Amplifying Responses With ADCs and Checkpoint Inhibitors in Hodgkin Lymphoma

Matthew G. Mei, MD

Doxorubicin, belomycin, vinblastine, and dacarbazine (ABVD) and doxorubicin, vinblastine, and dacarbazine (AVD) plus brentuximab vedotin (Adcetris; A+AVD) are both viable frontline treatment options for patients with advanced-stage Hodgkin lymphoma, said Matthew G. Mei, MD, and the decision between the two can be based on the extent of disease and, potentially, cost.

“Frontline treatment of patients with advanced-stage Hodgkin lymphoma comes down to deciding whether to use ABVD or A+AVD,” said Mei. “However, it’s hard to go wrong with either one. Both regimens are recommended by the National Comprehensive Cancer Network.”

Although ABVD had been the preferred standard of care in the frontline setting, treatment with A+AVD led to a 23% reduction in the risk of progression, death, or initiation of new therapy compared with ABVD in the phase III ECHELON-1 trial.¹ These results served as the basis for the regimen’s FDA approval in March 2018 for patients with stage III/IV classical Hodgkin lymphoma. Furthermore, 3-year follow-up data of the study showed a sustained PFS benefit favoring A+AVD (HR, 0.70; 95% CI, 0.55-0.90; P = .005).²

According to the subset analysis, the benefit of A+AVD was even more evident among patients with stage IV disease, multiple extranodal sites, and a higher international prognostic score. Whether the regimen should be restricted to such patients given its cost remains an area of debate.

“People have pointed out that A+AVD is significantly more costly than ABVD,” said Mei. “That is a [challenge]. At the same time, brentuximab vedotin does appear to decrease the need for salvage therapy and autologous transplant, which could offset some of the cost issues.”

Moreover, researchers are actively exploring antibody—drug conjugates (ADCs) and checkpoint inhibitors, the latter of which have shown encouraging single-agent activity.

In an interview during the 2019 OncLive^® State of the Science Summit^™ on Hematologic Malignancies, Mei, a hematologist/ oncologist and assistant clinical professor in the Department of Hematology & Hematopoietic Cell Transplantation, City of Hope, discussed current considerations in the frontline management of advanced-stage Hodgkin lymphoma as well as ongoing investigations with checkpoint inhibitors and cellular-based therapy.

OncLive^®:What does the treatment landscape look like for stage III Hodgkin lymphoma?

Mei: In the United States, we tend not to use BEACOPP (bleomycin, etoposide, doxorubicin hydrochloride, cyclophosphamide, vincristine, procarbazine, and prednisolone) in the frontline setting. The treatment landscape for the relatively fit patient with stage III disease really boils down to ABVD versus A+AVD. I don’t believe we’re completely settled on which one to use. Both regimens are viable options. Practically speaking, every patient will get 1 of those 2 regimens, provided they don’t have prohibitive comorbidities.

Could you expand on the use of A+AVD following the results of the ECHELON-1 trial?

The phase III ECHELON-1 trial was designed to see whether the bleomycin in ABVD could be substituted with brentuximab vedotin. ABVD has been the standard of care for decades; however, bleomycin is probably the least effective of the 4 drugs in ABVD. Brentuximab vedotin has fantastic activity, even as a single agent, in relapsed/refractory disease. Treatment with A+AVD resulted in about a 5% improvement in the prespecified endpoint of modified progression-free survival (PFS) compared with ABVD. No real overall survival (OS) benefit was seen with A+AVD. However, OS was very high in both arms. At 3 years of follow-up, the investigator-assessed PFS showed a 7% [improvement with A+AVD].

What are some emerging agents to look out for?

The next thing we’ll be looking at is the incorporation of checkpoint inhibitors into the frontline setting, as well as the incorporation of brentuximab vedotin into [the treatment of] earlier-stage disease. Smaller trials have looked at the role of brentuximab vedotin consolidation in early-stage disease in lieu of radiation therapy. Right now, a large trial is underway comparing A+AVD with AVD plus nivolumab (Opdivo) to see which one is better.

What is the work being done with checkpoint inhibition?

We know that [certain] drugs, such as nivolumab and pembrolizumab (Keytruda), are incredibly effective in Hodgkin lymphoma, with very high single-agent response rates. These responses often span for years, as opposed to the months seen with salvage chemotherapy. However, none of us are convinced that checkpoint inhibitors by themselves are curative for relapsed Hodgkin lymphoma. We need to study how to best incorporate them into earlier-line settings and perhaps use them as a bridge to autologous transplant; this captures some of the work we’ve been doing at City of Hope.

What research is being done with CAR T-cell therapy and ADCs in this space?

People have been looking at CD30-directed CAR T cells. Brentuximab vedotin is a CD30- directed ADC. Work is being done with CD25-directed ADCs, which have shown some responses in very heavily pretreated populations. Other targets and immunotherapies are being looked at in the field as well.

[The CD25-directed ADC] is still early in testing. CD25 is another antigen that is frequently expressed on the Reed— Sternberg cell. Preliminary data show significant responses with moderate toxicity. As such, that agent can potentially be an option for some of our more refractory patients.

What are some of the recent developments in stage IV Hodgkin lymphoma?

The big development in stage IV and stage III disease is the SWOG S1826 trial that recently opened. That trial is looking at A+AVD versus AVD plus nivolumab. It’s a very simple head-tohead trial to see which regimen is superior. We’re all [excited] to enroll our patients on it and are eagerly awaiting the results.

What challenges remain in the space?

We could do a better job of curing all stages of disease—especially advanced-stage Hodgkin lymphoma. Even with A+AVD, we still aren’t curing everyone. Significant toxicities are still experienced with treatment. Peripheral neuropathy is an issue, not just with A+AVD, but also with ABVD.

References

1. Connors JM, Jurczak W, Straus DJ, et al. Brentuximab vedotin plus doxorubicin, vinblastine, dacarbazine (A+AVD) as frontline therapy demonstrates superior modified progression-free survival versus ABVD in patients with previously untreated stage III or IV Hodgkin lymphoma (HL): the phase 3 ECHELON-1 study. Blood. 2017;130(suppl 1; abstr 6). bit.ly/2kpr2VN.
2. Straus DJ, Długosz-Danecka M, Alekseev S, et al. Brentuximab vedotin with chemotherapy for stage 3/4 classical Hodgkin lymphoma: three-year update of the ECHELON-1 study. J Clin Oncol. 2019;37(15 suppl; abstr 7532). doi: 10.1200/JCO.2019.37.15_suppl.7532.