Key Points:

• Nivolumab plus AVD significantly prolonged progression-free survival and was better tolerated when compared with brentuximab vedotin plus AVD in patients with advanced-stage Hodgkin lymphoma ≥ 12 years of age.
• Overall, < 1% of patients in the trial received end-of-treatment radiation therapy.
• Nivolumab plus AVD is poised to become a new standard of care for the treatment of classic Hodgkin lymphoma and marks a key step toward harmonizing the management of pediatric and adult patients.

Although longer-term data are needed, progression-free survival (PFS) outcomes of the randomized phase 3 SWOG-S1826 trial provide support for the use of nivolumab plus AVD (doxorubicin, vinblastine, and dacarbazine) chemotherapy for both adult and pediatric patients with newly diagnosed stage III through IV classic Hodgkin lymphoma (LBA4).

Results from the second planned interim analysis, based on 50% of the total expected PFS events among 976 evaluable patients, revealed a 52% reduction in the risk of disease progression or death with the use of nivolumab plus AVD versus brentuximab vedotin (BV) plus AVD (HR 0.48, 99% CI [0.27, 0.87]; P = .0005). With a median follow-up of 12.1 months, 1-year PFS rates were 94% with nivolumab/AVD versus 86% with BV/AVD (Figure 1).

Figure 1. N/AVD Improves PFS Compared to BV/AVD

The efficacy signal with nivolumab/AVD far exceeded the conservative protocol-specified statistical boundary, prompting the independent data monitoring committee to recommend early unblinding of the results, which were presented by Alex F. Herrera, MD, of City of Hope, at the Plenary Session of the 2023 ASCO Annual Meeting.

“Follow-up is ongoing to confirm the durability of PFS, assess overall survival, and assess patient-reported outcomes. But based on these results, nivolumab/AVD is poised to be a new standard therapy for the treatment of advanced-stage classic Hodgkin lymphoma across the age spectrum. This is a key step toward harmonizing pediatric and adult therapy of classic Hodgkin lymphoma,” Dr. Herrera stated.

“This is a practice-changing study given the favorable efficacy and toxicity associated with nivolumab/AVD. This study included children, adolescents, adults, and elderly patients, all of whom benefited from nivolumab/AVD,” remarked Discussant Ann S. LaCasce, MD, MMSc, of the Dana-Farber Cancer Institute. “Adolescent and young adult [AYA] patients are treated in both the pediatric and adult settings. Having the same treatment recommendations by both sets of providers is important,” she added.

“This is a practice-changing study given the favorable efficacy and toxicity associated with nivolumab/AVD.” – Dr. Ann S. LaCasce

SWOG-S1826 Rationale

BV, an antibody-drug conjugate targeting CD30 on the surface of Hodgkin Reed–Sternberg cells, has recently emerged as an integral component of frontline therapy in the United States for both adults and pediatric patients with advanced-stage Hodgkin lymphoma based on documented improvements in survival outcomes. However, apart from that, other treatment components differ between adults and children, most notably with regard to the chemotherapy backbone used with BV and the use of radiation. For adults, combined treatment with BV and AVD is the preferred first-line regimen based on the ECHELON-1 trial.1 For children, the preferred first-line regimen is BV combined with AVE-PC (doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide) based on the Children’s Oncology Group AHOD-1331 trial.2 The majority of pediatric patients with advanced-stage Hodgkin lymphoma also receive radiation therapy to target residual disease, whereas most adult patients do not.

“As part of the design and planning of [SWOG]-S1826, the adult and pediatric cooperative groups met and arrived at consensus on both the control and experimental regimens with the goal of harmonizing the treatment of Hodgkin lymphoma across the age spectrum,” Dr. Herrera explained.

For the experimental arm, the SWOG-S1826 investigators opted for nivolumab as a potentially better-tolerated and more efficacious replacement for BV.

As Dr. Herrera explained, despite its benefits, “incorporation of BV [with chemotherapy] adds toxicity, it requires G-CSF support, and there's still room to improve outcomes since a significant proportion of patients still have relapse. We sought to incorporate PD-1 blockade into the frontline treatment of Hodgkin lymphoma. PD-1 blockade has been shown to be effective for the treatment of relapsed/refractory Hodgkin lymphoma, and there have been several studies that have shown that incorporating PD-1 blockade into the frontline treatment of Hodgkin lymphoma has been well tolerated and yielded promising results.”

More than 1,000 centers across the National Clinical Trials Network participated in SWOG-S1826, making it the largest study of advanced-stage Hodgkin lymphoma in the history of the North American cooperative groups and the first prospective AYA collaboration across the adult and pediatric groups.

“The collaboration between the North American adult cooperative groups and the Children's Oncology Group was outstanding, and the fact that the study accrued ahead of schedule is unheard of in adult studies in Hodgkin lymphoma. In addition, the diversity of patients, including Black and Hispanic patients, was favorable compared to prior adult clinical trials in this disease,” Dr. LaCasce remarked.

Notably, of the 976 individuals included in the trial, Black patients comprised 12% and Hispanic patients comprised 13%.

Additional SWOG-S1826 Results

SWOG-S1826 was open to patients aged 12 years and older, with no upper age limit. Prior to random assignment to 6 cycles of nivolumab or BV, each in combination with AVD, patients were stratified by age (12-17 vs 18-60 vs > 60 years), international prognostic score (0-3 vs 4-7), and intended use of radiation therapy for residual disease (yes vs no).

The PFS benefit observed with nivolumab/AVD over BV/AVD in the overall population appeared to be consistent in all patient subgroups analyzed, including those broken down by age, international prognostic score, disease stage, and presence or absence of B symptoms.

Event-free survival outcomes also favored the nivolumab arm, with 1-year event-free survival rates of 91% among patients who received nivolumab/AVD versus 84% among patients who received BV/AVD.

Dr. Herrera revealed that only 6 patients out of the 976 individuals who participated in the trial went on to receive radiotherapy for residual disease—2 in the nivolumab arm (0.4%) and 4 in the BV arm (0.8%).

“This is particularly meaningful for children and AYA patients who are at very high risk for late toxicity associated with radiation, including second cancers and cardiovascular disease,” Dr. LaCasce emphasized.

As expected with combination chemotherapy, the most common adverse events (AEs) in both arms included gastrointestinal toxicities (eg, nausea), cytopenias, and fatigue. Notably, neutropenia occurred more frequently in the nivolumab/AVD arm compared with the BV/AVD arm (55% vs 32%). However, Dr. Herrera pointed out that G-CSF support was optional with use of nivolumab but was required with use of BV. The fact that only 54% of patients assigned to nivolumab/AVD received G-CSF likely accounts for the higher neutropenia rate to some degree. Importantly, no increases in the incidence of febrile neutropenia, sepsis, or infections occurred in the nivolumab arm despite the increased frequency of neutropenia.

Noteworthy AE differences favoring nivolumab/AVD over BV/AVD included a lower incidence of peripheral sensory neuropathy (29% vs 55%) and bone pain (8% vs 20%). The rate of treatment discontinuation was also lower with nivolumab versus BV (11% vs 22%).

From an immune toxicity standpoint, nivolumab proved to be well tolerated based on the low incidence of immune-related AEs (Figure 2).

Figure 2. Adverse Events of Interest: Immune/Other

“We will be following the patients on the study to confirm these early findings and continue to observe whether there is potentially an overall survival benefit as the study matures. We will perform several preplanned subset analyses within the main study cohort. We will also be evaluating patient-reported outcomes, as well as translational medicine analyses evaluating the prognostic and predictive value of circulating tumor DNA,” Dr. Herrera stated.

“I’d like to congratulate the authors on the results of this successful and highly collaborative study. I also think having a junior faculty member lead the study sets a positive example in academic medicine to promote and retain talent,” Dr. LaCasce said.

— Kara Nyberg, PhD