Source – BrECADD
According to information from the Phase III HD21 trial (NCT02661503), which included patients with advanced classical Hodgkin lymphoma, the BrECADD combination of brentuximab vedotin (Adcetris), etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone had noninferior efficacy and superior tolerability compared with escalated
In the intention-to-treat (ITT) population (n = 1482; HR, 0.63; 99% CI, 0.37-1.07), the estimated 3-year progression-free survival (PFS) rate with BrECADD (n = 742) was 92.3% (99% CI, 89.7%-94.9%) compared to 94.9% (92.8%-97.1%) with eBEACOPP (n = 742). BrECADD had a 1-year PFS rate of 97.5% (99% CI, 96%-99%).
“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 this sets a new benchmark for the primary cure rate in this disease.”
Patients with newly discovered stage IIB illness with a large mediastinal mass and/or extranodal lesions, stage III, or stage IV disease of classical Hodgkin lymphoma were included in the experiment, which was run by the clinical research consortium German Hodgkin Study Group (GHSG). The age range of the patients was from 18 to 60.
For 4 to 6 cycles, study participants were randomly allocated 1:1 to receive either eBEACOPP or PET2-guided BrECADD. Blinded panel evaluation of PET2 and PFS events was conducted, and noninferiority of the key efficacy end point of PFS was determined to be an absolute difference of less than 6% at 5 years, which translated to an HR of less than 1.69 for BrECADD in comparison to 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,” stated Borchmann, who is also the director of the Lymphoma Programme and the head of the GHSG.
At 233 clinical trial locations in 9 different countries, a total of 1500 participants were enrolled. Of the 1500 patients, 749 were chosen at random to receive eBEACOPP, and 751, BrECADD. Nine individuals from each arm were eliminated because a pathology evaluation did not confirm their illness. As a result, there were 740 and 742 patients in the ITT populations for the investigative and control arms, respectively.
According to Borchmann, the baseline demographic and patient variables were evenly distributed. The majority of patients had an ECOG performance level of 0 (68% vs 70%, respectively) and B symptoms (68% vs 67%), and the median age was 34 years in both the BrECADD and eBEACOPP groups (range, 18-61). In terms of histology, nodular sclerosis subtype was seen in 53% vs. 48% of individuals. 46.5% of patients had a high-risk condition across all arms, with an international prognostic score of at least 3.
Out of the 122 lymphoma patients screened, 39 (34%) were found to have TRBC1-positive disease. However, 20 of these patients did not enroll in the trial due to various reasons such as death, screening failure, disease progression, and other factors. So far, 19 patients have enrolled in the trial, out of which 13 have been treated. The remaining 6 enrolled patients were either awaiting treatment or discontinued the trial before receiving the treatment.
“We haven’t detected CAR in the majority of our patients’ [blood], but we have in the lymph nodes,” Cwynarski noted during the presentation. “The question is: Is this due to fast homing of the CARs to the tumor sites? We have ongoing work to assess persistence as well as the potential of T-cell fratricide.”
The trial involves two manufacturing processes, referred to as Process A and Process B. In Process A, frozen leukapheresis samples underwent TRBC1-positive cell depletion, followed by T-cell activation, transduction, and expansion to produce cryopreserved CAR-positive T cells. In Process B, frozen or fresh leukapheresis samples were subjected to TRBC1-positive cell depletion, CD4/8-positive cell selection, T-cell activation, transduction, and expansion to produce cryopreserved CAR-positive T cells.
In the dose escalation phase of the trial, patients received a pre-conditioning regimen before treatment. Process A dosed 10 patients across four cohorts with varying doses of AUTO4. Process B has only treated three patients so far.
The primary endpoint of the trial is safety, while secondary endpoints include overall response rate, duration of response, progression-free survival, and overall survival.
As of the data cutoff date of April 28, 2023, the median age of the patients across both processes was 57 years. Most patients had an ECOG performance score of 1, and they had received a median of 2 prior lines of therapy. The majority of patients had stage III/IV lymphoma at screening, with various subtypes represented. Prior autologous stem cell transplant had been received by a small portion of patients, and the majority had undergone bridging therapy. CD30-positive T-cell non-Hodgkin lymphoma was prevalent in the patient population, with some patients having received brentuximab vedotin as prior or bridging therapy.
In Process A, CAR presence was detected in the blood of two patients, and lymph node samples from five patients confirmed CAR presence. Among the patients enrolled in Process A, some achieved a complete response (CR) or partial response (PR), while others experienced progressive disease (PD).
At a median follow-up of 13.8 months, 80% of the patients in Process A were alive, and all patients who received the highest dose of AUTO4 achieved a response. The presentation also included case studies showcasing positive outcomes in individual patients with AITL who received AUTO4 treatment.
