Data for Nivolumab Plus AVD Could Help Harmonize Treatment of Older and Younger Advanced-Stage Hodgkin Lymphoma

Alex F. Herrera, MD

The progression-free survival (PFS) benefit and manageable toxicity profile observed for nivolumab (Opdivo) plus doxorubicin, vinblastine, and dacarbazine (AVD) compared with brentuximab vedotin (Adcetris) plus AVD could help blend the treatment of both younger and older patients with advanced-stage Hodgkin lymphoma, according to Alex F. Herrera, MD.

Updated findings from the phase 3 S1826 trial (NCT03907488) showed that at a median follow-up of 2.1 years (range, 0-4.2), patients treated with nivolumab plus AVD (n = 487) achieved a 2-year PFS rate of 92% (95% CI, 89%-94%) vs 83% (95% CI, 79%-86%) for those given brentuximab vedotin plus AVD (n = 483; HR, 0.45; 95% CI, 0.30-0.65).¹

“These [updated] results are an important step toward harmonizing therapy for pediatric or adolescent and adult advanced-stage Hodgkin lymphoma. Overall, this is a practice-changing study,” Herrera explained in an interview with OncLive^®.

In the interview, Herrera provided background on previously reported data from SWOG S1826,2 detailed the updated findings with longer-term follow-up, and explained the clinical implications of this study.

Herrera serves as chief of the Division of Lymphoma in the Department of Hematology & Hematopoietic Cell Transplantation, associate medical director of the Briskin Center for Clinical Research, and an associate professor in the Division of Lymphoma in the Department of Hematology & Hematopoietic Cell Transplantation at City of Hope in Duarte, California.

OncLive: What data were previously reported from the SWOG S1826 trial?

Herrera: At the 2023 ASCO Annual Meeting and the 2023 International Conference on Malignant Lymphoma, we presented the primary results of SWOG S1826. This was a randomized phase 3 study comparing nivolumab plus AVD with brentuximab vedotin plus AVD, [which was] the prior standard, in patients with advanced-stage Hodgkin lymphoma.

The initial results demonstrated that nivolumab combined with AVD prolonged PFS compared with brentuximab vedotin plus AVD. At a median follow-up of [12.1 months], the one-year PFS [rate] in the nivolumab arm was 94% [95% CI, 91%-96%] compared with 86% [95% CI, 82%-90%] in the brentuximab vedotin arm [HR, 0.48; 99% CI, 0.27-0.87; 1-sided log-ranK P = .0005].

We also demonstrated that nivolumab plus AVD was better tolerated than brentuximab vedotin plus AVD. There were more treatment discontinuations in the brentuximab vedotin arm and more toxic adverse effects in general. We also]demonstrated that less than 1% of patients received consolidated radiation at the end of treatment, which was a big change from the prior standard [of care (SOC)] in adolescent patients with advanced-stage Hodgkin lymphoma.

What knowledge gaps did this study seek to address?

For decades, we have used chemotherapy as the SOC treatment for advanced-stage Hodgkin lymphoma. In some parts of the world, we've used ABVD [doxorubicin, bleomycin, vinblastine, and dacarbazine]; in other parts of the world, we've used BEACOPP [bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone], which is a regimen developed in Germany.

About a decade ago, brentuximab vedotin plus AVD became part of the SOC treatment of advanced-stage Hodgkin lymphoma. Brentuximab vedotin combined with AVD improved outcomes compared with ABVD. The downside was that brentuximab vedotin plus AVD led to more toxic effects [compared with] ABVD. Even though we got rid of bleomycin and the pulmonary toxicity we see with it, there was much more peripheral neuropathy associated with brentuximab vedotin plus AVD, [along with] was more febrile neutropenia, sepsis, and infections, and that necessitated the use of [granulocyte colony–stimulating factor], which we previously didn't use with ABVD. Although we had moderately improved outcomes with brentuximab vedotin in the frontline setting, there was certainly room to improve.

The other thing that we wanted to address was that the treatment of adult and pediatric advanced-stage Hodgkin lymphoma has been different for decades. Pediatricians have used different chemotherapy backbones and a high rate of radiation, even though patients had advanced-stage disease.

We wanted to improve outcomes in advanced-stage Hodgkin lymphoma, reduce toxic effects, and harmonize the treatment of adult and pediatric advanced-stage Hodgkin lymphoma. We adjusted the way that radiation was used in the trial with the intent of using less radiation, which is important in these young patients who are particularly susceptible to the late effects of radiation.

What was the design of the trial and baseline characteristics of the population being studied?

With the intent of harmonizing the pediatric and adult treatment of advanced stage, we enrolled patients under 18 years of age, [meaning] patients as young as 12 years of age could enroll, and that's different than any trial that we've done. We also didn't have an upper age limit. In many previous and other trials in advanced-stage Hodgkin lymphoma, there has been an upper age limit—that cutoff is often 60 years of age—because of the intensity of some of the chemotherapy that has been used. However, because nivolumab had been well tolerated, we were able to include patients of any age [if they were] 12 years of age or older. [Twenty-four percent of patients were] under 18 years of age, and 10% of patients were over 60 years of age.

The other important thing to [note] is that because this trial was conducted in [conjunction with] the North American cooperative groups, we enrolled a diverse population. Approximately 25% of patients were either Black or Hispanic, which [helped make this trial] representative of the demographics of our population in North America.

Lastly, we did include patients living with HIV, [who] are often excluded from clinical trials and certainly have been excluded from the initial clinical trials in Hodgkin lymphoma for these newer drugs. Otherwise, it was a representative study of patients with high-risk advanced Hodgkin lymphoma. It's important to note in terms of the outcomes that we observed that this was a patient population that was high risk.

What were the key long-term findings from the study?

When we presented our initial data, there was only 1 year of follow-up, and the intent of treating advanced-stage Hodgkin lymphoma is that you're going to cure the disease. Most recurrences with advanced-stage Hodgkin lymphoma occur within the first couple of years after therapy; therefore, we knew we needed to observe that the benefit from nivolumab plus AVD was sustained over time.

Now we have results with [2.1] years of follow-up, and the benefit of nivolumab plus AVD was sustained over brentuximab vedotin plus AVD. The 2-year PFS [rate for] nivolumab plus AVD was 92% compared with 83% for brentuximab vedotin plus AVD, and the HR [improved] at 0.45 [from 0.48].

When you look across the subgroups of patients enrolled in the study, nivolumab plus AVD improved PFS in all of those groups. That was reassuring to see. Not only was the benefit sustained, but it was sustained across the groups of patients that we enrolled in the study.

We also had final toxicity results. We did confirm that once the patients had completed therapy—there was still a small number of patients who had ongoing therapy during the primary analysis—there were more treatment discontinuations in the brentuximab vedotin plus AVD arm; 22.2% of patients discontinued brentuximab vedotin at some point during the treatment as opposed to 9.4% for nivolumab. Additionally, [26.7%] of patients had dose reductions of brentuximab vedotin.

Ultimately, we didn't see any new safety signals [with the nivolumab regimen]. What we presented [in primary analysis] in terms of toxic effects was similar to what we observed now that the whole cohort has completed therapy. We also confirmed that there was no additional use of radiation therapy; it remained less than 1% of patients who received radiation.

Did you observe any differences in the toxicity profile among different age groups?

We did notice some important differences in the safety results from the trial by age; however, it was in the brentuximab vedotin arm that we noticed that there was quite a bit more toxicity in the patients 60 years or older. [These patients] who were treated with brentuximab vedotin [experienced] quite a bit more febrile neutropenia, sepsis, and infections. The death rate, unfortunately, was quite high in patients over 60 years of age. The non-relapse mortality [in this group] was [approximately] 16%.

Historically, patients who are older have worse outcomes with this disease. When we [previously] compared older patients vs younger patients [treated] with AVD alone or in combination with brentuximab vedotin, we understood that older patients experienced more toxic effects and had poorer PFS. The fascinating thing about S1826 is that older patients treated with nivolumab plus AVD had similar outcomes to younger patients. Part of that was probably that it's better tolerated.

The relatively lower relapse and [beneficial] PFS rate is encouraging, and the safety in these patients is encouraging. It's an important result from the trial that brentuximab vedotin combined with AVD is not an appropriate therapy for older patients. It's toxic, hard to deliver, and associated with a high death rate, whereas nivolumab plus AVD is very well tolerated and [is an] effective therapy for those patients.

What are the implications and clinical significance of this study?

With longer follow-up of the SWOG S1826 study, we've demonstrated that nivolumab combined with the AVD is a new standard of care for advanced-stage Hodgkin lymphoma. Nivolumab plus AVD is more effective than brentuximab vedotin plus AVD. Nivolumab plus AVD is better tolerated than brentuximab vedotin plus AVD, [which was] confirmed with no new safety signals. Overall, there was a very low rate of radiation usage, which suggests that radiation is not an important part of the therapy of advanced-stage Hodgkin lymphoma when you use nivolumab plus AVD.

Are there any limitations that are important to note regarding this research?

[Several] important limitations of the study to note are that, with this disease, we want to have long-term follow-up; this was an important time point to present our data, and the longer follow-up confirmed that the initial results were consistent over time. [However], for younger patients that we typically enroll to these trials with advanced-stage Hodgkin lymphoma, we want to present longer-term follow-up, and we will continue to follow these patients. Overall survival data were not yet mature at this point in the study, and we will continue following patients to observe this over time to see whether results are different between the arms.

There are other important things that we are planning to look at in the future, such as different subgroup analyses and patient-reported outcomes [PROs]. We don't have those data yet to report. PRO data are important because [we showed] that physician-reported toxicities were different, but how did the patients perceive the effects of the treatment?

The subgroup analyses weren't specifically powered. When we determined the sample size, it was for the overall study. The caveat to some of these subgroup analyses is that those results weren't powered, and the sample size wasn’t [powered appropriately to show differences]. Otherwise, this is a crucial study for advancing how we treat advanced-stage Hodgkin lymphoma.

Are there any trials seeking to incorporate immunotherapy with nivolumab for early-stage Hodgkin lymphoma?

An important future direction that we want to remember with the treatment is thinking about how to incorporate immunotherapy with nivolumab into the treatment of early-stage Hodgkin lymphoma. Now that we have these results in advanced-stage Hodgkin lymphoma, and we've established a new standard of care, should we consider bringing these drugs to patients with early-stage Hodgkin lymphoma?

References

1. Herrera AF, LeBlanc M, Castellino SM, et al. Nivolumab+AVD in advanced-stage classic Hodgkin's lymphoma. N Engl J Med. 2024;391(15):1379-1389. doi:10.1056/NEJMoa2405888
2. Herrera AF, LeBlanc ML, Castellino s, et al. SWOG S1826, a randomized study of nivolumab-AVD versus brentuximab vedotin-AVD in advanced-stage classic Hodgkin lymphoma. J Clin Oncol. 2023;41(suppl 17):LBA4. doi:10.1200/JCO.2023.41.17_suppl.LBA4