Nivolumab Cuts Risk of Disease Progression or Death by 52% in Untreated Hodgkin Lymphoma Compared With Brentuximab Vedotin

In patients newly diagnosed with classic Hodgkin lymphoma (cHL), the immune checkpoint inhibitor nivolumab (Opdivo) plus chemotherapy reduced by half the risk of disease progression and death compared with the CD30-targeted therapy brentixumab vedotin (Adcetris) and the same chemotherapy combination.

Results, announced this morning at the annual meeting of the American Society of Clinical Oncology (ASCO), will cap today’s plenary session, highlighting a remarkable journey in the treatment of patients with cHL. In this landmark study—a collaboration among all North American clinical trial groups—a unique trial design allowed seamless participation across adult and pediatric cHL populations that have historically been treated differently. The result was good news for patients of all ages.

“Traditionally, adults and children with advanced Hodgkin lymphoma in the United States 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, California.

Herrera

In this trial, adult and pediatric cooperative groups achieved 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 said.

Just last year at ASCO, long-term data from the ECHELON-1 trial showed that after 6 years, brentuximab vedotin plus the chemotherapy combination of doxorubicin (Adriamycin), vinblastine, and dacarbazine, called AVD, reduced the risk of death 41% over an older combination of bleomycin, vinblastine, and dacarbazine (ABVD).

But as Herrera explained in a press briefing, that success came at a cost, which was increased toxicity. On the pediatric side, he said, the disease’s tendency to strike young adults meant maximizing doses of radiation and chemotherapy to stave off a relapse. “That was decades ago; we've been slowly, steadily over time trying to walk that therapy back—and deescalate therapy.”

Today’s results push the therapeutic bar higher, with the use of a PD-1 inhibitor in first-line treatment.

“This trial was an unprecedented effort across all North American clinical trial cooperative groups to improve the cure rate in advanced stage Hodgkin lymphoma and harmonize treatment approaches between pediatric and adult patients,” Oreofe Odejide, MD, an ASCO commentator who is an assistant professor at Dana-Farber Cancer Institute, said in a statement. “The collaborations across adult and pediatric groups helped pave the way for a new standard of care that is better tolerated and results in a higher proportion of patients with durable remissions.”

In their abstract, investigators discuss rationale for their approach: When patients developed relapsed or refractory (R/R) cHL, “The PD-1 pathway is central to the pathogenesis of HL, and PD-1 blockade is effective in R/R HL.”

SWOG S1826 evaluated 976 people 12 years of age or older who had not previously been treated for cHL, which is characterized by the presence of large white blood cells that may have more than one nucleus. Median follow-up was 12.1 months. Enrollment was as follows:

• Of the 976 were eligible, 489 were randomized to the nivolumab group and 487 to the brentuximab vedotin group. Median age was 27 years, with a range of 12 to 83 years; 24% were less than 18 years of age, and 10% were more than 60 years of age.
• 56% were male, 76% were White, 12% were Black, and 13% were Hispanic.
• Among the group, 32% had an International Prognostic Score of 4-7. At the time of data cutoff, less than 1% of patients had received radiation therapy.

Herrera said the cooperation among the trial groups allowed enrollment to run ahead of schedule. At the planned second interim analysis, which occurred when the trial reached 50% of the total progression-free survival (PFS) events, the SWOG Data and Safety Monitoring Committee recommended that the primary results be reported, as 30 events had occurred in the nivolumab group vs 58 in brentuximab vedotin group. With a median follow-up of 12.1 months, the following data are being reported:

• PFS was superior in the nivolumab arm, with a hazard ratio (HR) of 0.48 (99% CI, 0.27-0.87, one-sided P = .0005).
• 12-month PFS is 94% in the nivolumab group vs 86% in the brentuximab vedotin group.
• 11 deaths, with 7 due to adverse events (AEs) were seen in the brentuximab vedotin group, vs 4 in the nivolumab group (3 due to AEs).
• Rates of grade 3 or higher hematologic AEs were 48.4% (45.1% grade 3 or higher neutropenia) in the nivolumab group vs 30.5% (23.9% grade 3 or higher neutropenia) in the brentuximab vedotin group. Rates of any grade of febrile neutropenia (5.6% nivolumab vs 6.4% brentuximab vedotin) were similar, as were pneumonitis (2.0% vs 3.2%) and colitis (1% vs 1.3%).
• Elevated alanine transmission was 30.7% for nivolumab and 39.8% for brentuximab vedotin. Peripheral neuropathy, which Herrera said is of particular concern for younger patients, was more common after brentuximab vedotin; sensory, 28.1% nivolumab vs 54.2% brentuximab, and motor, 4% nivolumab vs 6.8% brentuximab.

“I can't emphasize enough how important neuropathy is as a side effect in these young patients,” who may face these effects for the rest of their lives, Herrera said. “It’s fantastic to be cured from your cancer, but it’s tough to live with.”

And, according to data from ASCO, many do survive cHL but live with toxic effects of today’s therapies. An estimated 8830 new cases (4,850 men and 3,980 women) of Hodgkin lymphoma will be diagnosed in the United States in 2023, and an estimated 900 deaths (540 men and 360 women) will occur. Although the 5-year survival rate for advanced disease is 83%, some patients do not benefit and/or cannot tolerate the effects of current therapeutic options.

Herrera emphasized that the benefits of nivolumab were consistent across age groups, and that harmonization of care appears here at last. Although the trial format allowed patients to receive radiation if needed, less than 1% did in the nivolumab group. “I started by telling you that 55% to 60% of patients receive radiation therapy,” Herrera said. “So that's an incredible reduction in the use of radiotherapy, and hopefully delays the effects that these patients might experience.”

During Sunday's plenary session, Herrera noted that a study is under way that combines nivolumab with brentuximab vedotin. Officials from Seagan, which makes the therapy, noted this in an email sent Monday,

"Early SWOG data are promising but longer-term proven outcomes including overall survival data are important in a curative setting such as Hodgkin lymphoma. [Brentixumab vedoton] is the only regimen with a demonstrated overall survival benefit with a Category 1 NCCN guidelines recommendation."

The message continued, "Our ultimate goal is to achieve the highest cure rate possible by combining the 2 most active agents in [brentixumab vedoton] and an anti-PD1 and, as a result, further reduce chemotherapy burden for patients."

The SWOG S1826 study was funded primarily by NCI with some funding from Bristol Myers Squibb.

Reference

Herrera A, LeBlanc M, Castellino S, et al. SWOG S1826, a randomized study of nivolumab(N)-AVD versus brentuximab vedotin (BV)-AVD in advanced stage (AS) classic Hodgkin lymphoma (HL). Presented at: American Society of Clinical Oncology; Chicago, IL: June 2-6, 2023; Abstract LBA4.