In a phase III, multicentre, open-label, randomised S1826 study, treatment with nivolumab plus doxorubicin, vinblastine, and dacarbazine (AVD) significantly improved progression-free survival (PFS) as compared with brentuximab vedotin plus AVD in adolescent and adult patients with advanced-stage classic Hodgkin’s lymphoma.
The nivolumab plus AVD regimen had a better side-effect profile than brentuximab vedotin plus AVD, fewer patients stopped treatment early, fewer deaths occurred during treatment, and the incidence of immune-related side-effects was low. Very few patients (<1%) received consolidative radiotherapy. The findings are reported by Dr. Jonathan W. Friedberg of the University of Rochester Wilmot Cancer Institute in Rochester, NY, US and colleagues on 16 October 2024 in The New England Journal of Medicine.
Combination chemotherapy has been the standard treatment for advanced-stage Hodgkin’s lymphoma for decades. Divergent approaches are used in adult and paediatric patients, with modifications to chemotherapy backbones, positron emission tomography-based response adaptation, and the use of consolidative radiotherapy after completion of chemotherapy in 55-76% of paediatric patients.
The authors wrote in the background that incorporation of the CD30-directed antibody drug conjugate brentuximab vedotin into the treatment of advanced-stage Hodgkin’s lymphoma has led to improved outcomes. However, relapses after treatment occur and the use of brentuximab vedotin necessitates more growth factor support than prior regimens. Furthermore, brentuximab vedotin plus AVD is more toxic than ABVD chemotherapy regimen in adults, and 53% of paediatric patients still receive radiotherapy with brentuximab vedotin-based therapy.
PD-L1 expression is ubiquitous on Hodgkin’s Reed-Sternberg cells, owing in part to selective 9p24.1 amplification in those cells. PD1 blockade is a safe and effective for relapsed or refractory Hodgkin’s lymphoma, and high response rates and durable remissions are observed after PD1 blockade in untreated Hodgkin’s lymphoma.
The SWOG Cancer Research Network collaborated with the Children’s Oncology Group and adult patient groups of the National Clinical Trials Network to conduct the S1826 study in adolescent and adult patients with newly diagnosed stage III or IV classic Hodgkin’s lymphoma. Patients were randomly assigned to receive nivolumab plus AVD as compared with brentuximab vedotin plus AVD. Prespecified patients could receive radiotherapy directed to residual metabolically active lesions. The primary endpoint was PFS, defined as the time from randomisation to the first observation of progressive disease or death from any cause.
The study was inclusive and representative of the population of patients with advanced-stage classic Hodgkin’s lymphoma: approximately one quarter of the patients were younger than 18 years of age, 10% were older than 60 years of age, one quarter were from underrepresented backgrounds, and one third had International Prognostic Score greater than 3.
Of 994 patients who underwent randomisation, 970 were included in the intention-to-treat population for efficacy analyses. At the second planned interim analysis, with a median follow-up of 12.1 months, the threshold for efficacy was crossed, indicating that nivolumab plus AVD significantly improved PFS as compared with brentuximab vedotin plus AVD (hazard ratio [HR] for disease progression or death 0.48, 99% confidence interval [CI] 0.27 to 0.87; two-sided p = 0.001).
Owing to the short follow-up time, the study investigators repeated the analysis with longer follow-up; with a median follow-up of 2.1 years (range, 0 to 4.2 years), the 2-year PFS rate was 92% (95% CI 89 to 94) with nivolumab plus AVD, as compared with 83% (95% CI 79 to 86) with brentuximab vedotin plus AVD (HR for disease progression or death 0.45; 95% CI 0.30 to 0.65).
Overall, 7 patients received radiotherapy. Immune-related adverse events were infrequent with nivolumab; brentuximab vedotin was associated with more treatment discontinuation.
The authors concluded that based on the clinically meaningful improvement in PFS and excellent side-effect profile of nivolumab plus AVD, the opportunity to avoid potentially toxic consolidative radiotherapy, and the decreased drug-acquisition and supportive-care costs, nivolumab plus AVD should be a strong candidate for primary treatment in adolescent and adult patients with stage III or IV Hodgkin’s lymphoma.
In an accompanied editorial, Drs. James O. Armitage and Dan L. Longo of the University of Nebraska School of Medicine in Omaha, NE, US commented unexpected result of the superior treatment outcome seen in older patients who received nivolumab plus AVD. Hodgkin’s lymphoma in patients older than 60 years of age has been associated with a much poorer treatment outcome than that seen in younger patients. However, the 2-year PFS in this age group of 88% with nivolumab plus AVD, as compared with 65% with brentuximab vedotin plus AVD (HR for disease progression or death 0.30), is probably the best ever reported.
The editorialists also featured an enormously beneficial outcome in terms of the preservation of high rates of complete remission with very little use of radiotherapy. The nivolumab regimen is easy to deliver, is associated with modest side-effects, and is highly effective. The role of chemotherapy alone in the treatment of early-stage disease is expanding because of its remarkable efficacy and low risk of late effects. The findings from the S1826 study suggest that nivolumab plus AVD may become the treatment of choice for all stages of Hodgkin’s lymphoma.
The study was previously presented in part at the ASCO 2023 Annual Meeting, the 2023 International Conference on Malignant Lymphoma, and the 2023 ASH Annual Meeting.
The study was supported by grants from the US National Cancer Institute of the National Institutes of Health; Bristol Myers Squibb; the Emmet and Toni Stephenson Leukemia and Lymphoma Society Scholar Award, the Lymphoma Research Foundation Larry and Denise Mason Clinical Investigator Career Development Award, and the V Foundation Lloyd Family Clinical Scholar Fund (all to Dr. Alex F. Herrera), and the Miller Family Fund (to Dr. Margaret A. Shipp). Bristol Myers Squibb and SeaGen provided drugs used in the study.
References
- Herrera AF, LeBlanc M, Castellino SM, et al. Nivolumab+AVD in Advanced-Stage Classic Hodgkin’s Lymphoma. N Engl J Med 2024;391:1379-1389.
- Armitage JO, Longo DL. Therapy for Hodgkin’s Lymphoma — Can It Get Any Better? N Engl J Med 2024;391:1452-1454.