Nivolumab (Opdivo) combined with doxorubicin, vinblastine, and dacarbazine (N+AVD) has demonstrated a significant improvement in progression-free survival (PFS) and a more favorable toxicity profile compared to brentuximab vedotin (BV) plus AVD (BV+AVD) in patients with stage III or IV advanced-stage classic Hodgkin lymphoma. These findings come from the phase 3 S1826 trial, published in The New England Journal of Medicine.
Superior PFS with Nivolumab Plus AVD
The multicenter, open-label, randomized trial enrolled 994 patients aged 12 years and older with previously untreated classic Hodgkin lymphoma. Patients were randomized to receive either BV+AVD or N+AVD for 6 cycles. Nivolumab was administered at 240 mg in adults and 3 mg/kg (capped at 240 mg) in children ages 12 to 17 years. The primary endpoint was PFS.
After a median follow-up of 2.1 years, the 2-year PFS rate was 92% (95% CI, 89%-94%) with N+AVD compared to 83% (95% CI, 79%-86%) with BV+AVD (HR, 0.45; 95% CI, 0.30-0.65). These results indicate a substantial improvement in disease control with the nivolumab-containing regimen.
Tolerability and Safety Profile
In addition to improved efficacy, N+AVD was associated with a more tolerable safety profile. Notably, the incidence of grade 2 or higher peripheral sensory neuropathy was significantly lower in the N+AVD arm (3%) compared to the BV+AVD arm (32%). While the rates of febrile neutropenia, infection/infestation, and sepsis were similar between the two arms, these events occurred more frequently in older patients, especially those receiving BV+AVD.
"In the context of a disease in which a high proportion of patients are cured with standard therapy and the bar to change practice is set high, the improvement in efficacy and in the risk of adverse effects [AEs] was clinically meaningful," wrote lead study author Alex F. Herrera, MD, chief of the Division of Lymphoma at City of Hope.
Impact on Clinical Practice
The study authors suggest that the combination of improved PFS, a favorable adverse event profile, and the potential to avoid consolidative radiation therapy make N+AVD a strong candidate for primary treatment in adolescent and adult patients with stage III or IV Hodgkin lymphoma. Furthermore, the decreased drug-acquisition and supportive-care costs associated with N+AVD could provide additional benefits.
The extremely low use of radiotherapy in the trial, combined with the excellent outcomes observed after treatment with N+AVD, suggests that radiotherapy has limited utility in adolescent patients after they have received N+AVD.
Study Population and Design
The S1826 trial included a diverse patient population, with stratification by age, International Prognostic Score (IPS) group, and intent to use radiation. Patients with pre-existing interstitial lung disease, active autoimmune disease, or peripheral neuropathy of grade 2 or higher were excluded. The trial mandated granulocyte colony-stimulating factor (G-CSF) prophylaxis in patients receiving BV+AVD but allowed for investigator discretion in the N+AVD arm. Dexrazoxane was permitted to reduce the risk of doxorubicin-induced cardiac toxicities.
