Antibody Drug Conjugates for the Frontline Treatment of Patients With Advanced-Stage Hodgkin Lymphoma

Andrew Evens, DO, MBA, MSc, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey analyzes recent advancements in the frontline treatment of patients with advanced-stage Hodgkin lymphoma through the integration of antibody drug conjugates at the 2023 Great Debates & Updates in Hematologic Malignancies meeting in Boston, Massachusetts. 

Dr Evens discusses the outcomes of multiple trials in Hodgkin lymphoma, including AETHERA, ECHELON-1, and [Southwest Oncology Group] (SWOG) S1826, and how they add to the current treatment landscape.

Transcript: 

Hi. My name is Dr. Andy Evens. I'm at the Rutgers Cancer Institute of New Jersey, and I'm happy to be here at the Great Debates and Updates in Hematologic Malignancies in Boston, Massachusetts.

The talk that I gave was on the integration and use of antibody drug conjugates in Hodgkin lymphoma (HL). There's really been a robust amount of data that's been presented and published over the last few years, including in the last few months in this space. The first starts with the first and most prominent approved agent in this space, which is brentuximab vedotin. 

We know now it's been FDA-approved for over 10 years, for relapsed/refractory Hodgkin lymphoma after an autologous transplant, or not amenable to a transplant. But over time, as many novel therapeutics do, they work their way up toward the frontline setting. It garnered approval for post-transplant maintenance vis-à-vis the AETHERA study.

Ultimately, a large, more than 1300 [patient] randomized phase 3 study, the ECHELON-1 study, was published in January of 2018 in the New England Journal [of Medicine] for front-line advanced-stage Hodgkin lymphoma. In that study, it [brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine] (AAVD) was compared to classic [doxorubicin, bleomycin, vinblastine, and dacarbazine] (ABVD). When I say classic ABVD, that means 6 cycles of ABVD given in its usual form or fashion. We forget that, especially in the 1980s, 1990s, and even into the early 2000s, we didn't have novel therapeutics in the field. So, they used a different combo of chemotherapy agents. But really, ABVD had been the standard for almost 20 years, at least in the United States and many other countries.

[These treatments] went head-to-head. The study design was very straightforward and had a 1:1 randomization to ABVD or [brentuximab vedotin] (Adcetris), instead of bleomycin. Adcetris is the trade name for brentuximab vedotin. So, it was AAVD. That initial report, which garnered FDA approval in 2018, was a progression-free survival (PFS) improvement.

 I think it wasn't widely adopted initially, because there was some increase in toxicity, namely, neutropenic fever and peripheral neuropathy. But, it was FDA-approved. But what happened over time was important, and we needed to see [if] that PFS advantage persisted over time, and did those curves not come together?

The good news is, yes, [PFS] not only persisted—if anything, [the curves] came apart a bit more. Generally speaking, [this] led to a relative risk reduction or improvement in PFS of about 30%. The real game changer—-and I'll use the word landmark breakthrough, in the field, and specifically, this study—was the improvement in overall survival (OS). That was reported last year in the New England Journal [of Medicine] by Steve Ansell [Stephen Ansell, MD, PhD, Mayo Clinic) and colleagues. I was fortunate to be one of the co-authors of that [study]. 

At 6 years, [this treatment] showed an improvement in overall survival. That absolute improvement was 4.5%. In other words, going from 89.4% to 93.9% might not sound a lot, but it's a lot through 2 lenses. Lens number 1 is, that [is] a relative risk reduction, or another way to say a decreased risk of death, by more than 40%, [in] patients treated with AAVD versus classic ABVD.

Number 2 is [that] it is the first study to show an overall survival advantage, not just in the last 20 years, [but] ever, versus classic ABVD. It had [never] been shown. There have been over 15 studies trying to show that benefit.
It's difficult in Hodgkin lymphoma—we know we can salvage patients, even before novel therapeutic, take them to give them new chemotherapy, take them to an autologous transplant, et cetera. That sets a new standard, a new watermark so to speak, in terms of progression-free survival. Now to say—and we'll see if we can ever replicate it, I hope we can— [we are] moving the bar on overall survival. That really was an important update.

We're never satisfied, not just in Hodgkin lymphoma, but any cancer. Whatever the PFS, whatever the overall survival, we always want to take it higher, and of course, do it with [fewer] side effects, whether acute side effects or long-term side effects. 

How is that going to happen? It's probably going to happen through the integration of novel therapeutic agents. Hot off the press—meaning a couple [of] months ago—a [United States] cooperative group study called S1826, led by SWOG involved not only all the adult cooperative groups, [but] also involved the Children's Oncology Group and [National Citizen's Inquiry] NCI Canada.

That was a randomized study, designed in 2018. Thankfully, we had the foresight—in particular, Dr. Friedberg [Jonathan W. Friedberg, MD, MMSc, University of Rochester Medical Center] [and] Dr. Herrera [Alex Francisco Herrera, MD, City of Hope National Medical Center]—had the foresight to really say the standard of care arm, this is in 2018, would be ECHELON-1. In other words, the AAVD arm. What was the experimental arm? It was nivo, [or] nivolumab, PD-1 blockade, plus AVD. Again, [this is an] advanced stage study, [randomized 1:1] [with] almost 1000 patients, that finished accrual last year. 

We thought it was going to be a couple of years before we would see a report out and data. I'll say, we were surprised when alerted by the SWOG Data Safety Monitoring Committee, that already at 1 year, there was a significant difference in outcomes. That difference was nivo-AVD at 1 year—yes, an early time point— had an absolute improvement, or benefit in PFS, of 8 percentage points.

Generally speaking, [it] was better tolerated. There were a couple of signals—there weren't many immune side effects. There was some hypothyroidism, but no difference in [liver function tests] (LFTs), no difference in colitis, pneumonitis, et cetera, between the 2 arms. Maybe not surprisingly, there was more neuropathy on the AAVD arm.

It's early. It was just presented by Dr. Herrera at the plenary session at ASCO. We'll start to see more data and of course, we want that data to mature. There will be, hopefully, an impactful publication in the near future, based [on] the main study.

Like any study, once, of course, that's published, we want to start to look at subgroups. Because Hodgkin lymphoma, like every cancer, is not one disease, you have different populations. One is based on age. Because pediatric oncology colleagues were included, this included patients down to ages 12 and above. And when I say above, there was no upper age limit. Why? Because [bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisolone] (BEACOPP) was not part of it, that really intense regimen. Usually, once BEACOPP is included, even if it was [the] baseline, we'll not want to enroll patients over age 60. But, since it was just the nivo-AVD and BV-AVD, there was no upper age limit, and 10% of patients were over age 60.

It'll be very interesting to see [if there] is any differential efficacy difference or tolerability between those 2 regimens. It's really just an exciting time, and this is just newly diagnosed Hodgkin lymphoma. Obviously, there's plenty of activity, clinical trials, and other work being done, in terms of relapsed/refractory disease. 

Source: 

Evens A. Antibody Drug Conjugates – Where and When to Use Them in Hodgkin Lymphoma. Presented at the Great Debates and Updates in Hematologic Malignancies Meeting; August 17-19; Boston, Massachusetts.