Nivolumab Outperforms Brentuximab Vedotin in PFS in Classic Hodgkin Lymphoma

A 3-year follow-up of the randomized, phase 3 S1826 (NCT03907488) study confirms that the combination of nivolumab (Opdivo) with doxorubicin, vinblastine, and dacarbazine (AVD) provides a sustained and statistically significant improvement in progression-free survival (PFS) compared with the standard regimen of brentuximab vedotin (Adcetris) with AVD for adolescent and adult patients with previously untreated, advanced stage classic Hodgkin lymphoma (cHL).^1,2

At a median follow-up of 3.1 years, the 3-year PFS rate was 91% for nivolumab plus AVD vs 82% for brentuximab vedotin plus AVD (HR, 0.48; P <.0001). This benefit was consistently observed across all prespecified patient subgroups, including age, disease stage, and international prognostic score (IPS). Furthermore, nivolumab plus AVD demonstrated a favorable safety profile with no new signals and a lower incidence of second cancers. These durable results validate guidelines recommending nivolumab plus AVD as a preferred frontline treatment regimen for this patient population.

“This was the first Hodgkin lymphoma clinical trial to enroll adolescents along with adults,” said Kara Kelly, MD, of Roswell Park Comprehensive Cancer Center and senior author of the analysis, in a news release.³ “They represented the largest cohort in which the use of a checkpoint inhibitor was evaluated as a first-line treatment in a pediatric population.”

Key Findings at 3-Year Median Follow-up

The analysis, with a data cutoff date of July 1, 2025, confirms the superiority and durability of the nivolumab plus AVD regimen.¹

The primary end point of the study showed a significant and sustained advantage for the nivolumab plus AVD arm. The overall PFS was 91% in the nivolumab plus AVD arm vs 82% in the brentuximab vedotin plus AVD arm.

The risk of progression or death was reduced by 52% in the nivolumab plus AVD arm vs the brentuximab vedotin plus AVD arm (HR, 0.48; 95% CI, 0.34–0.69; P <.0001).

The PFS benefit of nivolumab plus AVD was robust and consistent across all prespecified patient subgroups, demonstrating its broad applicability. This includes patients considered high-risk due to age, disease stage, or IPS score.

1. Ages 12–17 years: 93% (nivolumab plus AVD) vs 82% (brentuximab vedotin plus AVD)
2. Ages 18–60 years: 91% vs 85%
3. Ages >60 years: 82% vs 58%
4. Stage III cHL: 93% vs 86%
5. Stage IV cHL: 89% vs 80%
6. IPS 0–3: 92% vs 84%
7. IPS 4–7: 87% vs 77%

Nivolumab plus AVD led to a significant improvement in event-free survival (EFS; HR, 0.56; 95% CI 0.41–0.78; P =.0004). A favorable trend in overall survival (OS) was observed for the nivolumab plus AVD arm, though it did not reach statistical significance at this follow-up point. There were 8 patient deaths in the nivolumab plus AVD arm vs 15 deaths in the brentuximab vedotin plus AVD arm. The 3-year OS rate was 98% vs 97%.

Safety and Tolerability Profile

The 3-year follow-up revealed no new safety signals for the nivolumab plus AVD regimen. Importantly, the incidence of second cancers was lower in the nivolumab plus AVD arm.

Severe immune-related adverse events were infrequent; however, thyroid dysfunction was observed is 7% of patients in the nivolumab plus AVD arm. Additionally, low rates of febrile neutropenia and sepsis were observed in both arms. Grade ≥2 sensory neuropathy was more frequent in the brentuximab vedotin plus AVD arm (14% vs 7%).⁴

Study Overview

The S1826 study is a randomized, phase 3 clinical trial designed to evaluate a novel treatment combination against a standard of care for patients with advanced stage cHL.¹

The objective of the trial was to compare the efficacy and safety of PD-1 blockade with nivolumab in combination with AVD against brentuximab vedotin combined with AVD. The primary end point was PFS, and the secondary end points included OS, EFS, safety, and patient-reported outcomes.

A total of 994 patients were enrolled between July 9, 2019, and October 5, 2022. The modified intent-to-treat (mITT) cohort comprised 970 patients. The median age was 27 years (range, 12–83), with 24% of patients being under 18 and 10% over 60. The cohort was 56% male, 76% White, 12% Black, and 13% Hispanic.

The use of consolidative radiation therapy was exceptionally low, with only 7 patients (0.7%) across both arms receiving it.

Patients were randomized 1:1 to receive 6 cycles of either nivolumab plus AVD or brentuximab vedotin plus AVD. The analysis was conducted on a mITT basis after a median follow-up of 3.1 years.

Conclusions and Implications

As a result of this follow-up data, the National Comprehensive Cancer Network guidelines have been updated to reflect this newly discovered best practice of combining nivolumab with AVD.

Continued follow-up of the S1826 cohort will further evaluate long-term outcomes, including late toxicities, OS, and patient-reported outcomes.

REFERENCES

1.Herrera A, Leblanc M, Castellino S, et al. 3-year follow-up of the S1826 study confirms improved progression-free survival with nivolumab-AVD compared to brentuximab vedotin-AVD in advanced stage classic Hodgkin lymphoma. Blood (2025) 146 (Supplement 1):151. doi: 10.1182/blood-2025-151.

2.Immunotherapy (nivolumab or brentuximab vedotin) plus combination chemotherapy in treating patients with newly diagnosed stage III-IV classic Hodgkin lymphoma. ClincalTrials.gov. Updated December 4, 2025. Accessed January 15, 2026. https://clinicaltrials.gov/study/NCT03907488

3.Roswell Park and Children’s Healthcare of Atlanta analysis confirms benefit of nivolumab combo in teens with advanced Hodgkin lymphoma. News release. Children’s Healthcare of Atlanta. January 12, 2026. Accessed January 15, 2026. https://tinyurl.com/36nwapu7

4.Castellino S, Li H, Herrera A, et al. Three-year follow-up of nivolumab-AVD versus brentuximab vedotin-AVD in adolescents with advanced-stage classic Hodgkin lymphoma on S1826. J Clin Oncol.doi: 10.1200/JCO-25-00203.