Nivolumab Plus AVD Prolongs PFS vs Brentuximab Vedotin Plus AVD in Advanced-Stage Hodgkin Lymphoma

Nivolumab (Opdivo) plus doxorubicin, vinblastine, and dacarbazine (N+AVD) was associated with a prolonged median progression-free survival (PFS) and a more tolerable toxicity profile compared with brentuximab vedotin (BV) plus AVD (BV+AVD) in adolescent and adult patients with stage III or IV advanced-stage classic Hodgkin lymphoma, according to findings from the phase 3 S1826 trial (NCT03907488) that were published in The New England Journal of Medicine.¹

At a median follow-up of 2.1 years (range, 0-4.2), the 2-year PFS rate was 92% (95% CI, 89%-94%) with N+AVD vs 83% (95% CI, 79%-86%) with BV+AVD (HR, 0.45; 95% CI, 0.30-0.65). Treatment outcomes were generally consistent across prespecified patient subgroups, including by age, disease stage, and International Prognostic Score (IPS).

“In the context of a disease in which a high proportion of patients are cured with standard therapy and the bar to change practice is set high, the improvement in efficacy and in the risk of adverse effects [AEs] was clinically meaningful,” lead study author Alex F. Herrera, MD, and coauthors, wrote in the paper.

Herrera is chief of the Division of Lymphoma in the Department of Hematology & Hematopoietic Cell Transplantation, as well as the associate medical director of the Briskin Center for Clinical Research and an associate professor in the Division of Lymphoma in the Department of Hematology & Hematopoietic Cell Transplantation at City of Hope in Duarte, California.

Trial Design

This multicenter, open-label, randomized trial enrolled patients at least 12 years of age with stage III or IV previously untreated classic Hodgkin lymphoma. Patients needed to have a Zubrod score of 0 to 2 (or a Lansky performance status of 50 to 100 in patients 17 years of age and younger), as well as adequate hematologic and organ function. Patients with controlled HIV infection were permitted to enroll. This trial excluded patients with pre-existing interstitial lung disease, active autoimmune disease, or peripheral neuropathy of grade 2 or higher.

Between July 19, 2019, and October 5, 2022, 994 patients were randomly assigned to receive intravenous BV+AVD (n = 498) or N+AVD (n = 496). Nivolumab was administered at a dose of 240 mg in adults and 3 mg/kg (capped at 240 mg) in children ages 12 to 17 years of age. Doxorubicin, vinblastine, and dacarbazine were given at doses of 25 mg/m², 6 mg/m², and 375 mg/m², respectively. BV was administered at a dose of 1.2 mg/kg (capped at 100 kg). Patients in both arms were treated on days 1 and 15 of each 28-day cycle for 6 cycles.

Granulocyte colony-stimulating factor (G-CSF) prophylaxis was mandated in patients who received BV+AVD but was optional and could be administered at the investigator’s discretion in patients who received N+AVD. Use of dexrazoxane was permitted to reduce the risk of doxorubicin-induced cardiac toxicities. Prespecified patients were permitted to receive 30 Gy of radiation therapy directed at residual metabolically active lesions at the end of treatment.

PFS served as the primary end point. Key secondary end points included AEs, overall survival (OS), and event-free survival (EFS).

Patient Characteristics

“The S1826 trial was inclusive and representative of the population of patients with advanced-stage classic Hodgkin lymphoma,” the authors noted.

A total of 970 patients were eligible for inclusion in the modified intention-to-treat (ITT) cohort (BV+AVD, n = 483; N+AVD, n = 487). Baseline characteristics were balanced between the 2 arms. Patients were stratified by age (12-17 years vs 18-60 years vs ≥ 61 years), IPS group (0-3 or 4-7), and intent to use radiation (yes vs no).

Overall, 7.6% and 12.0% of patients in the N+AVD and BV+AVD arms, respectively, discontinued all treatment early. AEs were the most frequent reason for treatment discontinuation in both arms. In total, 9.4% of patients in the N+AVD arm discontinued nivolumab, and 22.2% of patients in the BV+AVD arm discontinued BV. The BV dose was reduced in 26.7% of patients in the BV+AVD arm. Dose reductions of nivolumab were not permitted.

Dexrazoxane was administered to 28.1% of patients, including in 188 of 236 adolescent patients. G-CSF was administered to 56.3% of patients in the N+AVD arm vs 96.7% of those in the BV+AVD arm. Seven patients received radiation therapy, 3 in the N+AVD arm and 4 in the BV+AVD arm.

“The…extremely low use of radiotherapy in our trial…combined with the excellent outcomes observed after treatment with N+AVD, suggests that radiotherapy has limited utility in adolescent patients after they have received N+AVD,” the authors stated.

Efficacy Findings

Previously reported findings from the second planned interim analysis of the trial showed that at a median follow-up of 12.1 months (range, 0-38.6), treatment with N+AVD resulted in a significant PFS improvement vs treatment with BV+AVD (HR, 0.48; 99% CI, 0.27-0.87; 2-sided P = .001).2 The 1-year PFS rate was 94% (95% CI, 91%-96%) with N+AVD vs 86% (95% CI, 82%-90%) with BV+AVD. Due to the short follow-up time, investigators repeated this analysis at a median follow-up of 2.1 years to assess the durability of this PFS benefit.

The 2-year EFS rate was 90% in the N+AVD arm and 81% in the BV+AVD arm (stratified HR, 0.50; 95% CI, 0.36-0.71).1 The 2-year OS rates were 99% and 98% in these respective arms (HR, 0.39; 95% CI, 0.15-1.03).

Safety Findings

Any-grade AEs occurring in the modified ITT population included nausea (N+AVD, 65%; BV+AVD, 70%), fatigue (47%; 51%), decreased neutrophil counts (56%; 34%), anemia (39%; 46%), peripheral sensory neuropathy (29%; 56%), constipation (40%; 43%), increased alanine aminotransferase levels (33%; 42%), decreased white blood cell counts (41%; 27%), vomiting (28%; 33%), increased aspartate aminotransferase levels (26%; 34%), diarrhea (21%; 27%), alopecia (21%; 26%), decreased lymphocyte counts (21%; 23%), oral mucositis (22%; 21%), anorexia (13%; 22%), abdominal pain (12%; 22%), headache (14%; 16%), decreased platelet counts (11%; 18%), bone pain (8%), 20%), increased alkaline phosphatase (11%; 17%), fever (13%; 13%), arthralgia (13%; 12%), hyperglycemia (12%; 13%), maculopapular rash (11%; 12%), myalgia (11%; 12%), dyspnea (9%; 12%), weight loss (5%; 15%), and dysgeusia (7%; 12%).

Notably, 3% and 32% of patients in the N+AVD and BV+AVD arms, respectively, had grade 2 or higher peripheral sensory neuropathy. The rates of febrile neutropenia, infection/infestation, and sepsis were similar across the 2 arms, but these events occurred more frequently in older patients, especially those who received BV+AVD. The combined rate of these AEs was 33% in patients older than 60 years of age vs 20% in those ages 18 to 60 years and 18% in those ages 12 to 17 years. The rates of gastritis, rash, and colitis were similar between the 2 arms. Hypothyroidism and hyperthyroidism were more frequently observed following treatment in patients in the N+AVD arm (7% and 3%, respectively) vs those in the BV+AVD arm (< 1% and 0%, respectively).

Seven patients from the N+AVD arm died from any cause, 3 during treatment. Fourteen patients in the BV+AVD arm died from any cause, 8 during treatment. Sepsis or infection was the most common cause of death. Three patients died of lymphoma.

The authors noted that the limitations of this research included the short follow-up time, and that several preplanned secondary and subgroup analyses lacked adequate statistical power.

“On the basis of the clinically meaningful improvement in PFS and excellent AE profile of N+AVD, the opportunity to avoid potentially toxic consolidative radiation therapy, and the decreased drug-acquisition and supportive-care costs, N+AVD should be a strong candidate for primary treatment in adolescent and adult patients with stage III or IV Hodgkin lymphoma,” the authors concluded.

References

1. Herrera AF, LeBlanc M, Castellino SM, et al. Nivolumab+AVD in advanced-stage classic Hodgkin's lymphoma. N Engl J Med. 2024;391(15):1379-1389. doi:10.1056/NEJMoa2405888
2. Herrera AF, LeBlanc ML, Castellino SM, et al. SWOG S1826, a randomized study of nivolumab(N)-AVD versus brentuximab vedotin(BV)-AVD in advanced stage (AS) classic Hodgkin lymphoma (HL). J Clin Oncol. 2023;41(suppl 17):LBA4. doi:10.1200/JCO.2023.41.16_suppl.LBA4