Six-Year Survival Extends With Brentuximab Vedotin Plus Chemotherapy in Hodgkin Lymphoma

Stephen Ansell, MD, PhD

In the phase 3 ECHELON-1 trial (NCT01712490), the combination of brentuximab vedotin (Adcetris) plus doxorubicin, vinblastine, and dacarbazine (A+AVD) achieved a significant reduction in the risk of death vs doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in patients with previously untreated stage III/IV classical Hodgkin lymphoma.

The combination also showed a manageable safety profile consistent with prior findings in, according to 6-year follow-up data presented at the 2022 ASCO Annual Meeting.

At a median follow-up of 73 months, the estimated 6-year overall survival (OS) rates were 93.9% (95% CI, 91.6%-95.5%) with A+AVD vs 89.4% (95% CI, 86.6%-91.7%) with ABVD (HR 0.59; 95% CI, 0.40-0.88; P = .009). The median OS was not yet reached in either arm.

“Brentuximab vedotin plus AVD is the first regimen to show an improvement in OS compared with standard ABVD chemotherapy in patients with previously untreated, advanced stage classical Hodgkin lymphoma,” lead study author Stephen Ansell, MD, PhD, professor of medicine, consultant, and chair of Faculty Development and Recruitment in the Division of Hematology and Department of Internal Medicine at Mayo Clinic, said during a presentation on the findings. “Based on these data, AVD chemotherapy plus brentuximab vedotin should be considered a preferred first-line treatment in patients with previously untreated, advanced stage classical Hodgkin lymphoma.”

In ECHELON-1, 1,334 patients were randomized 1:1 to receive up to 6 cycles of A+AVD (n = 664) or ABVD (n = 670) intravenously on days 1 and 15 every 28 days.

Modified progression-free survival (PFS) per independent review committee served as the primary end point of the trial and was met, with 5-year follow-up analyses supporting the long-term PFS benefit with first-line A+AVD vs ABVD in patients with stage III/IV classical Hodgkin lymphoma, independent of interim positron emission tomography (PET) status.2

OS was the key secondary end point and was an event-driven, prespecified, alpha-controlled analysis in the intention-to-treat population.

Long-term follow-up assessments included PFS per investigator, subsequent treatment use, and safety outcomes including second malignancies, outcomes of pregnancy among patients and their partners, and peripheral neuropathy resolution and improvement rates.

Key patient characteristics indicated that most participants were male (n = 776; 58%) and the median age was 36 years (range, 26-52). Most patients were under the age of 60 years (n = 1148; 86%), had Ann Arbor stage IV disease at diagnosis (n = 846; 64%), an International Prognostic Score of 2 or 3 (n = 712; 53%), and negative PET2 status (n = 1166; 87%).

With a data cutoff of June 1, 2021, 39 and 64 OS events had occurred in the A+AVD and ABVD arms, respectively.

Additional findings revealed a consistent OS benefit for A+AVD vs ABVD across prespecified subgroups. Moreover, the OS benefit was upheld in a multivariable analysis when simultaneously adjusting for baseline demographic and disease factors (HR, 0.53; 95% CI, 0.34-0.83). Notably, age, non-White race, ECOG performance status, and PET2 status had the greatest association with OS.

The 6-year PFS estimates were 82.3% (95% CI, 79.1%-85.0%) with A+AVD vs 74.5% (95% CI, 70.8%-77.7%) with ABVD, respectively (HR, 0.68; 95% CI, 0.53-0.86; P = .002). A total of 112 and 159 PFS events had occurred in the A+AVD and ABVD arms, respectively.

In terms of safety, no new signals were identified, and A+AVD had a comparable long-term safety profile to that of ABVD.

Fewer patients died from Hodgkin lymphoma and disease- or treatment-related complications with A+AVD (n = 39; 5.9%) vs ABVD (n = 64; 9.7%). Other reasons for death were unknown (n = 1), accident or suicide (n = 3), heart failure (n = 1), and intracranial hemorrhage (n = 1) in the A+AVD arm and unknown (n = 5), COVID-19 (n = 1), heart failure (n = 1), and lower respiratory tract infection (n = 1) in the ABVD arm.

In the A+AVD arm, 19 patients who died had prior disease progression and 18 received subsequent therapy. In the ABVD arm, 28 patients who died had prior disease progression and 25 received subsequent therapy (brentuximab vedotin, n = 13).

Notably, the use of at least 1 subsequent therapy was less common with A+AVD (n = 135; 20%) vs with ABVD (n = 157; 24%). The type of subsequent therapy in the A+AVD and ABVD arms, respectively, included brentuximab vedotin or chemotherapy regimens (n = 78, 12%; n = 108, 16%), radiation (n = 54, 8%; n = 54, 8%), chemotherapy and radiation (n = 1, <1%; n = 4, <1%), high-dose chemotherapy and transplant (n = 44, 7%; n = 59, 9%), allogeneic transplant (n = 4, <1%; n = 12, 2%), immunotherapy (n = 18, 3%; n = 24, 4%), or other (n = 0, 0%; n = 1, <1%).

Additionally, fewer second malignancies were reported in the A+AVD arm (n = 23; hematologic malignancies, n = 9; solid tumors, n = 14) vs the ABVD arm (n = 32; hematologic malignancies, n = 17; solid tumors, n = 14), mirroring earlier findings. Two patients in each arm with second malignancies underwent transplant, and 3 patients in the ABVD arm received prior radiation.

Furthermore, pregnancy and peripheral neuropathy data were consistent with prior findings. More female patients in the A+AVD vs ABVD arms, respectively, reported pregnancies (n = 49 vs n = 28) and live births (n = 56 vs n = 23).

Among partners of male patients, 33 pregnancies and 40 live births were reported in the A+AVD arm vs 33 pregnancies and 36 live births in the ABVD arm. No stillbirths were reported in either arm.

The 2-year incidence of peripheral neuropathy was 67% with A+AVD vs 43% with ABVD. However, treatment-emergent peripheral neuropathy continued to resolve or improve in both arms, with 86% and 87% of cases in the A+AVD and ABVD arms, respectively, either completely resolving or improving by last follow-up.

The median time to resolution was 16 and 10 weeks, respectively.

Patients with ongoing peripheral neuropathy at last follow-up in the A+AVD and ABVD arms, respectively, consisted of grade 1 (n = 71, 11%; n = 39, 6%), 2 (n = 38, 6%; n = 16, 2%), 3 (n = 15, 2%; n = 4, <1%), and 4 (n = 1, <1%; n = 0, 0%) events.

“A+AVD improved OS vs ABVD despite the wide availability and use of active salvage treatment, including substantial use of subsequent brentuximab vedotin in the ABVD arm. The OS benefit with A+AVD was coupled with fewer second malignancies vs ABVD,” Ansell concluded. “The observed OS benefit with A+AVD, fewer disease-related deaths, and a concomitant reduction in disease progression, suggests that A+AVD has potentially cured more patients of their disease.”

_References

1. _{Ansell SM, Connors JM, Radford JA, et al. First-line brentuximab vedotin plus chemotherapy to improve overall survival in patients with stage III/IV classical Hodgkin lymphoma: an updated analysis of ECHELON-1. J Clin Oncol. 2022;40(suppl 16):7503. doi:10.1200/JCO.2022.40.16_suppl.7503}
2. _{Straus DJ, Dlugosz-Danecka M, Connors JM, et al. Brentuximab vedotin with chemotherapy for stage III or IV classical Hodgkin lymphoma (ECHELON-1): 5-year update of an international, open-label, randomised, phase 3 trial. Lancet Hematol. 2021;8(6);e410-e421. doi:10.1016/S2352-3026(21)00102-2}