Opdivo Combination Shows Superior Survival, Fewer Adverse Effects in Advanced Hodgkin Lymphoma

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The combination of Opdivo (nivolumab) plus chemotherapy was found to significantly improve progression-free survival (PFS) with fewer adverse effects (AEs) compared to Adcetris (brentuximab vedotin) plus chemotherapy in adolescent and adult patients with advanced-stage classic Hodgkin lymphoma, according to results of the Phase III S1826 trial (NCT03907488) published in The New England Journal of Medicine.^1,2 These findings hold particular significance because the Opdivo combination was found to also dramatically lower the need for radiotherapy, according to the trial investigators.

“The progression-free survival advantage observed with (nivolumab with doxorubicin, vinblastine, and dacarbazine [N+AVD]) was substantial and consistent across age, disease stage, and (International Prognostic Score [IPS])-score subgroups,” the study authors wrote. “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 events was clinically meaningful. The interim efficacy-analysis threshold was crossed during a preplanned interim analysis with a median follow-up of only 1 year, and the improvement in progression-free survival with N+AVD was sustained with longer follow-up.”¹

Opdivo is a monoclonal antibody that binds to the PD-1 receptor and inhibits tumor growth by improving T-cell function.^3,4 Opdivo has been approved across an array of indications, both as a single agent and in combination therapy, including for patients with unresectable or metastatic melanoma; metastatic NSCLC; advanced renal cell carcinoma; classical Hodgkin lymphoma; recurrent or metastatic squamous cell carcinoma of the head and neck; locally advanced or metastatic urothelial carcinoma; microsatellite instability-high or mismatch repair deficient metastatic colorectal cancer; and hepatocellular carcinoma.³

Adcetris is comprised of an anti-CD30 monoclonal antibody that is attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE). The antibody drug conjugate employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing cells.³

The multicenter, open-label, randomized S1826 trial enrolled patients aged at least 12 years with stage III or IV newly diagnosed Hodgkin lymphoma. Patients were randomly assigned to receive either Adcetris plus doxorubicin, vinblastine, and dacarbazine (BV+AVD) or N+AVD. Prespecified patients were eligible to receive radiation therapy directed to residual metabolically active lesions. The trial’s primary endpoint was PFS, which investigators defined as time from randomization to first observation of disease progression or death from any cause.

Among 994 randomized patients, 970 were placed in the intention-to-treat group to analyze efficacy. Findings from the second planned interim analysis show that at a median follow-up of 12.1 months, the Opdivo combination crossed the threshold for efficacy, which suggests it significantly improved PFS compared to the Adcetris combination (hazard ratio for disease progression or death, 0.48; 99% confidence interval [CI], 0.27 to 0.87; two-sided P=0.001).

To address the short follow-up time, investigators conducted another evaluation with a longer follow-up. At a median follow-up of 2.1 years (range, 0 to 4.2 years), two-year PFS was 92% (95% CI, 89 to 94) with the Opdivo combination compared to 83% (95% CI, 79 to 86) with the Adcetris combination (hazard ratio for disease progression or death, 0.45; 95% CI, 0.30 to 0.65).

A total of seven patients were administered radiation therapy. In terms of safety, immune-related AEs were infrequent with the Opdivo combination compared to the Adcetris combination, which was associated with more treatment discontinuations.

Investigators concluded that based on the clinically meaningful improved PFS, the superior AE profile, the potential to avoid the toxic impact of radiation therapy, and the lower drug-acquisition and supportive-care costs, the Opdivo combination is positioned as a strong candidate for primary treatment in adolescent and adult patients with stage III or IV Hodgkin lymphoma.

“The S1826 trial showed that N+AVD significantly improved progression-free survival as compared with BV+AVD in adolescent and adult patients with advanced-stage classic Hodgkin’s lymphoma,” the study authors wrote. “Event-free survival was also longer in patients receiving N+AVD. N+AVD had a better side-effect profile than BV+AVD—fewer patients stopped treatment early, fewer deaths occurred during treatment, and the incidence of immune-related toxic effects was low. Very few patients (<1%) received end-of-treatment radiotherapy, a dramatic reduction in the use of radiation in adolescent patients as compared with contemporary regimens.”¹

In an accompanying editorial also published in The New England Journal of Medicine, the authors noted that the Opdivo combination could become the new standard of care for all stages of the disease.⁵

“The (Opdivo) regimen is easy to deliver, is associated with modest toxic effects, and is highly effective,” the editorial authors wrote. “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. This latest trial suggests that N+AVD may become the treatment of choice for all stages of Hodgkin’s lymphoma.”⁵

References

1. Herrera A, et al. Nivolumab+AVD in Advanced-Stage Classic Hodgkin’s Lymphoma. Published October 16, 2024. N Engl J Med 2024;391:1379-1389. DOI: 10.1056/NEJMoa2405888. Vol. 391 No. 15.

2. Immunotherapy (Nivolumab or Brentuximab Vedotin) Plus Combination Chemotherapy in Treating Patients With Newly Diagnosed Stage III-IV Classic Hodgkin Lymphoma. ClinicalTrials.gov. Updated October 8, 2024. Accessed October 17, 2024. https://clinicaltrials.gov/study/NCT03907488

3. Opdivo. Prescribing information. Bristol Myers Squibb; 2021. Accessed October 17, 2024. https://packageinserts.bms.com/pi/pi_opdivo.pdf

4. FDA approves first immunotherapy for initial treatment of gastric cancer. News release. FDA. April 16, 2021. Accessed October 17, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-immunotherapy-initial-treatment-gastric-cancer

5. Armitage J and Longo D. Therapy for Hodgkin’s Lymphoma — Can It Get Any Better? Published October 16, 2024. N Engl J Med 2024;391:1452-1454. DOI: 10.1056/NEJMe2408724. Vol. 391 No. 15.