First line treatment including the CD30-directed antibody–drug conjugate brentuximab vedotin appears to offer a survival advantage in adult patients with advanced Hodgkin’s lymphoma.
The phase 3 trial compared a regimen of brentuximab, doxorubicin, vinblastine and dacarbazine (A+AVD) with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in 1,334 patients with previously untreated stage III or IV disease.
The international study, including sites in Australia, found overall survival significantly favoured A+AVD over ABVD (hazard ratio for death, 0.59; 95% CI, 0.40 to 0.88; P=0.009)
When analysed by pre-specified subgroups, the treatment effect was more favourable in <60 years, those with stage IV disease and those with a high-risk International Prognostic Score (IPS). Older patients, women and those in the low-risk IPS subgroup had a less favourable treatment effect.
“The 6-year progression-free survival estimates also favoured A+AVD over ABVD across various subgroups, including subgroups defined according to disease stage (III or IV) and PET2-negative status.”
The study, published in the NEJM, said it was historically difficult to show a survival benefit with first-line therapy given the wide availability and use of salvage therapies.
“The proportion of patients in the ABVD group who received subsequent therapy, including transplantation and subsequent use of brentuximab vedotin, as well as the consistency of these outcomes with other contemporary studies of ABVD, suggests that the observed survival benefit with A+AVD was not due to undertreatment of disease or underperformance of salvage agents administered in patients in the ABVD group,” the researchers said.
“Instead, the survival benefit and reduction in the risk of disease-related death with A+AVD may be attributed to the additional mechanisms of action that have been observed in other studies of brentuximab vedotin, including antibody-dependent cellular phagocytosis, bystander activity in the tumor microenvironment (owing to the release of monomethyl auristatin E), induction of immunogenic cell death, and depletion of CD30-expressing regulatory T cells.”
The study found about 90% of patients in both treatment arms completed the six cycles of trial therapy.
Ongoing peripheral neuropathy was more commonly reported with the brentuximab regimen than with ABVD (18.9% v 9.0% at last follow-up).
Most deaths in both groups were related to Hodgkin’s lymphoma or treatment complications; deaths attributed to second cancers were lower with brentuximab than in the ABVD group (1 v 11).
An accompanying editorial also highlighted more deaths from pulmonary toxic effects in the ABVD group than the brentuximab group.
“If the 10 excess deaths from second cancer and the 11 deaths from pulmonary toxic effects in the ABVD group were eliminated, the survival advantage with A+AVD might be smaller than it appears. However, the higher initial cure rate and a lower likelihood of subsequent therapy (20% in the A+AVD group vs. 24% in the ABVD group) could still be a reason to favour using A+AVD,” it said.
They noted factors weighing against the use of brentuximab vedotin included the increased incidence of neurotoxic effects and myelosuppression, requirement for routine administration of white-cell growth factors, and higher cost.
“At one of our institutions, the difference in cost for a patient with a body weight of 70 kg (body-surface area, 1.73 m2) between six cycles of A+AVD (including the white-cell growth factor) and ABVD is $275,150,” the US authors said.
They suggested a possible trial of ABVD followed by a switch to A+AVD therapy for patients without complete remission after two initial cycles.
The study was supported by Takeda.