The results of ECHELON-1 were presented by David J. Straus, MD, of Memorial Sloan Kettering Cancer Center, New York, at the 2022 National Comprehensive Cancer Network (NCCN) Annual Congress: Hematologic Malignancies. Dr. Straus said: “It is a great honor and privilege to present updated results that are quite remarkable in untreated advanced-stage lymphoma.” Data from the study established the regimen of brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (AVD) as an acceptable first-line therapy in patients with stage III or IV classical Hodgkin lymphoma. These results suggest that brentuximab vedotin plus AVD should be considered a first-line treatment option for patients with previously untreated stage III or IV classical Hodgkin lymphoma.”
David J. Straus, MD
Study Details and Background
The large global ECHELON-1 trial compared six cycles of brentuximab vedotin plus AVD vs six cycles of ABVD in more than 13,000 patients with stage III or IV classical Hodgkin lymphoma. Patients were randomly assigned in a 1:1 ratio. “This is one of the largest trials comparing a new therapy to ABVD, the standard of care,” Dr. Straus told listeners.
As background, he reminded the audience that three new drugs have changed the landscape for Hodgkin lymphoma: brentuximab vedotin (an antibody-drug conjugate), and two different checkpoint inhibitors—nivolumab and pembrolizumab. Of the three drugs, brentuximab vedotin is associated with similar overall response rates and complete response rates. “These three agents [in the relapsed/refractory setting] have activity roughly twice that of conventional chemotherapy and were speedily approved,” Dr. Straus noted.
Brentuximab vedotin is directed against CD30 and linked to a tubulin inhibitor. The drug attaches to CD30 on Hodgkin cells and delivers the chemotherapy payload to the cell nucleus, where it binds to tubulin, leading to cell-cycle arrest and apoptosis.
Key Findings
At 2 years, the difference in modified progression-free survival favored the experimental arm. With further 5-year follow-up, the difference in this primary endpoint was sustained and even slightly greater at 5 years than at 2 years—an absolute difference of around 7%.2
Brentuximab vedotin plus AVD resulted in a 6-year estimated progression-free survival of 82.3% for the experimental arm vs 74.5% with the standard of care.2 The number of deaths was 39 with brentuximab vedotin plus AVD vs 64 with ABVD, with most deaths being the result of Hodgkin lymphoma or its treatment, including 11 deaths from lung toxicity in bleomycin-containing arms.3
Second Malignancies and Peripheral Neuropathy
More second malignancies were found with ABVD compared with brentuximab vedotin plus AVD: 32 vs 23, respectively. Deaths due to second malignancies occurred in 11 patients vs 1 patient, respectively. Thus, most second malignancies were not fatal. More second hematologic cancers were seen in the ABVD arm (17 vs 10). Subsequent solid tumors were seen in 14 patients in both arms.
Peripheral neuropathy is a major side effect of these regimens. At 2 years, the majority of patients had peripheral neuropathy of some grade: 67% of those given brentuximab vedotin plus AVD vs 43% of those given ABVD.4 With further follow-up, peripheral neuropathy improved or resolved in about 86% of both treatment arms. The median time to resolution of peripheral neuropathy was 16 weeks with brentuximab vedotin plus AVD vs 10 weeks with ABVD.
Interim PET
The investigators found that the interim PET scan performed during the study did not change treatment.
“Although interim PET was performed in the study, and progression-free survival was inferior for PET-positive patients, only about one-third [of these patients] relapsed. This is the same result as a PET-guided risk-adapted trial, where you can change to a more intensive regimen for PET-positive patients. For that reason, we have given up interim PET when we use brentuximab vedotin plus AVD. This simplifies treatment and reduces anxiety for patients,” Dr. Straus explained. “It also avoids the complexity of variable institutions doing PET in the real world,” he added.
Cost and Patient Selection
Andrew D. Zelenetz, MD, PhD
During the discussion following the presentation, session moderator Andrew D. Zelenetz, MD, PhD, of Memorial Sloan Kettering Cancer Center, New York, brought up the high cost associated with brentuximab vedotin plus AVD.
Dr. Straus agreed that cost is a real problem but noted that if more lives are saved, that strengthens the case for front-line treatment with brentuximab vedotin plus AVD. “A real-world analysis of costs would help determine if the survival advantage seen in the clinical trial translates to a real-world benefit.”
DISCLOSURE: Dr. Straus reported financial relationships with Elsevier, Seagen, and Takeda. Dr. Zelenetz reported financial relationships with AbbVie, ADC Therapeutics, Biotechnologies Corp, Arvinas, AstraZeneca, BeiGene, Bristol Myers Squibb, Curio Science, Dava Oncology, Genentech, Instituto de Ciencias Integradas, Kyowa Kirin, MEI Pharma, Medscape, Oncopeptides AB, Sandoz, Secura Bio, and Suzhou Liangyihui Network Technology.
REFERENCES
1. Straus D: ECHELON-1: Do updated results change the first-line treatment of stage III-IV classical Hodgkin lymphoma? 2022 NCCN Annual Congress: Hematologic Malignancies. Presented October 15, 2022.
2. Straus D, Dlugosz-Danecja M, Connors JM, et al: Brentuximab vedotin with chemotherapy for stage III or IV classical Hodgkin lymphoma: 5-year update of an international, open-label, randomized, phase 3 trial. Lancet Haematol 8:410-421, 2021.
3. Ansell SM, Radford J, Connors JM, et al: Overall survival with brentuximab vedotin in stage III or IV Hodgkin’s lymphoma. N Engl J Med 387:310-320, 2022.
4. Connors JM, Jurczak W, Straus DJ, et al: Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin’s lymphoma. N Engl J Med 378:331-344, 2018.
