Is nivolumab superior to standard of care for classic Hodgkin lymphoma?
A new first-line treatment involving the PD-1 inhibitor nivolumab for advanced-stage classic Hodgkin lymphoma could soon make its way into clinics.
Nivolumab plus a chemotherapy cocktail known as AVD (doxorubicin, vinblastine, dacarbazine) improved progression-free survival and appeared to have reduced side effects, compared with brentuximab vedotin (BV) with AVD in patients with stage 3 or 4 cHL.
The results were published in the Oct. 17 issue of The New England Journal of Medicine.
The phase III, multicenter, open-label, randomized trial followed nearly 1,000 patients ages 12 to 83 across the U.S. and Canada for a median time of about two years.
Nivolumab (Opdivo) is sponsored by Bristol Myers Squibb and was granted accelerated approval by FDA for relapsed or refractory cHL in 2016.
The new results follow an interim analysis that was scheduled to take place after 50% of a prespecified number of disease progression events or deaths occurred.
However, the interim results—analyzed after only one year of follow-up—surprised the research team, said senior author Jonathan Friedberg, director of the Wilmot Cancer Institute and the Samuel Durand Professor of Medicine at the University of Rochester Medical Center.
“The difference here [between the experimental and control groups] was so much more than what we had expected, that it crossed the efficacy threshold at the one-year look,” Friedberg said to The Cancer Letter. “About a year and a half ago, we got the phone call from the data safety monitoring committee, recommending stopping the study and immediately reporting the results.”
Those interim results were shared during the 2023 American Society of Clinical Oncology annual meeting.
“But with only one year of follow-up, the results are far less clinically meaningful—so, we intentionally planned for the manuscript to wait an additional year,” Friedberg said.
Lymphoma experts are glad to see these long-anticipated clinical trial results.
“This was an awaited practice-changing study that clearly had shown that we can improve the outcomes of patients with advanced cHL,” Ajay Gopal, the Stephen Hans Petersdorf, MD Endowed Chair in Cancer Care and professor of medicine in the Division of Hematology Oncology at the University of Washington, said to The Cancer Letter.
Gopal was not involved in the study.
“This regimen will change the standard of care, and this publication will assist physicians in obtaining insurance approval for this regimen,” said Gopal, a professor in the Clinical Research Division and the clinical research director and medical director of Hematology and Hematologic Malignancies at the Fred Hutchinson Cancer Center.
Perfect fit for a PD-1 inhibitor
PD-1 inhibitors are a fitting approach for cHL, Friedberg said. “There’s a chromosomal translocation or amplification that is almost universally seen in Hodgkin lymphoma, and because of that, the response rates of Hodgkin lymphoma to checkpoint inhibitors—either nivolumab or pembrolizumab—even as single agents, is extremely high.”
Other hematologic cancers show mixed results with PD-1 inhibitors, he said.
However, choosing the control arm treatment proved to be the hardest part of designing the trial, Friedberg said.
“When we designed the trial in 2016 and 2017, there was some controversy in the field as to whether the brentuximab+AVD regimen should be the control, or whether an ABVD with bleomycin should be the control in a response-adapted way,” he said. “Fortunately, we chose the brentuximab regimen, because subsequent to our decision, long-term follow-up of another trial called the ECHELON-1 trial demonstrated overall survival benefit to the brentuximab+AVD regimen as compared to ABVD.”
For the past few years, BV+AVD has been widely considered the standard of care for advanced-stage Hodgkin lymphoma in North America, Friedberg said.
Still, BV+AVD is more toxic than other treatment regimens in adults, and about half of pediatric patients undergo radiation therapy with BV-based therapy.
The clinical trial was conducted by the SWOG Cancer Research Network and pediatric and adult groups of the NCI National Clinical Trials Network.
The trial included 970 patients ages 12 and older with previously untreated stage 3 or 4 cHL, Zubrod performance status of 0 to 2 (or Lansky performance status of 50 to 100 in patients under 18), and adequate hematologic and organ function. Patients were randomized between July 19, 2019 and Oct. 5, 2022, for a total of 487 patients in the nivolumab+AVD group and 483 patients in the BV+AVD group.
The two groups were balanced across three stratification factors: age (12-17 years old, 18-60 years old, >60 years old), score group (0-3 or 4-7) on the International Prognostic Score, and the intent to use radiation. About 25% of participants were under age 18, and 10% were above age 60.
Patients received the therapies intravenously on days 1 and 15 during each of six 28-day cycles. Treatment doses included doxorubicin at 25 mg/square meter of body-surface area, vinblastine at 6 mg/square meter, and dacarbazine at 375 mg/square meter with either nivolumab at 240 mg in adults and 3 mg/kg of body weight in children 12 to 17 years old, capped at 240 mg, or brentuximab vedotin at 1.2 mg/kg, capped at 100 kg.
Based on a statistical analysis, the final analysis of the trial was planned to take place when 179 events of disease progression or death from any cause occurred across both groups, at a one-sided significance level of 0.021. Interim analyses were planned at 25%, 50%, and 75% of the anticipated events.
At a median follow-up time of 12.1 months, the trial reached the 50% benchmark. The threshold for efficacy was also crossed, and nivolumab+AVD significantly improved PFS compared with BV+AVD (hazard ratio for disease progression or death, 0.48; 99% CI: 0.27-0.87). With nivolumab+AVD, one-year PFS was 94% (95% CI: 91-96), and with BV+AVD, one-year PFS was 86% (95% CI: 82-90).
Analysis after an additional year—with a median follow-up time of 2.1 years—revealed similarly robust results (hazard ratio for disease progression or death, 0.45; 95% CI: 0.30-0.65). Two-year PFS with nivolumab+AVD was 92% (95% CI: 89-94), and with BV+AVD, it was 83% (95% CI: 79-86).
Even at the two-year median follow-up mark, the study reached just 70% of the prespecified number of disease progression or death events.
“We didn’t quite hit 75%, and part of that is because the group that got nivolumab is doing so well that the event rate is lower than we had initially projected,” Friedberg said. “We may never reach the 100% mark because the outcome in the experimental arm was so favorable.”
Not only did the nivolumab combination yield better PFS results than the BV combination; participants taking the former treatment had fewer adverse events compared with those on the standard of care.
Except for neutropenia and arthralgia, all logged adverse events occurred more frequently in the BV+AVD group.
Further, fewer patients stopped treatment early in the nivolumab+AVD group, at 37 patients, or 7.6%, compared with the BV+AVD group, at 58 patients, or 12%.
A new standard of care
“This study sets a new standard for the treatment of advanced-stage classic Hodgkin lymphoma,” Jane Winter, professor of medicine in the Division of Hematology and Oncology at Northwestern University Feinberg School of Medicine and member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, said to The Cancer Letter.
“Not only is it more effective than the current standard, but N+AVD delivers excellent outcomes without radiotherapy, commonly used in children and young adults, and without bleomycin, a drug that has potential lung toxicity,” said Winter, who was not involved in the study.
Only seven patients in the clinical trial received radiation therapy. “That’s a dramatic decrease in radiation use in the pediatric population, where historically 50% to 70% of those patients were getting radiation,” Friedberg said. “We strongly anticipate that by omitting radiation, there’ll be fewer late effects, including second cancers.”
Both Winter and Gopal said that following these patients for several more years will be necessary for understanding long-term effects and overall survival benefits of nivolumab+AVD.
Friedberg agrees. This observation could be especially relevant for the younger patients, he said.
“About a quarter of the patients on this trial were children. So, they have 60-70 years of life ahead of them. We have to make sure that we’re not causing any late problems,” Friedberg said
Friedberg and colleagues plan to continue monitoring the participants for many years.
The study also represented a new paradigm for NCTN, Friedberg said. “The pediatric and adult groups had not collaborated at this level before in the hematologic malignancy or lymphoma space,” Friedberg said. “We now have a harmonized regimen where we’re working from the same regimen and same backbone.”
That harmonizing between age groups is a “big step forward,” Winter said.
Bristol Myers Squibb is pursuing a label for nivolumab to be a first-line treatment in cHL, and the application should go to FDA in the next few months, Friedberg said.
Experts said they are hopeful that this nivolumab-containing regimen will get into treatment guidelines.
“We really feel that these results are sufficiently compelling—that quickly, guidelines will change to recommend this as a preferred regimen,” Friedberg said.
