ECHELON-1: Evaluating Brentuximab Vedotin in Hodgkin's... : Oncology Times (2024)

The therapeutic combination of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) has been the standard of care for the treatment of advanced stage Hodgkin's lymphoma for roughly 30 years. Despite the success with this regimen, a significant number of patients treated for Stage III or IV Hodgkin's lymphoma undergo a relapse with disease that is ultimately resistant to that therapy. Despite there being several attempts to find an effective replacement for this regimen, there has not been a regimen which has shown clear superiority to ABVD. As a result, there is still a significant, unmet need for a therapy for patients with Hodgkin's lymphoma that is resistant to treatment with ABVD.

In the Phase III ECHELON-1 clinical trial (NCT01712490), the standard ABVD regimen was used as an active comparator for the evaluation of the brentuximab vedotin plus doxorubicin, vinblastine and dacarbazine (A+AVD) combination in patients with previously untreated Stage III or IV Hodgkin's lymphoma.

The lead investigator for this trial was Stephen Ansell, MD, PhD, Chair of the Division of Hematology at the Mayo Clinic. “In this analysis for ECHELON-1, we were able to show a continued advantage for the A+AVD regimen, even at a median follow-up time of more than 6 years,” Ansell stated. The results from this analysis of the 6-year data were published in New England Journal of Medicine (2022; doi: 10.1056/NEJMoa2206125).

Brentuximab Vedotin

Brentuximab vedotin is an antibody-drug conjugate which combines a CD30-targeting monoclonal antibody that is coupled to an antineoplastic drug (a monomethyl auristatin E analog) via a cleavable linker. In principle, the conjugate is directed to malignant cells (such as Hodgkin's lymphoma cells) which have an overexpression of CD30 on the surface. Once directed to the cell by the antibody, the conjugate is internalized within the malignant cell, where the cytotoxic warhead is released by endogenous protease activity.

Since both Hodgkin's lymphoma and anaplastic large cell lymphoma cells overexpress CD30 on their surfaces, these malignancies were suitable for using brentuximab vedotin. Indeed, the initial FDA approval for brentuximab vedotin in August 2011 was for these two diseases. Notably, the approval for brentuximab vedotin was the first by the FDA for Hodgkin's lymphoma since 1977, and the first ever specifically for anaplastic large cell lymphoma. In 2017, the FDA approved the use of brentuximab vedotin for CD30-expressing mycosis fungoides and primary cutaneous anaplastic large cell lymphoma. Most recently, in March 2018, the FDA approved the A+AVD regimen for previously untreated Stage III or IV Hodgkin's lymphoma.

ECHELON-1

In ECHELON-1, there were a total of 1,334 patients enrolled: 664 in the A+AVD arm and 670 in the ABVD arm (N Engl J Med 2018;378:331-44). Patients in both arms had similar demographics and disease characteristics at baseline. In addition, almost 15 percent of the patients included in this trial were aged 60 years or older. Previously, a 5-year analysis of the data for ECHELON-1 showed that progression-free survival favored the A+AVD regimen over ABVD, with a hazard ratio of 0.68 for disease progression or death (Lancet Haematol 2021;8: e410-21).

In this analysis, the median follow-up was 73.0 months, with a range of 0.0 to 100.6 months. “In terms of the deaths that occurred in this study, there were a total of 103, 39 in the A+AVD and 64 in the ABVD arms respectively,” Ansell noted. “Overall survival analyses clearly favored the A+AVD regimen relative to the ABVD one, with a hazard ratio of 0.59,” he added. In addition, estimates for 6-year survival rates also favored the A+AVD regimen, with a value of 93.9 percent for those patients compared to 89.4 percent for the patients receiving ABVD.

“Subgroup analyses showed that the greatest advantages for the A+AVD regimen were in North American patients, and those with Stage IV disease, those younger than 60 years, and those who had high-risk IPS (International Prognostic Score) disease,” Ansell added.

Conversely, lower treatment effects for A+AVD relative to ABVD were noted for women, those over 60 years or with low-risk IPS disease.

“When adjusting for baseline demographics and disease characteristics, the overall survival analyses revealed a hazard ratio of 0.53 for death for the A+AVD patients relative to those in the ABVD arm,” Ansell noted. “Among the factors that we identified in our analysis as having the greatest association with survival were age, race (non-White), ECOG (Eastern Cooperative Oncology Group) performance score, and PET2 (Cycle 2 positron emission tomography) status.”

When stratified by PET2 status, both the 6-year survival and hazard ratio for death for the A+AVD group was favorable relative to the values for the ABVD group for patients with PET2-negative status (94.9% vs. 90.6% and 0.54); this trend was even more pronounced for those with PET2-positive status (95% vs. 77% and 0.16).

Discussion

When asked about the significant findings from their analysis, Ansell replied, “In these patients with treatment-naïve Stage III or IV Hodgkin's lymphoma, the risk of death for patients on the A+AVD arm was more than 40 percent less than that observed for those receiving ABVD therapy; as a result, the difference in mortality between the two study arms was 4.5 percent at 6 years.”

Some success has been noted for overall survival in trials using other regimens in the advanced Hodgkin's lymphoma patient population. “In one trial,” Ansell noted, “a post-study analysis showed that escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) had a survival benefit relative to a regimen of alternating ABVD and COPP (cyclophosphamide, vincristine, procarbazine, and prednisone) at 10 years.

“Despite this success with the escalated BEACOPP regimen, it has not been widely utilized because of significant issues with that therapy,” Ansell stated. “There are significant short- and long-term sequelae for this regimen, including the risk of a second malignancy or fertility issues; additionally, since the therapy is a bit more vigorous, it may not be appropriate for older patients or those with underlying comorbidities.”

Regarding the survival advantages observed in this analysis, Ansell stated, “The advantages seen for the A+AVD regimen were despite the widespread use of salvage therapies. Part of the difficulty with showing a survival benefit to the ABVD regimen in the first-line setting is the use of salvage therapy in those patients that experience relapse or refractory disease.”

When asked about those salvage therapies, Ansell replied, “Some salvage strategies have included various chemotherapy combinations, stem cell transplantation, checkpoint inhibitor therapy, such as nivolumab, or more recently, brentuximab vedotin in combination with bendamustine or nivolumab.”

“The number of patients in the ABVD arm receiving subsequent therapy and the similarity of the outcomes when compared with other clinical trials involving the ABVD regimen would seem to suggest that the survival benefit observed for the A+AVD regimen in this study was not a result of substandard disease treatment or less-effective salvage therapies for patients in the ABVD arm,” Ansell said.

In other studies with brentuximab vedotin, additional mechanisms of action have been noted, including antibody-dependent cellular phagocytosis, elimination of regulatory T cells (which express CD30), induced immune cell death, and release of the cytotoxic agent monomethyl auristatin E from brentuximab vedotin in the tumor microenvironment. It is thought that some of these causes may be contributing to the survival advantage and reduced risk for disease-related death observed for the A+AVD regimen in this study.

“Another important consideration for Hodgkin's lymphoma therapies is the risk for developing a secondary malignancy as a result of the initial therapy,” Ansell observed. “This is especially crucial when one considers the general treatability of Hodgkin's lymphoma and the risk that the secondary disease carries to these patients. One study showed that roughly 4 percent of patients that were treated with ABVD developed a secondary cancer, while for the more vigorous BEACOPP regimen, the figure was roughly 6.5 percent.

“In this study there were 23 patients with cancer in the A+AVD arm (3.5%), while there were 32 patients (4.9%), including a greater number of hematologic malignancies, in the ABVD arm. An important observation was that more than 40 percent of the secondary cancers observed occurred in patients over 60 years of age, despite the fact that this age group accounted for only 14 percent of the patients in this trial,” Ansell said.

“The use of salvage therapies was also more frequent in the ABVD arm, however, the use of radiation for salvage was similar between both groups,” he added. In the patients who developed a secondary cancer, three in the ABVD group and none in the A+AVD group had previously undergone radiation therapy, while two in each group had undergone stem cell transplant.

Regarding their analysis, Ansell stated, “We are very excited by these findings, as it has been some time since a therapy has shown an advantage in overall survival compared to the standard ABVD regimen.” “In addition,” Ansell observed, “there were fewer secondary cancers in the A+AVD arm; there were also fewer long-term toxicities, including pregnancy effects than associated with the escalated BEACOPP protocol.”

Richard Simoneaux is a contributing writer.

Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.
ECHELON-1: Evaluating Brentuximab Vedotin in Hodgkin's... : Oncology Times (2024)
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