A randomized, multi-country, prospective, open-label phase 3 study (HD21) funded by the German Hodgkin Study Group (GHSG) and supported by Takeda Oncology showed that BrECADD, a novel therapy combination including brentuximab vedotin (Adcetris®; Pfizer and Takeda), an anti-CD30 antibody-drug conjugate (ADC), combined with etoposide, cyclophosphamide, doxorubicin, dacarbazine, dexamethasone, cured classic Hodgkin lymphoma more effectively and with fewer side effects than the established standard of care, an intensive chemotherapy regimen of BEACOPP, a drug combination which includes bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone in patients with newly diagnosed Stage IIb/III/IV classical Hodgkin lymphoma.[1][2]

According to the International Agency for Research on Cancer, in 2020, over 83,000 people worldwide were diagnosed with Hodgkin lymphoma and approximately 23,000 people died from this cancer.

At a preplanned three-year analysis, the study met its co-primary endpoints, with the brentuximab vedotin combination regimen demonstrating significantly improved safety as assessed by treatment-related morbidity (TRMB) and non-inferior PFS.

The study found that the addition of brentuximab vedotin to this chemotherapy regimen improved the risk-to-benefit profile of the combination treatment, maintaining efficacy with significantly fewer acute and long-lasting treatment-related toxicities than the comparator arm.

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“We initiated the HD21 trial with the hope of improving outcomes currently being achieved by a standard of care, as many patients with newly diagnosed disease often experience a high treatment burden,” said Peter Borchmann, MD, PhD, University Hospital of Cologne, Germany, and trial chairman of the HD21 study.

“The presented analysis, in which the brentuximab vedotin regimen demonstrates superior progression-free survival, as well as a tolerable safety profile, reveals the meaningful potential this brentuximab vedotin + ECADD regimen has to offer these patients.”

In the GHSG HD21 trial, 742 patients were randomized to receive BrECADD and 740 to receive BEACOPP. The age of the participating patients averaged 31 years of age, and 7 of every 10 patients were younger than 40 years of age.

The ASCO presentation provides details of a four-year PFS analysis of the HD21 study conducted by GHSG. After 48 months, BrECADD showed superior efficacy to BEACOPP (94.3% PFS for BrECADD and 90.9% PFS for eBEACOPP; hazard ratio “HR”: 0.66 [95% CI:88.7-93.1]; p<0.035).

In earlier reports the three-year analysis, treatment with BrECADD was also associated with a significant reduction in the incidence of treatment-related morbidity (TRMB) compared with BEACOPP (n=738; 42% vs 59%; p<0.001), as well as clinically meaningful reductions in adverse events (AEs).

The safety profile of brentuximab vedotin in patients receiving BrECADD remained consistent with other approved brentuximab vedotin combination regimens, and no new safety signals were identified.

“In our ongoing effort to improve outcomes for patients with lymphoma, we’ve partnered with the GHSG on the HD21 study to deepen our understanding of how brentuximab vedotin could further benefit patients in need of new options,” said Awny Farajallah, chief medical officer, global oncology at Takeda.

The outcome of the study will be presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, taking place May 31-June 4 in Chicago, Illinois.

Old vs New
“Classic Hodgkin lymphoma can be cured with chemotherapy in most patients. However, the cure is accompanied by the cost of acute, chronic, and sometimes long-lasting severe side effects. With this new BrECADD regimen, we aimed to improve the balance of risks and benefits of effective systemic treatment,” explained the study’s lead author Peter Borchmann, MD, University Hospital of Cologne, and Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf and German Hodgkin Study Group.[2]

The researchers used positron-emission tomography to help decide whether to give patients four or six cycles of treatment. If the cancer responded well to the treatment as shown by relatively cancer-free PET scans after two cycles, then fewer cycles of treatment would be given. If the cancer did not respond to treatment, more cycles would be given.

Important Findings

  • At 4 years follow-up, 430 patients (64%) receiving BrECADD and 430 patients (64%) receiving BEACOPP were eligible for fewer treatment cycles.
  • The progression-free survival was 94.3% for BrECADD and 90.9% for BEACOPP, while overall survival was 98.5% for BrECADD and 98.2% for BEACOPP.
  • Most significantly, people in the BrECADD group had a 34% lower risk of disease progression than those in the BEACOPP group. Most of the patients (64%) who were in the BrECADD group finished their treatment in four cycles (about 3 months).
  • Researchers also compared levels of follicle-stimulating hormone (FSH), which plays an important role in sexual development and fertility, in patients after treatment.
    • In men, FSH recovery rates were 67% in the BrECADD group and 24% in the BEACOPP group (FSH cut-off 12.4 U/l). In women, FSH recovery rates were 89% i the BrECADD group and 68% in the BEACOPP group (FSH cut-off 21.5 U/l).
    • There were 60 babies born in the BrECADD group, compared to 43 babies born in the BEACOPP group.

Adverse events
The most common side effects were abnormal blood cell counts. The researchers found that severe blood-related side effects arose in 31% of people in the BrECADD group and 52% of people in the BEACOPP group. Patients receiving BrECADD required fewer transfusions of red blood cells and platelets. Side effects that were not blood-related were less frequent in both groups (19% for BrECADD and 17% for BEACOPP). Most serious side effects went away after one year.

What’s Next
The researchers plan to explore ways to make the treatment more effective without causing more side effects. This could increase the number of patients who would only require four cycles of treatment. They are evaluating adding PD-1 inhibitors to the BrECADD regimen.

Clinical trial
HD21 for Advanced Stages – ClinicalTrials.gov ID NCT02661503

Highlights of prescribing information
Brentuximab vedotin (Adcetris®; Pfizer and Takeda)[Prescribing Information]

Conference presentation
This data will be presented as a late-breaking oral presentation at the 60th American Society of Clinical Oncology (ASCO) Annual Meeting (LBA7000) and at the 29th European Hematology Association (EHA) Annual Meeting (S225).

[1] Damaschin C, Goergen H, Kreissl S, Plütschow A, Breywisch F, Mathas S, Meissner J, Sökler M, Topp MS, Vucinic V, Zimmermann A, von Tresckow B, Fuchs M, Engert A, Borchmann P, Eichenauer DA. Brentuximab vedotin-containing escalated BEACOPP variants for newly diagnosed advanced-stage classical Hodgkin lymphoma: follow-up analysis of a randomized phase II study from the German Hodgkin Study Group. Leukemia. 2022 Feb;36(2):580-582. doi: 10.1038/s41375-021-01386-z. Epub 2021 Aug 18. PMID: 34408266; PMCID: PMC8807388.
[2] Eichenauer DA, Plütschow A, Kreissl S, Sökler M, Hellmuth JC, Meissner J, Mathas S, Topp MS, Behringer K, Klapper W, Kuhnert G, Dietlein M, Kobe C, Fuchs M, Diehl V, Engert A, Borchmann P. Incorporation of brentuximab vedotin into first-line treatment of advanced classical Hodgkin’s lymphoma: final analysis of a phase 2 randomised trial by the German Hodgkin Study Group. Lancet Oncol. 2017 Dec;18(12):1680-1687. doi: 10.1016/S1470-2045(17)30696-4. Epub 2017 Nov 10. PMID: 29133014.

Featured image:General views of the Annual Meeting of the American Association of Clinical Oncology (ASCO) – held in the McCormick Place in Chicago, Ill. Courtesy: © 2023 – 2024 ASCO/David Eulitt. Used with permission.

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