Nivolumab (Opdivo®; Bristol-Myers Squibb), an immune checkpoint inhibitor, in combination with chemotherapy (doxorubicin, vinblastine, and dacarbazine also known as AVD) significantly reduced the risk of disease progression and disease-related death compared with standard treatment with brentuximab vedotin (Adcetris®; Seagen), a CD30-targeted antibody-drug conjugate (ADC), plus chemotherapy in pediatric and adult patients with previously untreated stage III or IV Hodgkin lymphoma.

This is the conclusion of a federally funded clinical trial will be presented at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting being held June 2 – 6, 2023 in Chicago, Illinois. The study was funded by the National Cancer Institute of the National Institutes of Health.[1]

The addition of brentuximab vedotin to initial chemotherapy improves overall survival (OS) in adults and progress free survival (PFS) in pediatric patients with advanced stage (AS) classic Hodgkin lymphoma. However, frontline brentuximab vedotin adds toxicity to treatment, most pediatric patients receive radiation therapy (RT), and 7-20% of patients still develop relapsed/refractory (RR) Hodgkin lymphoma.

The PD-1 pathway is central to the pathogenesis of Hodgkin lymphoma and PD-1 blockade is effective in relapsed/refractory Hodgkin lymphoma.

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Hodgkin lymphoma
According to the American Cancer Society, about 8,830 new cases (4,850 men and 3,980 women) of Hodgkin lymphoma will be diagnosed in the United States in 2023. And, as a result of the disease, it is estimated that about 900 patients (540 men and 360 women) will die in 2023. The current five-year survival rate for advanced disease is 83%

About one-quarter of people with Hodgkin lymphoma do not benefit from therapy. Some newer therapies can be fairly aggressive and toxic for the majority of patients, especially those over age 60.  Treatment with nivolumab in this trial had limited adverse events due to the immunotherapy. The most common side effects were typical of combination chemotherapies, including low blood cell counts and gastrointestinal toxicities, such as nausea. Immune-related adverse events were infrequent.

Study design
To evaluate nivolumab + chemotherapy (AVD) vs brentuximab vedotin + chemotherapy (AVD) in patients with newly diagnosed advanced stage (AS) classic Hodgkin lymphoma, the adult and pediatric cooperative groups of the National Clinical Trials Network (NCTN) conducted the randomized, phase 3 study (SWOG S1826).

The study was a randomized, phase 3 trial of advanced Hodgkin lymphoma (stage 3 – 4) which enrolled 976 people 12 years of age or older who had not received previous treatment for the disease. Patients were randomly assigned (1:1) to receive either nivolumab, an FDA-approved PD-1 immune checkpoint inhibitor or brentuximab vedotin, an FDA-approved antibody-drug conjugate directed against tumor necrosis factor receptor CD30. Patients who were randomized to receive brentuximab vedotin + chemotherapy were required to also receive G-CSF neutropenia prophylaxis.  This was optional for patients who were randomized to receive nivolumab + chemotherapy. Pre-specified patients were also eligible to receive receive radiation therapy (RT) to residually metabolically active lesions on end of treatment PET.

All participating patients were stratified by age, international prognostic score (IPS), and intent to use radiation therapy (RT). The investigators used the 2014 Lugano Classification to asses response and disease progression. The primary endpoint was Progression Free Survival (PFS), with secondary endpoints including Overall Survival (OS), event-free survival (EFS), patient-reported outcomes (PROs), and safety.

Study findings
From the 994 enrolled patients, 976 were eligible to participate in the study and were randomized to receive either nivolumab + chemotherapy (n=489) or brentuximab vedotin + chemotherapy (n=487). The median age of the participating patients was 27 years of age (range, 12-83year), with 56% male patients, of which 76% were white, 12% were black, and 13% were Hispanic. Furthermore, 24% of participating patients were < 18 year 10% were > 60y, and 32% had IPS 4-7. So far, < 1% of patients received radiation therapy (RT).

At the planned 2nd interim analysis (50% of total Progression Free Survival events) the SWOG Data and Safety Monitoring Committee recommended to report the primary results because the primary PFS endpoint crossed the protocol-specified conservative statistical boundary.

A total of 30 PFS events occurred after treatment with nivolumab + chemotherapy vs 58 events after treatment with brentuximab vedotin + chemotherapy.

The study results demonstrated that, with a median follow-up of 12.1 months, there was a 52% reduction in risk of disease-related death with nivolumab vs. brentuximab vedotin (nivolumab + chemotherapy arm [HR 0.48, 99% CI 0.27-0.87, one-sided p=0.0005).

The one-year progression-free survival (PFS) with nivolumab was 94% vs. 86% for brentuximab vedotin.  There were 11 deaths (7 due to adverse events) with brentuximab vedotin vs. 4 with nivolumab (3 due to adverse events).

The rate of grade ≥ 3 hematologic adverse events was 48.4% (45.1% gr ≥ 3 neutropenia) after nivolumab + chemotherapy compared to 30.5% (23.9% gr ≥ 3 neutropenia) after brentuximab vedotin + chemotherapy.

Rates (any grade) of febrile neutropenia (5.6% nivolumab vs 6.4% brentuximab vedotin), pneumonitis (2.0% nivolumab vs 3.2% brentuximab vedotin), ALT elevation (30.7% nivolumab vs 39.8% brentuximab vedotin), and colitis (1% nivolumab vs 1.3% brentuximab vedotin) were similar. Hypo/hyperthyroidism was more frequent after nivolumab + chemotherapy (7%/3% nivolumab vs <1% brentuximab vedotin) while peripheral neuropathy (any grade) was more common after brentuximab vedotin + chemotherapy (sensory: 28.1% N vs 54.2% brentuximab vedotin; motor: 4% nivolumab vs 6.8% brentuximab vedotin).

“Traditionally, adults and children with advanced Hodgkin lymphoma in the U.S. have been treated with different chemotherapy regimens and the majority of children also receive radiation treatment whereas the use of radiation has been uncommon in adult patients,” said Alex Francisco Herrera, MD, lead author and a hematologist-oncologist at City of Hope in Duarte, CA.

“As part of the design and planning of our trial, adult and pediatric cooperative groups met and arrived at a consensus on both the control and experimental regimens, with the goal of harmonizing the treatment of Hodgkin lymphoma across all ages, which is a truly unique outcome,” Herrera added.

Next Steps
Longer follow-up is needed to assess overall survival and other patient-related outcomes such as health related Quality of Life (hrQoL).

Clinical trial
Immunotherapy (Nivolumab or Brentuximab Vedotin) Plus Combination Chemotherapy in Treating Patients With Newly Diagnosed Stage III-IV Classic Hodgkin Lymphoma (SWOG S1826) – NCT03907488

Highlights of prescribing Information
Nivolumab (Opdivo®; Bristol-Myers Squibb)[Prescribing Information]
Brentuximab vedotin (Adcetris®; Seagen)[Prescribing Information]

[1] Herrera AF, LeBlanc ML, Castellino SM, Li H, Rutherford SC, Evens AM, Davison K, 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 41, 2023 (suppl 17; abstr LBA4) DOI 10.1200/JCO.2023.41.17_suppl.LBA4

Featured image:General views of the Annual Meeting of the American Association of Clinical Oncology (ASCO) – held in the McCormick Place in Chicago, Ill. Courtesy: © 2017 – 2023 ASCO/David Eulitt. Used with permission.

This article was first published in Onco’Zine.



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