Classic Hodgkin lymphoma (cHL) is highly curable with frontline therapy. However, around 20% of patients with advanced stage III/IV disease tend to relapse after standard chemotherapy, such as doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). While individualized intensity positron emission tomography (PET)-guided treatment strategies have improved tolerability and disease control, these approaches have not shown meaningful survival advantage versus ABVD. Novel therapies, including antibody drug conjugate, brentuximab vedotin and anti-PD-1 immunotherapy (nivolumab, pembrolizumab) were approved in the relapsed and refractory setting based on improved outcomes and favorable toxicity profiles, and these agents have now been explored in combination with chemotherapy in earlier treatment lines.

Brentuximab vedotin in combination with chemotherapy has already received FDA approval as first-line treatment for patients with previously untreated advanced stage cHL, based on results from the randomized phase III ECHELON-1 trial, which showed a significant improvement in modified progression free survival (mPFS) and a manageable safety profile. In ECHELON-1, 1,334 patients with previously untreated stage III (36%) or stage IV (64%) cHL received six cycles of either ABVD or brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A+AVD). At ASCO 2022, data from a prespecified overall survival (OS) analysis at a median follow-up of 6 years were presented. Treatment with A+AVD improved OS significantly, with a 41% reduction in the risk of death compared with ABVD (Hazard Ratio [HR], 0.59; P=0.009). Estimated 6-year OS rates were 93.9% with A+AVD vs 89.4% with ABVD. The median OS was not reached. The OS benefit was generally consistent across subgroups. Age, non-white race, ECOG performance status and cycle 2 PET status were most closely associated with OS. Of interest, males appeared to benefit more than females. The A+AVD regimen also reduced the risk of progression or death by 32% compared with ABVD (HR, 0.68; P = 0.002). The estimated 6-year PFS rates were 82.3% and 74.5% with A+AVD vs ABVD, respectively. No new safety signals were reported. While the incidence of treatment-related peripheral neuropathy at 2 years was higher with A+AVD (67 vs 43%), after 6 years follow-up it either resolved or continued to improve in the majority of patients in both treatment groups. Importantly, fewer second malignancies were observed with A+AVD (23 vs 32). Stephen Ansell, MD (Mayo Clinic, Rochester, US) who presented these data, concluded that based on the results ‘’A+AVD should be considered a preferred first-line treatment option for patients with previously untreated stage III or IV cHL’’.

The discussant, Alison J. Moskowitz, MD (Memorial Sloan Kettering Cancer Center, New York, US) noted that when the primary results from ECHELON-1 were first reported, 2-year modified PFS showed only “modest” differences between the trial arms; however, with a longer follow-up the PFS advantage has been maintained and now translates into an OS benefit. In addition, she highlighted that the brentuximab vedotin regimen showed superior event free survival with 59% risk reduction and no increase in toxicity, in a phase III AHOD1331 trial in pediatric patients (up to age 21 years) with newly diagnosed high-risk Hodgkin lymphoma. In her conclusion she said, “I would say that, at this point, for both advanced-stage Hodgkin lymphoma, as well as high-risk Hodgkin lymphoma pediatric patients, brentuximab-based chemotherapy is now the standard”. However, she pointed out that there are many unanswered questions, including whether PD-1 blockade should be incorporated into the frontline setting. Results from ongoing studies exploring this strategy are eagerly awaited.

References:
Ansell SM, et al. ASCO 2022: Abstract 7503.
Castellino SM, et al. ASCO 2022: Abstract 7504.