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Four-year follow-up data of ECHELON-1 support the robust and durable benefit of brentuximab vedotin + AVD over ABVD as frontline treatment for advanced Hodgkin lymphoma

Chemotherapy with of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) has long been the standard of care first-line treatment for patients with advanced-stage Hodgkin lymphoma. However, in 2017 this standard was challenged by results of the phase III ECHELON-1 trial, by demonstrating a statistically significant reduction in the risk of progression, death, or need for additional anticancer therapy with a combination of brentuximab vedotin plus doxorubicin, vinblastine, dacarbazine (A+AVD) compared to ABVD. Four-year follow-up data of this trial, presented at ASH 2019, confirm these primary findings with a 4-year PFS rate of 81.7% for A+AVD as compared to 75.1% with ABVD (HR 0.69 [95% CI: 0.54-0.88]). This PFS benefit was seen across all investigated subgroups, irrespective of PET2 status, disease stage, age and IPS score. Importantly, the peripheral neuropathy seen with A+AVD continued to improve over time with most patients experiencing complete resolution.

Background

In ECHELON-1, 1,334 patients with stage III (36%) or IV (64%) classical Hodgkin lymphoma (cHL) were randomized (1:1) to receive A+AVD (n= 664) or ABVD (n= 670) on days 1 and 15, for up to six 28-day cycles. The primary endpoint of ECHELON-1 was modified progression-free survival (mPFS), defined as the time until progressive disease, death, or subsequent anticancer therapy following detection of a non-complete response at the end of frontline therapy. Two years ago, A+AVD proved to be superior to ABVD for this endpoint with a hazard ratio (HR) of 0.77 and 2-year mPFS rates of 82.1% and 77.2% with A+AVD and ABVD, respectively. At a median follow-up of 3 years, PFS results supported the durable benefit of A+AVD over ABVD with rates of 83.1% and 76.0%, respectively (HR 0.70 [95% CI: 0.55-0.90]). During ASH 2019, 4-year follow up data of this trial were presented.

Results

In this updated analysis, treatment with A+AVD was associated with a 31% reduction in the risk of disease progression or death compared to ABVD (HR 0.691 [95% CI: 0.542-0.881]; p=0.003). The corresponding PFS rates at 4 year were 81.7% for A+AVD and 75.1% for ABVD (median follow-up: 48 months). As such, the PFS hazard ratio of 0.69 is similar to the HR reported after 2 (HR: 0.70) and 3 years (HR: 0.70) underlining the sustained and durable benefit of A+AVD over ABVD. The PFS benefit of A+AVD over ABVD was seen irrespective of age, IPS score, disease stage, the number of extranodal sites at baseline and the ECOG performance status (PS). Overall, 89% of patients in the A+AVD arm and 86% of ABVD treated patients were PET2-negative, while 7% and 9% of patients were PET positive with A+AVD and ABVD, respectively (PET2 unknown in remaining patients). Importantly, a PFS benefit of A+AVD over ABVD was seen in all patients, independent of the PET2 status.

At the primary analysis of ECHELON-1, 442 patients (67%) in the A+AVD arm and 286 patients (43%) in the ABVD arm had PN. At 4 years of follow-up, 83% and 84% of A+AVD and ABVD patients, respectively, experienced complete resolution of their PN symptoms. At the 4-year landmark, 142 patients in the A+AVD arm (21%) and 69 patients (10%) treated with ABVD had ongoing PN (mainly grade 1 or 2). The median time to complete PN resolution of PN that were ongoing at the end of treatment was 30 weeks in the A+AVD arm and 15 weeks in patients who received ABVD. The median time for PN improvement (for patients without complete resolution) was 41 weeks with A+AVD and 12 weeks with ABVD.

Conclusions

The presented PFS analysis of ECHELON-1, with 4 years of follow-up, further supports the robust and durable benefit of A+AVD over ABVD in the frontline treatment of patients with stage III/IV cHL. This PFS benefit was seen across all subgroups, including patients with a PET2 positive status, patients above 60 years of age, patients with stage IV disease and patients with a dismal IPS score. The PN observed in the initial analysis of this study continued to resolve, with the majority of patients experiencing complete resolution of their PN symptoms. As such, A+AVD compares favorably to PET-adapted treatment strategies in patients with stage III or IV cHL, without the need for a therapy change based on PET2 status and without patient exposure to bleomycin.

Reference

Bartlett N, et al. Brentuximab Vedotin with Chemotherapy for Stage 3/4 Classical Hodgkin Lymphoma (cHL): 4-Year Update of the Echelon-1 Study. Presented at ASH 2019; Abstract 4026.

Speaker Nancy Bartlett

Bartlett

Nancy L. Bartlett, MD, Washington University Sch. of Med. Siteman Cancer Center, Saint Louis, MO, USA

 

See: Keyslides

 

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