The addition of nivolumab, an immune checkpoint inhibitor, to chemotherapy significantly improved progression-free survival in adults and children with advanced classical Hodgkin lymphoma with reduced toxicity compared with standard-of-care brentuximab vedotin plus chemotherapy, according to the results of the phase III SWOG S1826 trial presented at the 2023 ASCO Annual Meeting.¹ The addition of nivolumab to the regimen of doxorubicin, vinblastine, and dacarbazine (AVD) was associated with about a 52% reduction in the risk of disease progression or death compared with brentuximab vedotin plus AVD in patients from ages 12 to 83.

“SWOG S1826, the largest Hodgkin lymphoma study in National Clinical Trials Network history, is a key step toward harmonizing the pediatric and adult treatment of advanced-stage Hodgkin lymphoma.”

— Alex Francisco Herrera, MD

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“SWOG S1826, the largest Hodgkin lymphoma study in National Clinical Trials Network history, is a key step toward harmonizing the pediatric and adult treatment of advanced-stage Hodgkin lymphoma. Based on the magnitude of benefit and with nivolumab being better tolerated than brentuximab vedotin, we anticipate these results will be practice-changing, and nivolumab [plus chemotherapy] is poised to become a new standard of care [in this patient population],” said lead author Alex Francisco Herrera, MD, Chief of the Division of Lymphoma at City of Hope Medical Center.

“We are thrilled that the strength of the data at this interim analysis allowed early unblinding, getting results (and access to this regimen) to patients sooner,” stated ASCO Chief Medical Officer and Executive Vice President, Julie R. Gralow, MD, FACP, FASCO, at a premeeting press conference where these results were reported.

Background

Hodgkin lymphoma affects about 8,000 people per year in the United States, most commonly younger people, with about 900 deaths annually. The current 5-year survival rate for those with advanced disease is 83%. Positron-emission tomography (PET)-adapted chemotherapy is the standard of care for advanced-stage Hodgkin lymphoma. In younger people, the late toxic effects of treatment, including radiotherapy, are especially problematic.

The incorporation of the antibody-drug conjugate brentuximab vedotin plus AVD as first-line treatment for advanced-stage Hodgkin lymphoma improved outcomes. However, relapses occur in 20% to 25%, and brentuximab vedotin adds toxicity to the regimen.

“Currently, approaches for adults and children differ, and most pediatric patients still receive radiation therapy. Studies of PD-1 blockade in classical Hodgkin lymphoma have been promising to date, and genetic changes present in Hodgkin lymphoma tumor cells make it a perfect target for PD-1 blockade incorporated into front-line treatment,” explained Dr. Herrera.

Study Details

“For the first time ever, adult and pediatric groups cooperated in conducting the SWOG S1826 trial to compare the two regimens in both populations with advanced Hodgkin lymphoma,” he said.

Between July 2019 and October 2022, 976 patients were randomly assigned to receive treatment with six cycles of either nivolumab or brentuximab vedotin plus AVD. The median patient age was 27; 24% were younger than 18, and 10% were older than 60. A total of 56% were male, about 11.5% were Black, 13% were Hispanic, and 76% were non-Hispanic White. Sixty-four percent had stage IV disease. Radiation was given at the end of treatment if indicated. Granulocyte colony-stimulating factor support was optional for the nivolumab arm and mandated for the brentuximab vedotin arm.

“This was a representative trial, inclusive of a diverse population of patients in terms of demographics as well as patients with higher-risk Hodgkin lymphoma. S1826 is an example of the broad inclusion that is possible through cooperative group trials,” Dr. Herrera noted.

Key Results

At the second planned interim analysis, at a median follow-up of 12.1 months, the study met its primary endpoint. The rate of 1-year progression-free survival was 94% with AVD plus nivolumab and 86% with AVD plus brentuximab vedotin, significantly favoring the checkpoint inhibitor (P < .0005). This represents a 52% reduction in the risk for disease progression or death with nivolumab plus AVD.

The benefit of the immune checkpoint inhibitor was consistent across all subgroups, including all ages and risk groups, and was most marked in stage IV disease.

Less than 1% of patients given nivolumab required end-of-treatment radiation therapy. “Traditionally, adults and children with advanced Hodgkin lymphoma in the United States have been treated with different chemotherapy regimens, and most children also receive radiation treatment, whereas the use of radiation has been uncommon in adults. That is a dramatic reduction in the proportion of the very youngest patients receiving radiotherapy,” stated Dr. Herrera.

Although overall survival was immature, the numbers trended in favor of the nivolumab combination therapy at this early point. A total of 11 deaths were reported in the group given brentuximab vedotin combination therapy, 7 were associated with treatment-related adverse events. As for the group given nivolumab combination therapy, there were four deaths, with three associated with treatment-related adverse events.

Toxicity

The rate of grade 3 or higher adverse events was higher with nivolumab than with brentuximab vedotin: 48.4% vs 30.5%. Grade 3 or higher neutropenia was reported in 45.1% and 23.9%, respectively. Bone pain was reported in 8% vs 20%, respectively. The rate of neutropenia of any grade was similar for both nivolumab and brentuximab vedotin (5.6% vs 6.4%), as were the rates of pneumonitis (2% vs 3.2%), elevated alanine aminotransferase (30.7% vs 30.9%), and colitis (1% vs 1.3%). The rates of adverse events that were higher with nivolumab included hypo- and hyperthyroidism.

Peripheral neuropathy of any grade was more common with brentuximab vedotin: sensory, 54.2% with brentuximab vedotin vs 28.1% with nivolumab; motor, 6.8% with brentuximab vedotin vs 4% with nivolumab.

Neuropathy is an adverse event of particular concern in younger patients. “I can’t emphasize how important neuropathy is as a side effect in young patients who have the rest of their lives ahead of them. It’s fantastic to be cured of cancer, but it is tough not to be able to feel your fingers and toes,” stated Dr. Herrera.

There were twice as many treatment discontinuations with brentuximab vedotin plus AVD than with nivolumab plus AVD (22% vs 11%). Immune-related toxicity was infrequent with the nivolumab combination therapy.

Longer follow-up is needed to determine overall survival, as well as patient-related outcomes including quality of life.

Additional Commentary

According to ASCO expert Oreofe Odejide, MD, MPH, of Dana-Farber Cancer Institute and Harvard Medical School, the results of the SWOG S1826 trial are “unprecedented.”

Dr. Odejide continued: “Although most patients with advanced-stage Hodgkin lymphoma will be cured with initial therapy, about 20% of patients still have relapsed or refractory disease. Therefore, the findings of this study represent a huge step forward in the management of advanced-stage Hodgkin lymphoma in children and adults, leading to an improved and well-tolerated standard of care.”

“These results have strong potential to change the standard of care for previously untreated patients with advanced-stage Hodgkin lymphoma.”

— Oreofe Odejide, MD, MPH

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“Brentuximab vedotin plus AVD set a high bar for the treatment of advanced-stage Hodgkin lymphoma, as it was the first regimen to show a meaningful improvement in disease-related death compared with ABVD [AVD plus bleomycin] chemotherapy in several years,” Dr. Odejide noted. “The fact that SWOG S1826 now shows a significant benefit with nivolumab plus AVD over brentuximab vedotin plus AVD—and included both pediatric and adult patients, unlike prior studies—is highly compelling. These results have strong potential to change the standard of care for previously untreated patients with advanced-stage Hodgkin lymphoma.” 

DISCLOSURE: The study was funded by the National Cancer Institute and Bristol Myers Squibb. Dr. Herrera reported financial relationships with AbbVie, ADC Therapeutics, Adicet Bio, AstraZeneca, MedImmune, Bristol Myers Squibb, Caribou Biosciences, Genentech/Roche, Genmab, Karyopharm Therapeutics, Merck, Pfizer, Regeneron, Seagen, Takeda, and Gmbh. Dr. Gralow and Dr. Odejide reported no conflicts of interest.

REFERENCE

1. Herrera AF, LeBlanc ML, Castellino SM, et al: SWOG S1826, a randomized study of nivolumab-AVD versus brentuximab vedotin-AVD in advanced stage classic Hodgkin lymphoma. 2023 ASCO Annual Meeting. Abstract LBA4. Presented June 4, 2023.