First-line brentuximab vedotin regimen extends OS in advanced classical Hodgkin lymphoma
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CHICAGO — The addition of brentuximab vedotin to frontline chemotherapy significantly extended OS among patients with advanced classical Hodgkin lymphoma, according to study results presented at ASCO Annual Meeting.
The experimental regimen conferred a 41% reduction in risk for death compared with standard chemotherapy, updated results of the randomized phase 3 ECHELON-1 trial showed.
“In Hodgkin lymphoma, we don’t commonly see survival advantages in clinical trials,” Stephen M. Ansell, MD, PhD, professor of medicine and consultant in the division of hematology at Mayo Clinic in Rochester, Minnesota, and a HemOnc Today Editorial Board member, told Healio. “That is why this is a unique finding and represents important progress in the field. This shows what we do as frontline therapy impacts outcomes, particularly for younger patients.”
Background and methodology
New therapies have improved outcomes when used in later-line settings for patients with relapsed or refractory classical Hodgkin lymphoma. However, efforts to identify upfront treatment regimens that can extend OS have proven challenging, Ansell said.
“ABVD chemotherapy has been a standard in Hodgkin lymphoma for a very long time, and it has been exceedingly difficult to show substantial improvements over that,” Ansell said.
Brentuximab vedotin (Adcetris, Seagen) — an antibody-drug conjugate — consists of an anti-CD30 monoclonal antibody attached to a microtubule-disrupting agent, monomethyl auristatin E, through a protease-cleavable linker. The agent uses a linker system designed to be stable in the bloodstream but to release monomethyl auristatin E when it internalizes into cells that express CD30.
The open-label ECHELON-1 trial included 1,334 patients (median age, 36 years; 58% men) with previously untreated stage III (36%) or stage IV (64%) classical Hodgkin lymphoma.
Researchers assigned 664 patients to brentuximab vedotin plus AVD chemotherapy, which consists of doxorubicin, vinblastine and dacarbazine. The other 670 patients received ABVD, which consists of doxorubicin, bleomycin, vinblastine and dacarbazine.
Patients received their assigned treatment on days 1 and 15 every 28 days for up to six cycles.
Modified PFS — defined as time to progression, death or evidence of incomplete response followed by subsequent anticancer therapy — determined by independent review served as the primary endpoint.
OS served as the key secondary endpoint.
Study results
Previously released results based on 5-year follow-up showed a long-term PFS benefit with the brentuximab vedotin regimen, along with a manageable long-term safety profile.
In 2018, the FDA approved brentuximab vedotin plus doxorubicin, vinblastine and dacarbazine for previously untreated stage III/stage IV classical Hodgkin lymphoma based on results of ECHELON-1.
At ASCO, Ansell presented results of a prespecified OS analysis performed after 39 OS events in the brentuximab vedotin-AVD group and 64 OS events in the ABVD group.
Median follow-up was 73 months.
Results showed significantly longer OS in the brentuximab vedotin-AVD group (HR = 0.59; 95% CI, 0.39-0.87). Researchers estimated 6-year OS rates of 93.9% (95%, 91.6-95.5) with the experimental regimen and 89.4% (95% CI, 86.6-91.7) with the standard regimen.
The OS benefit with brentuximab vedotin and AVD appeared consistent across prespecified subgroups.
“The way patients were managed if they progressed was exactly the same in both treatment arms, and yet we see this survival advantage,” Ansell said. “This suggests adding this agent clearly makes a difference.”
Researchers reported estimated 6-year PFS rates of 82.3% (95% CI, 79.1–85) with the brentuximab vedotin regimen vs. 74.5% (95% CI, 70.8–77.7) with ABVD (HR = 0.67; 95% CI, 0.53-0.86).
The two regimens exhibited comparable long-term safety profiles, and researchers reported no new safety signals.
Two-thirds (66.7%; n = 443) of patients assigned brentuximab vedotin-AVD and slightly less than half (42.6%; n = 286) of those assigned ABVD developed treatment-emergent peripheral neuropathy. However, by last follow-up, the majority of those cases in both treatment groups had either completely resolved (72% vs. 79%) or were improving (14% vs. 8%).
More female patients assigned the brentuximab vedotin regimen reported pregnancy (49 vs. 28) and live births (42 vs. 19). Researchers reported no stillbirths.
Results showed fewer second malignancies (23 vs. 32) in the brentuximab vedotin-AVD group.
"Interestingly, this is not related to solid tumor malignancies, which we often see with longer-term follow-up. They were identical in the two treatment arms," Ansell said. "Fewer patients in the experimental arm than the standard arm developed other lymphomas, suggesting brentuximab vedotin may target a stem cell that may be the culprit in some patients developing a second hematologic malignancy.”
Implications
Brentuximab vedotin with AVD has been accepted as a standard of care and is widely used in practice, Ansell said.
“Patients want to be treated, get into remission and be done,” Ansell told Healio. “Often, though, there is a sentiment that patients can come back and be salvaged. ... That could mean a lot of additional therapy, which no patient would be super excited about. Now we can show that initial therapy actually impacts survival. That strengthens the case for doing it right from the beginning.”
An ongoing U.S. intergroup phase 3 study is designed to compare AVD with either brentuximab vedotin or nivolumab (Opdivo, Bristol Myers Squibb), an anti-PD-1 antibody, as frontline therapy. The trial will enroll approximately 1,000 patients.
“That study has almost completely accrued, and hopefully we will begin to see data soon,” Ansell said. “Brentuximab vedotin with AVD has already pushed the bar higher, and we’ll see whether PD-1 blockade pushes the bar higher yet.”
Perspective
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Catherine S.M. Diefenbach, MD
This is the first study in frontline Hodgkin lymphoma to demonstrate an improvement in OS in decades. Earlier studies, such as the RATHL or RAPID trials, have demonstrated improvement in PFS without a corresponding improvement in OS. The long-term safety data was comparable in both arms, and the peripheral neuropathy continued to resolve. That the ECHELON-1 study was able to demonstrate a survival advantage even with the approval of checkpoint inhibitor therapy in the relapsed setting is important and significant. These data confirm brentuximab vedotin and AVD as a standard of care for the frontline management of advanced-stage Hodgkin lymphoma. Some questions remain and likely will be discussed in the oral presentation. These include which subset of patients had the most significant benefit, and whether patients benefitted across all stages and risk categories. The contribution of second malignancies to this outcome — as both arms appear somewhat higher than expected for second malignancies — also will be important to understand. But with these data, it is clear that brentuximab vedotin and AVD should be a regimen of choice for patients with newly diagnosed advanced-stage Hodgkin lymphoma.
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Ansell SM, et al. Abstract LBA7503. Presented at: ASCO Annual Meeting; June 3-7, 2022; Chicago.
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