HL-147: Brentuximab Vedotin with Chemotherapy for Patients with Previously Untreated Stage III/IV Classical Hodgkin Lymphoma: 5-Year Update of the ECHELON-1 Study

Abstract

<h3>Objective</h3> Historically, nearly all relapses in classical Hodgkin lymphoma (cHL) occur within the first 5 years of treatment (Radford et al., BMJ 1997;314:346). In ECHELON-1, brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) significantly improved modified progression-free survival (PFS) versus doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in patients with stage III/IV cHL (Connors <i>et al.,</i> NEJM 2018;378:331). We report updated efficacy and safety results; median follow-up was 60.9 months. <h3>Design</h3> This phase 3, open-label study (NCT01712490) randomized patients with previously untreated stage III/IV cHL to receive 6 cycles of A+AVD or ABVD. Patients underwent an interim positron emission tomography scan after cycle 2 (PET2). An exploratory analysis of PFS per investigator was conducted. <h3>Results</h3> There were 664 and 670 patients randomized to receive A+AVD and ABVD, respectively. 64%, 62%, and 58% of patients had stage IV disease, extranodal involvement at diagnosis, and B symptoms, respectively. Five-year PFS was 82.2% (95% confidence interval [CI]: 79.0–85.0) with A+AVD and 75.3% (95% CI: 71.7–78.5) with ABVD. Overall, PFS favored A+AVD (hazard ratio [HR]: 0.681; 95% CI: 0.534–0.867; P=0.002). PFS benefits were observed regardless of PET2 status and International Prognostic Score. Estimated 5-year PFS with A+AVD <i>versus</i> ABVD was 84.9% <i>versus</i> 78.9% in PET2-negative patients (HR: 0.663; 95% CI: 0.502–0.876; P=0.004), and 60.6% <i>versus</i> 45.9% in PET2-positive patients (HR: 0.702; 95% CI: 0.393–1.255; P=0.229). Treatment-emergent peripheral neuropathy (PN) resolved or improved in 85% (n=375/443) and 86% (n=245/286) of the patients with PN on A+AVD and ABVD, respectively. Secondary malignancies occurred in 19 and 29 patients with A+AVD and ABVD, respectively. A total of 131 female patients or partners of male patients reported a pregnancy; both arms showed similar proportions of ongoing pregnancies or live births. <h3>Conclusions</h3> At 5 years, A+AVD still demonstrates clinically meaningful improvement in PFS versus ABVD, independent of PET2 status, with a manageable safety profile, including resolution or improvement of PN. The PFS benefit observed with A+AVD at this important milestone suggests that A+AVD is an attractive treatment option for all patients with previously untreated stage III/IV cHL. <h3>Funding</h3> Millennium Pharmaceuticals and Seagen