification factors included region (America vs Europe vs Asia) and International Prognostic Score (IPS) risk group (low vs intermediate vs high).
Modified PFS served as the trial’s primary end point, and OS served as a key secondary end point.
In the total population (n = 1334), the median age was 36 years (range, 18-83) and 58% were male. Regarding region, 50% of patients were from Europe, 39% were from the United States, and 11% were from Asia. Most patients had stage IV disease (64%), followed by stage III disease (36%), and stage II disease (<1%); this information was not applicable, unknown, or missing for 4 patients. In terms of IPS risk group, 53% of patients had a score of 2 or 3, 26% had a score of 4 to 7, and 21% had a score of 0 or 1.
Fifty-five percent of patients had an ECOG performance status of 0, 39% had a status of 1, and 4% had a status of 2; this information was missing for 2 patients. More than half of patients (62%) had extranodal involvement at the time of diagnosis, with 33% having 1 extranodal site and 29% having more than 1 site. Fifty-nine percent of patients had any B symptom.
Additional OS subgroup analyses revealed that more favorable survival estimates were observed with A+AVD vs ABVD in those who were under 60 years of age (HR, 0.51; 95% CI, 0.29-0.89), those with stage IV disease at baseline (HR, 0.48; 95% CI, 0.29-0.80), those in the high-risk IPS subgroup (HR, 0.48; 95% CI, 0.26-0.88), and those who resided in North America (HR, 0.33; 95% CI, 0.15-0.70).3 Less favorable estimates of treatment effect with A+AVD vs ABVD were noted in those aged 60 years or older (HR, 0.83; 95% CI, 0.47-1.47), female patients (HR, 0.96; 95% CI, 0.51-1.80), and those in the low-risk IPS subgroup (HR, 0.97; 95% CI, 0.34-2.77).
With a longer follow-up of 72.6 months, PFS outcomes favored A+AVD vs ABVD. The estimated 6-year PFS rate in the investigative arm was 82.3% vs 74.5% in the control arm (HR, 0.68; 95% CI, 0.53-0.86). This trend was observed across various patient subsets, including those defined by disease stage or PET2-negative status.
A total of 662 patients in the A+AVD arm and 659 patients in the ABVD arm comprised the safety population.2 Any-grade adverse effects (AEs) were reported in 99% of those in the investigative arm vs 98% of those in the control arm; these effects were grade 3 or higher for 83% and 66% of patients, respectively. Serious toxicities were reported in 43% and 27% of patients, respectively.
The most common AEs reported in the A+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%).
With longer follow-up, 32 of the 39 deaths reported in the A+AVD arm were noted to be related to the disease or treatment complications; 1 death was due to second cancer, 1 due to unknown cause, 3 due to accident or suicide, 1 due to heart failure, and 1 due to intracranial hemorrhage.3
The use of subsequent treatment was found to be less frequent in the A+AVD arm vs the ABVD arm, at 20.4% and 23.8% of patients, respectively. Fewer subsequent autologous transplants were observed in the investigative arm vs the control arm, at 6.6% and 9.0%, respectively; the same was true for allogeneic stem cell transplants, at 0.6% vs 1.8%, respectively.
The most common subsequent treatment in the ABVD arm was brentuximab vedotin monotherapy or in combination with another a gent (10.5%). In the A+AVD arm, use of immunotherapy was less frequent than what was observed in the ABVD arm, at 2.7% vs 4.2%, respectively. Subsequent radiation administration was similar between the arms, at 8.3% vs 8.8%, respectively.
A second cancer was observed in 3.5% of those in the investigative arm vs 4.9% of those in the control arm. In the A+AVD arm, there were 14 solid tumors and 10 hematologic cancers.