Long-Term Data Spark Investigation of Brentuximab Combos in Hodgkin Lymphoma Subgroups

Ayad Hamdan, MD

The addition of the antibody-drug conjugate brentuximab vedotin (Adcetris) to the advanced Hodgkin lymphoma treatment paradigm is having a more widespread effect across patient subgroups, said Ayad Hamdan, MD.

Brentuximab vedotin was initially approved for the treatment of patients with Hodgkin lymphoma and systemic anaplastic large cell lymphoma in 2011. In March 2018, the approval was expanded to include for use in combination with chemotherapy in the first-line setting for patients with stage III/IV classical Hodgkin lymphoma (cHL), based on results of the phase III ECHELON-1 study.

Data from a 4-year follow-up of ECHELON-1, which were presented at the 2019 ASH Annual Meeting, demonstrated a 31% reduction in the risk of disease progression or death with the combination of brentuximab vedotin and doxorubicin, vinblastine, and dacarbazine (AVD) compared with ABVD (AVD plus vincristine). At a median follow-up of 48.4 months, the 4-year progression-free survival (PFS) rates were 81.7% (95% CI, 78.3-84.6) and 75.1% (95% CI, 71.4-78.4), in the brentuximab vedotin and ABVD arms, respectively.

“The follow-up data highlighted that this PFS advantage has continued and persisted, even at the 4-year mark,” explained Hamdan. “I tend to use A+AVD in patients who have stage IV disease, have an elevated Hasenclever International Prognostic Score, and do not have concerning comorbidities that would make them prone to neuropathy or neutropenia.”

Ongoing clinical trials are investigating brentuximab vedotin in combination with checkpoint inhibitors and chemotherapy for elderly patients with cHL and in patients with HIV-associated disease respectively, explained Hamdan.

In an interview during the 2020 OncLive^® State of the Science Summit^™ on Hematologic Malignancies, Hamdan, a hematologist and an associate professor of medicine at Moores Cancer Center at the University of California, San Diego, discussed the impact of the 4-year follow-up data from the ECHELON-1 trial in advanced-stage Hodgkin lymphoma.

OncLive: There was initial criticism regarding the modified PFS endpoint used in ECHELON-1. Is this follow-up sufficient to say that A+AVD is an accepted regimen in the frontline setting?

Hamdan: This is a good question, and I do think that A+AVD is an accepted regimen that can be used. The 4-year data support its use. My concern is more regarding the high rate of neuropathy that is associated with the use of brentuximab vedotin.

The 4-year follow-up, however, showed some significant improvement [in peripheral neuropathy], as well as some patients who had [complete] resolution. The updated data showed that the A+AVD arm had more neuropathy than the ABVD arm; however, it is reassuring to know that there has been resolution in a good number of patients.

Are there prophylactic strategies that can be used to manage neuropathy?

It does have to be monitored closely. Although the mechanisms of action are obviously different, we think about managing neuropathy [in Hodgkin lymphoma] the same way we think about managing neuropathy in other cancers.

[It is important] to be mindful of which patients may benefit [from brentuximab vedotin]. I would be hesitant to use A+AVD in a patient who has baseline neuropathy; however, A+AVD would be an option for patients who are healthy and do not have comorbidities.

What other factors help you determine which regimen to pursue for a particular patient?

That is an ongoing discussion that we have in our lymphoma tumor boards. In the United States, we have a lot of experience with ABVD; we have been using it for decades. It has good results, but we know that there are toxicities associated with it. At least right now, we have another regimen we can use that will provide a similar if not improved benefit.

Time will tell how the National Comprehensive Cancer Network (NCCN) guidelines will evolve to incorporate [brentuximab vedotin]. ABVD is still considered the preferred regimen regarding the NCCN guidelines, but A+AVD is absolutely an option in the frontline setting.

Combinations with brentuximab vedotin and checkpoint inhibitors are being looked at in clinical trials. What potential impact could those combinations have in this space?

In Hodgkin lymphoma, most patients are young; however, we have a subset of patients who are ≥60 [years old]. Historically, these patients have not done very well with ABVD. They tend to have more pronounced toxicities.

At the 2019 ASH Annual Meeting, there was an abstract presented regarding the use of brentuximab vedotin and nivolumab (Opdivo) for the treatment of patients ≥60 years old with advanced-stage cHL. Although the trial was small, the results are potentially encouraging and could provide an option for treating these patients.

Could you discuss the pilot phase I/II trial of brentuximab and chemotherapy for patients with HIV-associated HL?

It is a phase II AIDS Malignancy Consortium trial looking at using frontline A+AVD in patients who have cHL in the setting of HIV.

It also showed favorable outcomes in terms of PFS and overall survival; however, there was more concern about neuropathy with brentuximab vedotin given in combination with other antiretroviral medications.

Should patients with HIV infection be included in large randomized clinical trials?

I strongly feel that patients who have HIV infection that is well controlled should be included in all clinical trials. HIV status should not be an exclusion criterion.

What is the role of interim PET scanning with regard to the ECHELON-1 trial?

In advanced Hodgkin lymphoma, we definitely use interim PET scan to direct therapy or predict outcomes for patients. This is based on many large clinical trials that have demonstrated the prognostic importance of interim PET, or what we call PET2.

What is interesting about the ECHELON-1 study is that the results we have are regardless of PET2 status.

Could interim PET scans will become irrelevant since the ECHELON-1 results were irrespective of PET status?

It will absolutely still have a role, but that role is evolving. We just don't know how [yet]. As a clinician, it is something I think about when I have patients who are PET2-positive, but I am not sure what other alternatives I have [available] to give them.

When a patient is PET-positive, we need to biopsy them. If they still have disease and we don't escalate therapy, we should be worried about refractory disease that required more high-dose therapy.

Bartlett NL, Straus DJ, Dlugosz-Danecka M, et al. Brentuximab vedotin with chemotherapy for stage 3/4 classical Hodgkin lymphoma (cHL): 4-year update of the ECHELON-1 study. Presented at: 2019 ASH Annual Meeting; December 7-10, 2019; Orlando, FL. Abstract 4026.