The AETHERA Trial: Results of a Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of Brentuximab Vedotin in the Treatment of Patients at Risk of Progression Following Autologous Stem Cell Transplant for Hodgkin Lymphoma

Background

Autologous stem cell transplant (ASCT) is the standard of care for patients (pts) with relapsed/refractory Hodgkin lymphoma (HL), providing a cure for approximately 50% of pts; however, most pts with risk factors will progress post-ASCT (Sureda 2005).  Brentuximab vedotin comprises an anti‑CD30 antibody conjugated by a protease-cleavable linker to a microtubule-disrupting agent, monomethyl auristatin E (MMAE), and has an objective response rate of 75% in relapsed or refractory HL.  The AETHERA trial was initiated to evaluate whether early treatment with brentuximab vedotin post-ASCT can prevent progression in pts with HL (ClinicalTrials.gov #NCT01100502).

Methods

The AETHERA trial is a phase 3, randomized, double-blind, placebo-controlled, multicenter study.  After ASCT, pts received brentuximab vedotin 1.8 mg/kg q3wk or placebo for up to 16 cycles.  Pts with disease progression were to discontinue therapy and could request unblinding; these pts may have received subsequent brentuximab vedotin on another clinical trial or on-label in some regions.  The primary endpoint is progression-free survival (PFS) per an independent review facility (IRF). 

Results

A total of 329 pts were randomized at 78 sites in the US and Europe.  The median age was 32 years (range, 18–76) and 53% were male.  Pts were enrolled in 1 of 3 high-risk categories: refractory to frontline (FL) therapy: 196 pts (60%), relapse <12 mos after FL therapy: 107 pts (33%), and relapse ≥12 mos after FL therapy with extranodal disease: 26 pts (8%).  Response to salvage therapy pre-ASCT was complete remission: 137 pts (42%), partial remission: 112 pts (34%), and stable disease: 80 pts (24%).  The median number of prior systemic therapies was 2 (range, 2–8); 47% of pts received more than 2 prior systemic therapies.  Prior to pre-ASCT salvage therapy, 106 pts (32%) had extranodal involvement and 87 pts (26%) had B symptoms.  Prior to ASCT, 110 pts (33%) were PET‑negative, 116 pts (35%) were PET-positive, and PET status was unknown for 103 pts (31%).  All pts had completed or discontinued study treatment as of August 2013.  The median number of treatment cycles was 15. 

Adverse events (AEs) of any grade in >15% of all pts were peripheral sensory neuropathy (36%), upper respiratory tract infection (25%), neutropenia (24%), fatigue (21%), cough (19%), and pyrexia (17%).  Grade 3 or higher AEs in ≥10 pts were neutropenia (20%), peripheral sensory neuropathy (6%), thrombocytopenia (3%), and peripheral motor neuropathy (3%).   

The primary results were released on September 29^th, 2014.  The PFS per IRF for patients who received brentuximab vedotin was statistically significantly improved compared to patients who received placebo (hazard ratio 0.57; P=0.001).

Conclusions

Brentuximab vedotin significantly improved the post-ASCT PFS of patients with HL.  Complete efficacy and safety data will be presented at the conference.