Brentuximab vedotin-chemo confers OS advantage over bleomycin-containing chemo for advanced HL

In the 6-year follow-up of the ECHELON-1 trial, a combination of the CD30-directed ADC* brentuximab vedotin and a chemotherapy (CT) regimen comprising doxorubicin, vinblastine, and dacarbazine (A+AVD), showed a survival advantage over a combination comprising the same CT regimen plus bleomycin (ABVD) in patients with previously untreated stage III or IV Hodgkin’s lymphoma (HL).

First-line ABVD has been the standard of care for advanced-stage classic HL. [N Engl J Med 1992;327:1478-1484] However, a substantial proportion of individuals with stage III/IV disease relapse or are refractory to ABVD. [J Clin Oncol 2013;31:684-691; J Clin Oncol 2016;34:2028-2036]

Though proven to render a survival benefit in this setting, escalated BEACOPP** therapy is toxic. [J Clin Oncol 2009;27:4548-4554] BEACOPP-based regimens may also adversely impact fertility and are tied to an increased risk of second cancers. [Cancer Med 2020;9:6565-6575; J Clin Oncol 2013;31:231-239] “[As such,] BEACOPP has not been widely adopted despite the reported improvement in disease control,” said the researchers.

“The introduction of … brentuximab vedotin and its high response rate as a salvage treatment, including durable responses in some patients, offers a new approach,” noted Drs Dan Longo and James Armitage from the University of Nebraska, Omaha, Nebraska, US, in an accompanying editorial. [N Engl J Med 2022;387:370-372] “The hope has been that brentuximab vedotin, when substituted for bleomycin in the ABVD regimen, would lead to better survival when used as primary therapy, without the serious toxic effects … associated with escalated BEACOPP.”

In ECHELON-1, 1,334 patients were randomized 1:1 to receive up to six cycles of A+AVD or ABVD. The A+AVD regimen consisted of brentuximab vedotin 1.2 mg/kg of body weight (BW) plus CT***. The ABVD regimen comprised the same CT regimen and bleomycin 10 U/m². The agents were administered intravenously on days 1 and 15 of each 28-day cycle. [N Engl J Med 2022;387:310-320]

After a median follow-up of 73 months, fewer patients died in the A+AVD vs the ABVD arm (n=39 vs 64), translating to a significantly lower risk of death with the former vs the latter regimen (hazard ratio, 0.59; p=0.009). The 6-year OS estimates in the respective A+AVD and ABVD arms were 93.9 percent and 89.4 percent, yielding an overall mortality difference of 4.5 percentage points in favour of A+AVD.

“[T]he OS improvement with A+AVD vs ABVD was observed despite the wide availability and use of active salvage therapies,” they continued. “Historically, it has been difficult to show a survival benefit in the context of first-line therapy, in part because approximately half the patients with relapsed or refractory disease can receive salvage therapy^#.”

The percentage of ABVD recipients who received subsequent therapy (24 percent) suggests that the observed survival benefit with A+AVD was not due to undertreatment, or underperformance of the salvage agents given to ABVD recipients, the researchers noted. “Instead, the survival benefit ... with A+AVD may be attributed to the additional^## mechanisms of action that have been observed in other studies of brentuximab vedotin.”

Safety

Fifty-five patients developed second cancers (mostly haematologic^### and solid tumours), with more occurring in the ABVD vs the A+AVD arm (n=32 and 23). More than 40 percent of these cancers occurred in patients aged ≥60 years, which only comprised about 14 percent of the overall cohort. “Given that historical and contemporary trials often did not enrol older adults, [these rates] better approximates the expected incidence of second cancer with A+AVD and ABVD in clinical practice,” they continued.

Despite the high incidence of peripheral neuropathy with A+AVD than with ABVD (n=443 vs 286) and more ongoing neuropathy on last follow-up (19 percent vs 9 percent), about 90 percent of patients had amelioration or complete resolution of symptoms. Also, most events were grade 1/2.

The researchers noted that the incidence of ongoing grade 2 neuropathy on last follow-up (6 percent [A+AVD] and 2 percent [ABVD]) “highlights the importance of monitoring for neuropathy and making appropriate dose modifications in a timely manner”.

There was also a higher incidence of pulmonary toxic effects with ABVD than with A+AVD during treatment, particularly among older patients. Given evidence showing reduced incidence of pulmonary toxic effects due to reduced bleomycin use, excluding bleomycin from first-line therapy may be an important consideration in the treatment of some patients. [Hematol Oncol 2015;33:121; Haematologica 2022;107:1086-1094]

Once fatal, now curable

“The treatment of advanced HL has been a success story in oncology, but only modest progress has been made in past decades,” said the study investigators. “A once uniformly fatal disorder is now curable, even in an advanced stage, in the great majority of patients,” added Longo and Armitage.

“Given the greater activity of brentuximab vedotin than of bleomycin, it seems reasonable that some patients who would not be cured with the ABVD regimen might be cured with the incorporation of brentuximab vedotin into primary therapy,” continued Longo and Armitage.