BrECADD Proves Noninferior to eBEACOPP in Advanced Classical Hodgkin Lymphoma

The BrECADD combination comprised of brentuximab vedotin (Adcetris), etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone had noninferior efficacy and superior tolerability compared with escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) in patients with advanced classical Hodgkin lymphoma, according to data from the phase 3 HD21 trial (NCT02661503) presented at the 17th International Conference on Malignant Lymphoma.1

At a median follow-up of 40 months, the estimated 3-year progression-free survival (PFS) rate with BrECADD (n = 740) was 94.9% (99% CI, 92.8%-97.1%) vs 92.3% (99% CI, 89.7%-94.9%) with eBEACOPP (n = 742) in the intention-to-treat (ITT) population (n = 1482; HR, 0.63; 99% CI, 0.37-1.07). The 1-year PFS rate with BrECADD was 97.5% (99% CI, 96%-99%).2 The estimated 3-year overall survival (OS) rate was 98.5% in both the BrECADD and eBEACOPP arms.¹

“These mature survival results demonstrate that individualized treatment with PET2-guided BrECADD is the most effective therapy currently available for advanced stage classical Hodgkin lymphoma,” said Peter Borchmann, MD, trial chairman and assistant medical director in the Department of Hematology and Oncology at the University Hospital of Cologne, Germany, in a presentation of the data during a late-breaking session. “HD21 thus sets a new benchmark for the primary cure rate in [this disease].”

The trial, which was coordinated by the clinical research cooperative German Hodgkin Study Group (GHSG), enrolled patients with newly diagnosed classical Hodgkin lymphoma who had stage IIB disease with large mediastinal mass and/or extranodal lesions, stage III, or stage IV disease.1,3 Patients were between the ages of 18 years and 60 years.¹

Study participants were randomly assigned 1:1 to received PET2-guided BrECADD or eBEACOPP for 4 to 6 cycles. PET2 and PFS events were examined by blinded panel review, and noninferiority of the primary efficacy end point of PFS was defined as having an absolute difference of less than 6% at 5 years, which equated to a HR of less than 1.69 for BrECADD compared with eBEACOPP.

“A point estimate of HR bound of less than 1.02 would show statistical significance of noninferiority and termination of the trial for efficacy,” added Borchmann, who is also the head of the Lymphoma Program and head of the GHSG.

A total of 1500 patients were enrolled at 233 clinical trial sites spanning 9 countries. Of the 1500 patients, 749 were randomly assigned to eBEACOPP and 751 were assigned to BrECADD. Nine patients in each arm were excluded because their disease was not confirmed by pathology review. Thus, the ITT populations for the investigative and control arms were comprised of 740 and 742 patients, respectively.

The demographic and patient characteristics at baseline were well balanced, according to Borchmann. The median age was 34 years in both the BrECADD and eBEACOPP arms (range, 18-61) and most patients had an ECOG performance status of 0 (68% vs 70%, respectively) and B symptoms (68% vs 67%). Regarding histology, 53% vs 48% of patients had subtype nodular sclerosis. Across the arms, 46.5% of patients had high-risk disease, with an international prognostic index of at least 3.

“When we look at efficacy, the number of treatment cycles given in a PET-adaptive design could influence outcome,” Borchmann noted. “That’s why we looked at the CR rates, the metabolic remissions after 2 cycles and the preplanned and administered treatment.”

Four out of the 4 planned cycles were received by 57.3% of those in the BrECADD arm and 57.7% of those in the BECAOPP arm. “It’s [almost] exactly the same,” Borchmann said. Moreover, 6 out of the 6 planned cycles of treatment were received by 38.3% and 37.6% of patients, respectively. “There are very few patients who received more cycles or less cycles than planned,” he added.

Consolidative radiotherapy was recommended by blinded central review for 16.6% of those in the BrECADD arm and 17% of those in the eBEACOPP arm; 13.8% and 15.1% of patients, respectively, actually received this treatment.

When looking at PFS events, Borchmann noted that 4.3% of those in the BrECADD arm and 7.4% of those in the eBEACOPP arm experienced progression or relapse. Progression rates were 0.7% and 1.9%, respectively. Additionally, 1.5% and 3.1% of patients, respectively, had early relapse; 2.2% and 2.4% of patients, respectively, had late relapse, occurring after 1 year. Investigators also accounted for death without prior progression or relapse (n = 7 vs n = 6). A total of 39 PFS events were reported in the BrECADD arm and 61 PFS events were reported in the eBEACOPP arm.

“Coming to the test for noninferiority, what we see is a bit more complicated because its an interim analysis. The hazard ratio of 1.02 should not be met…We observed a [hazard ratio] of 0.63…noninferiority is fully established…,” Borchmann said. “Obviously, if you have such a good hazard ratio, you would like to know if there is superiority. We can test it with a 99% confidence interval because it’s an interim analysis, and you see it ranges from 1.07 to 0.37. It just misses significance but indicates a very strong trend toward superiority; [this] needs to be determined in the final analysis with a 95% confidence interval.”

Regarding causes of death, 2 patients in the BrECADD arm and 1 patient in the eBEACOPP arm died from Hodgkin lymphoma. Some patients in the eBEACOPP arm had treatment-related mortality. “We do not see [this] with BrECADD,” Borchmann noted. Hodgkin lymphoma and treatment-specific mortality with BrECADD is 0.26% at a median follow-up of 40 months, “which is extremely low,” according to Borchmann.

Twelve-month post-treatment safety findings proved to be consistent with what was previously reported with the regimens at the 2022 ASH Annual Meeting.²

“[There is an] excellent risk-benefit ratio observed with BrECADD; it is not only more active, it is better tolerated,” Borchmann concluded. “[Thus,] the HD21 trial defines a new standard of care within the GHSG for adult patients with newly diagnosed advanced stage classical Hodgkin lymphoma.”

Editor’s Note: Dr Borchmann disclosed that he serves in an advisory position or has expert activity with Takeda Oncology, Bristol Myers Squibb, Roche, Amgen, Novartis, Celgene, Miltenyi Biotech, Gilead, and Incyte. He also received honoraria from Takeda Oncology, Novartis, Bristol Myers Squibb, Roche, MSD, Celgene, Miltenyi Biotech, Gilead, AbbVie, and Incyte. Scientific research funding was provided by Takeda Oncology, MSD, Novartis, and Incyte.

References

1. Borchmann P, Moccia Al, Greil R, et al. BrECADD is non-inferior to eBEACOPP in patients with advanced stage classical Hodgkin lymphoma: efficacy results of the GHSG phase III HD21 trial. Hematol Oncol. 2023;41(suppl 2):881-882. doi:10.1002/hon.3196_LBA5
2. Phase 3 trial of Adcetris (brentuximab vedotin) with modified chemo regimen shows non-inferiority with unprecedented 3-year progression free survival of 94.9% vs less tolerable international standard of care in advanced classical Hodgkin lymphoma. News release. Seagen Inc. June 20, 2023. Accessed June 21, 2023. https://investor.seagen.com/press-releases/news-details/2023/Phase-3-Trial-of-ADCETRIS-brentuximab-vedotin-with-Modified-Chemo-Regimen-Shows-Non-Inferiority-with-Unprecedented-3-Year-Progression-Free-Survival-of-94.9-vs-Less-Tolerable-International-Standard-of-Care-in-Advanced-Classical-Hodgkin-Lymphoma/default.aspx
3. HD21 for advanced stages. ClinicalTrials.gov. Updated August 8, 2022. Accessed June 21, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT02661503