Incorporating Brentuximab Vedotin into First-Line Therapy for Advanced Hodgkin Lymphoma: The ECHELON-1 Trial

Karen M. Fancher, PharmD BCOP
Assistant Professor of Pharmacy Practice
Duquesne University School of Pharmacy
Clinical Pharmacy Specialist
University of Pittsburgh Medical Center Passavant
Pittsburgh, PA

Over the past four decades, significant progress has been made in the treatment of Hodgkin lymphoma. Five-year survival rates are unparalleled, and every newly diagnosed patient who receives appropriate treatment has an overwhelming likelihood of being cured.¹ For this reason, concerns about long-term toxicity should be considered when one is selecting therapy.

The most commonly used treatment regimen—doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD)—includes bleomycin, an antitumor antibiotic that has been associated with both acute and chronic pulmonary toxicity. Bleomycin-induced pulmonary toxicity (BPT) occurs in up to 46% of patients, with mortality as high as 27%.^2-4 Risk factors for the development of BPT may include age, renal insufficiency, receipt of radiation therapy, underlying lung disease, smoking, and the use of granulocyte colony–stimulating factor (G-CSF) support.² Minimizing or eliminating the risk of such toxicity in a potentially curable malignancy has been a topic of great interest.

Alternatively, brentuximab vedotin (BV) is an antibody-drug conjugate composed of an anti-CD30 monoclonal antibody conjugated to monomethyl auristatin E, a microtubule-disrupting agent. This agent has substantial activity as monotherapy and thus gained approval by the U.S. Food and Drug Administration (FDA) for the treatment of relapsed Hodgkin lymphoma after failure of autologous stem cell transplantation or two or more chemotherapy regimens. It is also approved for consolidation after stem cell transplantation in patients who are at risk for relapse or disease progression.⁵

A phase 1 dose-escalation study incorporated brentuximab vedotin into frontline therapy for advanced Hodgkin lymphoma with promising results.⁶ On the basis of these findings, the phase 3 ECHELON-1 trial was conducted, which compared regimens containing brentuximab vedotin and bleomycin, and the results have recently been published.⁷

The ECHELON-1 Trial
ECHELON-1 was an open-label multicenter phase 3 trial in patients with previously untreated stage 3 or 4 classic Hodgkin lymphoma. Patients were randomly assigned in a 1:1 ratio to receive brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) or ABVD on days 1 and 15 for up to six cycles. Patients were stratified according to treatment region and International Prognostic Score (IPS) risk group (low, intermediate, and high). Patients with pre-existing peripheral or motor neuropathy, known cerebral or meningeal disease, clinically relevant cardiac conditions, or diagnosis of a previous cancer were not eligible to participate in the trial.⁷

The primary end point was modified progression-free survival, defined as time to disease progression, modified disease progression, or death. Modified progression was characterized as evidence of noncomplete response after completion of first-line therapy as assessed by independent reviewers via a Deauville score of 3–5 on positron emission tomography (PET), followed by subsequent anticancer therapy. The study investigators chose to use a modified end point because metabolically detectable residual disease is a reliable predictor of imminent disease progression, and it is accepted practice to initiate subsequent anticancer treatment on the basis of the results of imaging scans at the end of first-line chemotherapy. The key secondary end point was overall survival.⁷ Patients were assessed with computed tomographic (CT) and PET scans after cycle 2 and after administration of the last dose of first-line therapy.⁷

Results
A total of 1,334 patients at 218 sites in 21 countries underwent randomization, and baseline characteristics were well balanced between the treatment groups. At a median follow-up of 24.6 months (range 0–49.3 months), the rate of modified progression-free survival as assessed by independent reviewers was 82.1% (95% confidence interval [CI], 78.8–85) in patients who received A+AVD compared to 77.2% (95% CI, 73.7–80.4) in patients who received ABVD. This corresponded to a 23% risk reduction in progression, modified progression, or death (hazard ratio [HR] .77, 95% CI, .6–.98, p = .04). Investigator assessment revealed similar findings, with a 91% concordance between independent review and investigator assessment of the primary end point. Complete response and overall response rates were similar between the two groups (73% vs. 70% and 86% vs. 83%, respectively).⁷

The benefits of A+AVD were noted in the majority of subgroups, with some subgroups showing greater benefit than others: men, patients from North America, those with stage 4 disease, and those under 65 years of age all had an HR less than 1 for modified progression-free survival.

The interim 2-year overall survival rate was 96.6% (95% CI, 94.8–97.7) in patients who received A+AVD compared to 94.2% (95% CI, 92–95.9) in patients who received ABVD. This end point was not statistically significant at the time of study publication, but investigators noted that the final overall survival analysis will be conducted after 112 deaths have occurred.⁷

Adverse Effects
Grade 3 or higher adverse events and serious adverse events were more common in the A+AVD group than in those who received ABVD (83% vs. 66% and 43% vs. 27%, respectively). Neutropenia was experienced by 58% of patients who received A+AVD and by 45% of patients who received ABVD. Febrile neutropenia was reported in 19% and 8% of patients, respectively. After 75% of study enrollment was complete, the independent data and safety monitoring committee recommended the initiation of primary prophylaxis with G-CSF for patients who were yet to be enrolled and would receive A+AVD.⁷

Peripheral neuropathy occurred in 67% of patients who received A+AVD and in 43% of patients who received ABVD, resulting in the discontinuation of a study drug in 10% of patients in the A+AVD group compared to 4% in the ABVD group. Among patients in the A+AVD group who developed peripheral neuropathy, two-thirds had resolution or improvement by at least one grade at the time of the last follow-up visit.⁷

Pulmonary toxicity was reported in 2% of patients who received A+AVD and in 7% of patients who received ABVD. No deaths related to pulmonary toxicity occurred in the A+AVD group; 11 patient deaths were due to or related to pulmonary toxicity in the ABVD group.⁷

Summary and Implications
The phase 3 ECHELON-1 trial demonstrated that treatment with brentuximab vedotin in combination with AVD resulted in a statistically significant improvement in modified progression-free survival as compared to treatment with ABVD. The benefit of A+AVD was observed in the majority of patient subgroups, and the results of the interim overall survival analysis favored A+AVD as well. The surprisingly high incidence of febrile neutropenia with brentuximab vedotin resulted in a protocol modification to administer primary prophylaxis with G-CSF in patients who received A+AVD. Peripheral neuropathy was reported more frequently in the A+AVD group but was reversible in the majority of patients. Pulmonary toxicity was reported less frequently with A+AVD than with ABVD.⁷ On the basis of these results, the incorporation of brentuximab vedotin into first-line therapy should be considered in patients with stage 3 or 4 Hodgkin lymphoma.⁸

However, other recently published studies suggest that a response-adapted approach may allow for bleomycin to be omitted from the ABVD regimen after negative findings on interim PET scans without compromising efficacy. Such findings may minimize the concerns about BPT.^9,10 Further, brentuximab vedotin has traditionally been used in the salvage setting; its subsequent use after incorporation into the first-line setting remains undefined. Finally, the use of a first-line monoclonal antibody conjugate will undoubtedly increase cost of treatment.

The ECHELON-1 trial represents an important and exciting possibility in the treatment of advanced Hodgkin lymphoma. Updates to treatment guidelines, revised position statements, and future trials are all eagerly awaited to further determine its ultimate place in therapy.

References

1. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Hodgkin Lymphoma v1.2018. Available at www.nccn.org. Accessed February 10, 2018.
2. Martin WG, Ristow KM, Habermann TM, et al. Bleomycin pulmonary toxicity has a negative impact on the outcome of patients with Hodgkin’s lymphoma. J Clin Oncol. 2005;23:7614-7620.
3. Sleijfer S. Bleomycin-induced pneumonitis. Chest. 2001;120:617-624.
4. Lewis BM, Izbicki R. Routine pulmonary function tests during bleomycin therapy: tests may be ineffective and potentially misleading. JAMA. 1980;243:347-351.
5. Adcetris [package insert]. Bothell, WA: Seattle Genetics, Inc., 2017.
6. Younes A, Connors JM, Park SI, et al. Brentuximab vedotin combined with ABVD or AVD for patients with newly diagnosed Hodgkin’s lymphoma: a phase 1, open-label, dose-escalation study. Lancet Oncol. 2013;14:1348-1356.
7. Connors JM, Jurczak W, Straus DJ, et al. Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin’s lymphoma. N Engl J Med. 2018;378:331-344.
8. Johnson P, Federico M, Kirkwood A, et al. Adapted treatment guided by interim PET-CT scan in advanced Hodgkin’s lymphoma. N Engl J Med. 2016;374:2419-2429.
9. Longo DL, DeVita VT. Progress in the treatment of Hodgkin’s lymphoma. N Engl J Med. 2018;378:392-394.
10. Behringer K, Goergen H, Hitz F, et al. Omission of dacarbazine or bleomycin, or both, from the ABVD regimen in treatment of early-stage favourable Hodgkin’s lymphoma (GHSG HD13): an open-label, randomised, non-inferiority trial. Lancet. 2015;385;1418-1427.