Chemoimmunotherapy in Advanced-Stage Hodgkin Lymphoma: Can We Define a Unified Regimen for All Ages?

A Phase III, Randomized Study of Nivolumab Plus AVD or Brentuximab Vedotin Plus AVD in Patients (Age ≥ 12 years) with Newly Diagnosed Advanced Stage Classical Hodgkin Lymphoma [S1826]

NCT03907488

Southwest Oncology Group (SWOG) in collaboration with the National Cancer Institute National Clinical Trials Network

987 patients over four years

All SWOG sites (lead organization) and National Clinical Trials Network (NCTN) organizations: Alliance for Clinical Trials in Oncology, Children’s Oncology Group (COG), Eastern Cooperative Oncology Group–American College of Radiology Imaging Network (ECOG-ACRIN) Cancer Research Group, Canadian Cancer Trials Group, and NRG Oncology. The study is open at both academic centers, as well as larger community oncology practices in the United States.

S1826 is a randomized, phase III clinical trial designed to examine the efficacy of combining nivolumab or brentuximab vedotin (BV) with a chemotherapy backbone of doxorubicin, vinblastine, and dacarbazine (AVD) as the initial treatment for older children and adult patients (age ≥ 12 years) with newly diagnosed stage III or stage IV classical Hodgkin lymphoma (HL). The primary endpoint of this trial is two-year progression-free survival (PFS). Secondary and correlative endpoints include estimating response rates, event-free survival, overall survival, and measuring quality of life measures, specifically, patient-reported fatigue, neuropathy, health-related quality of life and patient-reported symptoms. Also, this trial will collect biospecimens and bank positron emission tomography (PET) –computed tomography images for future imaging and translational medicine proposals.

Advanced-stage, classical HL is curable for the majority of children and adults with contemporary combination chemotherapy regimens. In parts of Europe, escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) is standard, whereas ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) -based regimens remain standard in most of the rest of the world. With ABVD-based regimens, approximately 25 percent of patients have refractory disease or relapse after completing frontline chemotherapy.^1-4  Historically, high-dose salvage therapy with autologous hematopoietic stem cell rescue is successful in approximately 50 percent of patients who progress after induction treatment; however, these therapies incur significant toxicity, including treatment-related mortality, which can occur in more than 10 percent of patients.^5,6  Thus, clinical trials for advanced-stage HL during the past decade have focused on the following strategies: 1) using a response-adapted chemotherapy regimen guided by interim PET imaging, in which the treatment regimen is escalated in intensity for an unfavorable response, or the treatment intensity is reduced or maintained for an early favorable response to minimize toxicity^7-9 ; or 2) optimizing the frontline chemotherapy regimen with novel agents.^10,11 

Although early results of the PET-adapted approach were promising, long-term follow-up of the S0816 trial demonstrated that approximately 25 percent of patients with no evidence of disease based on interim PET scan who had completed the planned six cycles of ABVD therapy had relapsed after five years.¹² 

The incorporation of novel agents into the standard chemotherapy regimens may be a more promising approach to improve the outcomes for advanced-stage HL. The ECHELON-1 trial was an international phase III randomized trial for patients with a new diagnosis of advanced-stage classical HL in which ABVD was compared with a regimen of AVD and BV — a CD30 antibody drug conjugate that targets the CD30 antigen on Reed-Sternberg cells.¹⁰  The two-year modified PFS (with events defined as death, disease progression, or lack of complete response at the end of therapy followed by administration of a subsequent antilymphoma therapy) was 82 percent for the BV-AVD regimen and 77 percent in the ABVD group. The acute toxicities of neutropenia and neuropathy were higher in the BV-AVD arm, but the overall toxicity profile favored the BV-AVD regimen.

The programmed death-1 (PD-1) pathway is badly disordered in HL through genetic alterations at chromosome 9p24.1, and it is an essential component of the pathogenesis of the disease. Nivolumab, a monoclonal antibody that targets the PD-1 receptor, has significant single-agent activity in relapsed HL¹³  and seems safe and effective as combination therapy in the frontline setting.¹¹ 

To this end, S1826 is comparing PD-1 blockade with AVD to BV-ABD with a goal to further improve safety and efficacy of therapy.

This trial is a unique collaboration between three U.S. National Clinical Trials Network components (SWOG, ECOG-ACRIN, and Alliance for Clinical Trials in Oncology), the National Cancer Institute Canada, and COG, making it the largest U.S. intergroup effort in HL ever conducted. Currently, the preferred treatment for advanced-stage HL differs with age, favoring chemotherapy with ABVD backbone with infrequent use of radiation therapy for adults, while in pediatric patients, COG has used a modified ABVD chemotherapy regimen of doxorubicin, bleomycin, and vincristine, plus etoposide, prednisone, and cyclophosphamide (ABVE-PC), with risk-adapted response–based use of radiotherapy (approximately 76% of pediatric patients receive radiation treatment). On S1826, for the first time, adults and children will be treated with a uniform chemotherapy backbone regimen of AVD, with the addition of a monoclonal antibody and elimination of bleomycin. Radiation therapy may be used at the discretion of investigators under certain protocol-defined circumstances. Importantly, although HL is characteristically a disease of young patients (median age, 29 years), approximately 20 percent of patients with HL are older than 60 years.¹⁴  In older adults, response rates are lower, and toxicity is increased with ABVD, particularly the pulmonary toxicity associated with bleomycin. This trial provides an opportunity to also improve the outcomes of older adults with HL and to explore the quality of life metrics in treating this vulnerable patient population. The randomized incorporation of novel agents into frontline therapy is for advanced HL is enthusiastically anticipated.