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

For the past 20 years, high-dose therapy plus autologous stem cell transplant (ASCT) has been the standard of care for patients (pts) with chemosensitive relapsed/refractory Hodgkin lymphoma (HL), providing a cure for approximately 50% of pts (Sureda 2005). Despite optimization of salvage chemotherapy, supportive care, and pt selection, improvements in outcomes post-ASCT have plateaued, likely due to disease progression (PD) in pts with pre-salvage therapy risk factors. The majority of pts with multiple risk factors will progress post-ASCT and novel therapy is urgently needed. Brentuximab vedotin (ADCETRIS®) 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. Pts were enrolled in 1 of 3 high-risk categories: refractory to frontline therapy: 196 pts (60%), relapse <12 months after frontline therapy: 107 pts (33%), and relapse ≥12 months after frontline therapy with extranodal disease: 26 pts (8%). Pts were required to have obtained a CR, partial remission (PR), or stable disease (SD) to salvage therapy prior to ASCT. After ASCT, pts received brentuximab vedotin 1.8 mg/kg q3wk and best supportive care (BSC) or placebo and BSC for up to 16 cycles (approximately 12 months). Pts with PD were to discontinue study 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 PFS per an independent review facility (IRF); additional endpoints include overall survival (OS) and safety/tolerability.

Results

A total of 329 pts were randomized at 78 sites in the United States and Europe. Of the 329 enrolled pts, 327 received study treatment. The median age was 32 years (range, 18–76) and 53% were male. The median number of prior systemic therapies (frontline and salvage) was 2 (range, 2–8); 47% of pts received more than 2 prior systemic therapies. Response to salvage therapy pre-ASCT was CR: 137 pts (42%), PR: 112 pts (34%), and stable disease (SD): 80 pts (24%). 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%). Overall, 78% of pts had multiple risk factors for progression.

All pts had completed or discontinued study treatment as of August 2013. The median number of treatment cycles was 15, and 159 pts (49%) received 16 cycles. Reasons for treatment discontinuation were: PD: 93 pts (28%), adverse event (AE): 61 pts (19%), patient decision: 15 pts (5%), and investigator decision: 1 pt (<1%). At the time of this analysis (June 2014), the median follow-up time from randomization was 24.4 mos (range, 0–43 mos). For the pooled study population at 24 mos, the Kaplan Meier estimates were 54% (95% CI: 47%, 60%) for PFS and 88% (95% CI: 84%, 91%) for OS. Of the 50 deaths, 8 occurred prior to PD.

AEs of any grade in >15% of 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%). As assessed by a Standardised MedDRA Query, 144 pts (44%) had treatment-emergent events of peripheral neuropathy (PN). Grade 3 PN was reported for 23 pts (7%) and was mostly sensory; no Grade 4 events were observed. Resolution or at least 1 grade of improvement in PN has occurred in 80% of pts with neuropathy events; the median time to resolution or improvement was 11.7 weeks (range, 0.1–128.0 weeks).

Conclusions

Based on analysis of blinded pooled efficacy data, the estimated 2-year PFS rate was 54% and the estimated 2 year OS rate was 88%. The most common reason for treatment discontinuation was disease progression. The primary analysis for the study will be performed in September 2014 and unblinded efficacy and safety data will be publicly presented for the first time at the conference.

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