NCI Launches Phase 3 Trial of Adcetris and Opdivo in Early-Stage Hodgkin Lymphoma
Largest Phase 3 Trial in Early-Stage Hodgkin Lymphoma
The AHOD2131 trial, sponsored by the National Cancer Institute (NCI), is a randomized Phase 3 study enrolling 1,875 newly diagnosed patients aged 5 to 60 with Stage 1 or 2 classical Hodgkin lymphoma. All patients will initially receive ABVD for two cycles and then be randomized based on PET2 response and risk factors to either standard chemotherapy/radiation or an immunotherapy combination. The primary endpoint is 3-year progression-free survival (PFS). As the largest early-stage classical Hodgkin lymphoma (cHL) trial in the history of the North American Inter-Group, it has the potential to significantly impact treatment guidelines.
Targeting CD30 and PD-1 Simultaneously
Adcetris (brentuximab vedotin) is an antibody-drug conjugate (ADC) that targets CD30, rather than CD3, on Hodgkin and Reed-Sternberg cells, delivering the microtubule-disrupting agent MMAE into the cells. Opdivo (nivolumab) is a monoclonal antibody that blocks PD-1 on T cells, inhibiting tumor immune evasion. The trial will administer these two drugs for four cycles, aiming to demonstrate superior PFS while reducing exposure to bleomycin and cumulative chemotherapy, and in some patients, radiation.
Competing on Toxicity After High Cure Rates
Early-stage cHL achieves cure rates exceeding 90% with ABVD and response-adapted radiation therapy. Therefore, reducing long-term side effects such as secondary cancers, cardiotoxicity, and infertility is a key competitive factor, rather than simply extending survival. The standard arm includes ABVD/AVD, and the high-risk slow-responder group includes intensified BEACOPP and involved-field radiation therapy. Keytruda (pembrolizumab, Merck), a competing PD-1 inhibitor, has been approved by the FDA for relapsed/refractory cHL, but this trial of BV and nivolumab in the first-line treatment of early-stage (Stage 1/2) patients is establishing differentiated late-stage evidence.
Regulatory and Commercial Context
The FDA initially approved Adcetris on August 19, 2011, for relapsed/refractory Hodgkin lymphoma and expanded its use on March 20, 2018, as a combination with AVD for newly diagnosed Stage 3/4 cHL. Opdivo received accelerated approval on May 17, 2016, for relapsed/refractory cHL and full approval on March 20, 2016, as an N-AVD regimen for newly diagnosed Stage 3/4 cHL, demonstrating commercial success in later stages. However, the combination of BV and nivolumab in early-stage (Stage 1/2) patients is still in clinical trials. The global Hodgkin lymphoma treatment market was approximately USD 1.2 billion in 2024, and Opdivo's total revenue was USD 10.05 billion in 2025, highlighting the strategic value of expanding indications.
This Phase 3 trial, based on 1,875 patients and 3-year PFS, will determine whether BV and nivolumab can provide superior disease control while reducing chemotherapy and radiation exposure in early-stage cHL, where cure rates exceed 90%. Success will provide Pfizer (PFE) with evidence to expand the use of its CD30 ADC, Adcetris, and Bristol Myers Squibb (BMY) with evidence to expand the use of its PD-1 inhibitor, Opdivo, to the first-line treatment of Hodgkin lymphoma, a market of approximately USD 1.2 billion. In the short term, key clinical indicators include enrollment speed, the proportion of patients with rapid responses on PET2, and safety signals. In the medium to long term, the use of ABVD/AVD and intensified BEACOPP/radiation therapy, as well as the competitive landscape with Merck's (MRK) Keytruda, will be affected. The use of the same protocol for both children and adults will have a direct impact on long-term toxicity and quality of life studies, as well as the demand for hematologist-oncologists.
Source: ClinicalTrials.gov (api_ct)