Nivolumab regimen halves risk for progression, death in Hodgkin lymphoma
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Key takeaways:
- Nivolumab plus chemotherapy significantly improved PFS for individuals with advanced Hodgkin lymphoma compared with standard of care.
- Results showed fewer adverse events in the nivolumab group.
Nivolumab plus chemotherapy significantly extended PFS for children and adults with newly diagnosed advanced Hodgkin lymphoma compared with standard of care, according to results of a randomized phase 3 trial.
Researchers reported fewer treatment discontinuations and adverse events among patients assigned nivolumab (Opdivo, Bristol Myers Squibb).
“The results really surprised all of us,” Jonathan W. Friedberg, MD, MMSc, director of the Wilmot Cancer Institute at University of Rochester Medical Center and chair of the lymphoma committee at SWOG Cancer Research Network, said during a press briefing. “Only 1 year into follow-up, the data safety monitoring committee recommended closing the trial early because the signal was so great. We waited an additional year of follow up to report these results because we wanted the results to be meaningful. Now, with 2 years of follow up, the trends are actually higher, such that we’re curing substantially more patients with this regimen.”
Background and methods
Individuals are typically diagnosed with Hodgkin lymphoma when they are young, with median age at diagnosis of 30 years, Friedberg said.
Combination chemotherapy had long been the standard of care.
However, the addition of brentuximab vedotin (Adcetris, Seagen), an antibody-drug conjugate directed against CD30, to regimens such as AVD chemotherapy — which consists of doxorubicin, vinblastine and dacarbazine — improved survival and reduced toxicities, according to study background.
“Hodgkin lymphoma has been one of the greatest success stories in oncology,” Friedberg said. “In the 1960s, this was a uniform death sentence for patients, and now the vast majority of patients with Hodgkin lymphoma are cured. However, a few issues remain. There’s still about 20% to 25% of patients [who present with advanced-stage disease] who are not cured, and those patients need to go on and get significant toxic therapy.”
More than 50% of pediatric patients receive radiotherapy after brentuximab vedotin plus AVD.
Because Hodgkin lymphoma commonly expresses PD-1, researchers in the SWOG S1826 trial evaluated nivolumab, a PD-1 inhibitor, against standard care.
The trial, conducted across 256 sites in the U.S. and Canada, included 970 patients aged 12 years or older with previously untreated stage III or stage IV Hodgkin lymphoma.
Researchers randomly assigned 487 patients (median age, 27.6 years; range, 12-83.7; 56% male; 76% white) to nivolumab (240 mg for adults; 3 mg/kg to a max of 240 mg for children) plus AVD.
The other 483 patients (median age, 26.8 years; range, 12-81.7; 57% male; 75% white) received 1.2 mg/kg brentuximab vedotin plus AVD.
Patients received treatment on days 1 and 15 of each 28-day cycle for six cycles.
Friedberg said researchers “were happy” with the trial’s diversity (11.8% Black; 12.8% Hispanic), adding this would make the results “exportable to broad patient populations.”
This also is the first study in the United States to include children and adults together.
“Historically, patients under the age of 18 were treated slightly differently from adult patients using different chemotherapy backbones, as well as more radiation therapy,” Friedberg said.
PFS served as the primary endpoint. Adverse events, OS and EFS served as secondary endpoints.
Results and next steps
Median follow-up was 2.1 years (range 0-4.2).
Researchers reported higher rates of 2-year PFS (92% vs. 83%; HR = 0.45; 95% CI, 0.3-0.65) and EFS (90% vs. 81%; HR = 0.5; 95% CI, 0.36-0.71) in the nivolumab group.
Nearly all patients assigned nivolumab and brentuximab vedotin remained alive at 2 years (99% vs. 98%; HR = 0.39; 95% CI, 0.15-1.03).
Seven patients — three(0.6%) in the nivolumab cohort and four (0.8%) in the brentuximab vedotin group — required radiation therapy.
A higher percentage of patients assigned brentuximab vedotin experienced nausea (70% vs. 65%), fatigue (51% vs. 47%), anemia (46% vs. 39%) and peripheral sensory neuropathy (56% vs. 29%).
A higher percentage of patients assigned nivolumab experienced neutropenia (56% vs. 34%).
A higher percentage of patients assigned brentuximab vedotin discontinued treatment for any reason (22.2% vs. 9.4%).
“Our study results have led to a major change in how we treat advanced-stage (stage III or stage IV) classic Hodgkin lymphoma,” said Alex Herrera, MD, the study’s first author, trial lead investigator and chief of the division of lymphoma at City of Hope. “Nivolumab with AVD chemotherapy led to more durable remissions, was associated with fewer side effects and was better tolerated than brentuximab vedotin-AVD, the old standard. Importantly, less than 1% of patients needed radiation after nivolumab-AVD, a dramatic reduction in the proportion of patients receiving radiation. This is absolutely critical in a disease that often impacts adolescents and young adults who are particularly vulnerable to the late effects of radiotherapy."
Researchers acknowledged study limitations, including short follow-up time.
“If you can keep people disease free and alive for 2 years, generally speaking, it’s very unlikely that beyond 2 years you’re going to have a lot of events,” Friedberg said. “Therefore, we’re quite optimistic these results are going to be durable. But of course it’s going to be important to follow these patients for a longer period.”
Friedberg and colleagues are attempting to develop assays to predict which individuals may not be cured with nivolumab plus AVD.
More research is needed to evaluate if certain patients would perform better on brentuximab vedotin, a well as patient-reported outcomes on quality of life, including impact on fertility, lifestyle issues and depression.
“We’re optimistic many physicians and practices will quickly change to this new regimen,” Friedberg said. “All of these drugs are approved. And because the regimen is less expensive than the previous regimen, less toxic and more active, we anticipate that guidelines will rapidly change to recommend this as a preferred treatment option.”
James O. Armitage, MD, Joe Shapiro professor of medicine in the division of oncology and hematology at University of Nebraska Medical Center, and Dan L. Longo, MD, professor of medicine at Brigham and Women’s Hospital, expressed a similar sentiment in an accompanying editorial.
“The nivolumab regimen is easy to deliver, is associated with modest toxic effects, and is highly effective,” Armitage and Longo wrote. “This latest trial suggests that nivolumab plus AVD may become the treatment of choice for all stages of [Hodgkin] lymphoma.”
References:
- Armitage JO, et al. N Engl J Med. 2024;doi:10.1056/NEJMe2408724.
- Herrera AF, et al. N Engl J Med. 2024;doi:10.1056/NEJMoa2405888.
Reference:
Perspective
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Henry Chi Hang Fung, MD, FACP, FRCPE
This study has established the combination of nivolumab plus AVD as the new standard of care for patients with advanced-stage classic Hodgkin lymphoma in United States.
Nivolumab plus AVD compared favorably with brentuximab plus AVD, with improved disease control and fewer side effects. A PFS rate of 92% at 2 years was hard to beat.
The HD21 trial, conducted in Europe, compared eBEACOPP — bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone and procarbazine — with BrECADD, which includes brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine and dexamethasone. The latter had shown better disease control with more favorable toxicity. A 4-year PFS of 94.3% was unprecedented. Based on the results from HD21, the investigators recommended BrECADD as the new standard treatment for advanced-stage Hodgkin lymphoma.
Although there's no prospective study comparing nivolumab plus AVD vs. BrECADD, the latter appeared to have more peripheral neuropathy and more neutropenic fever after the first cycle.
Overall, it's good news for our patients with advanced-stage Hodgkin lymphoma, as most of them are potentially curable either with nivolumab plus AVD or BrECADD, and both regimens have a more favorable toxicity profile compared with the prior treatment standard. Based on the toxicity profile, I recommend nivolumab plus AVD as the new standard for treatment of advanced-stage Hodgkin lymphoma.
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