Very early [18F]FDG-PET-guided targeted therapy in untreated advanced-stage classic Hodgkin lymphoma (EORTC-1537-COBRA): primary results of a single-arm, multicentre, phase 2 trial.
Brentuximab vedotin combined with doxorubicin, vinblastine, and dacarbazine (A-AVD) improves outcomes in advanced-stage classic Hodgkin lymphoma, but patients with a positive early interim PET have inferior prognosis. We evaluated whether very early [18F]fluorodeoxyglucose ([18F]FDG)-PET-guided treatment adaptation after one cycle of A-AVD improves activity while limiting exposure to intensive chemotherapy.
This single-arm, multicentre, phase 2 trial was conducted at 16 centres in seven countries (the Netherlands, Spain, Denmark, Belgium, Portugal, Slovakia, and Poland). Adults aged 18-60 years with previously untreated advanced-stage classic Hodgkin lymphoma, WHO performance status 0-2, and adequate organ function received one cycle of A-AVD (brentuximab vedotin 1·2 mg/kg intravenously, doxorubicin 25 mg/m2 intravenously, vinblastine 6 mg/m2 intravenously, and dacarbazine 375 mg/m2 intravenously, all on days 1 and 15), followed by centrally reviewed [18F]FDG-PET-CT (PET1). PET1-negative (Deauville score 1-3) patients received five additional A-AVD cycles; PET1-positive (Deauville score 4-5) patients switched to six cycles of BrECADD (brentuximab vedotin 1·8 mg/kg intravenously on day 1; etoposide 150 mg/m2 intravenously on days 2-4; cyclophosphamide 1250 mg/m2 intravenously on day 2; doxorubicin 40 mg/m2 intravenously on day 2; dexamethasone 40 mg orally on days 2-5; dacarbazine 250 mg/m2 intravenously on days 3-4). The primary endpoint was 2-year modified progression-free survival (mPFS), defined as the proportion of patients alive and free of progression, relapse, or death from treatment start, with initiation of new systemic therapy for persistent disease counted as an event. Analyses were prespecified and conducted in the evaluable population (registered and eligible patients, who commenced the allocated treatment according to PET1 results after 1 cycle of A-AVD). The safety population consists of all patients who started A-AVD treatment (ie, received at least one dose of study therapy). This is the primary analysis of a completed trial. This trial is registered on ClinicalTrials.gov (NCT03517137) and EudraCT 2017-000498-35).
From Aug 1, 2019, to Aug 31, 2021, we enrolled 150 patients (81 males [54%] and 69 females [46%]; median age 32 years [IQR 23-39]) who received one cycle of A-AVD, after which 90 (60%) of them had a negative PET1 and 60 (40%) a positive result. 145 were evaluable for efficacy; the median follow-up at the clinical cutoff (Sept 1, 2023; database lock Dec 11, 2023) was 30·1 months (IQR 24·6-36·4). 16 patients experienced an mPFS event. The estimated 2-year mPFS was 89·5% (80% CI 85·7-92·4). The most common grade 3-4 adverse event was neutropenia (53 [35%] of 150) followed by anaemia (18 [12%]) and peripheral sensory neuropathy (nine [6%]). Serious adverse events occurred in 45 (30%) of 150 patients. No deaths occurred.
Very early PET-guided intensification with BrECADD yields high activity in advanced-stage classic Hodgkin lymphoma while sparing most patients intensive chemotherapy.
Takeda Oncology.
This single-arm, multicentre, phase 2 trial was conducted at 16 centres in seven countries (the Netherlands, Spain, Denmark, Belgium, Portugal, Slovakia, and Poland). Adults aged 18-60 years with previously untreated advanced-stage classic Hodgkin lymphoma, WHO performance status 0-2, and adequate organ function received one cycle of A-AVD (brentuximab vedotin 1·2 mg/kg intravenously, doxorubicin 25 mg/m2 intravenously, vinblastine 6 mg/m2 intravenously, and dacarbazine 375 mg/m2 intravenously, all on days 1 and 15), followed by centrally reviewed [18F]FDG-PET-CT (PET1). PET1-negative (Deauville score 1-3) patients received five additional A-AVD cycles; PET1-positive (Deauville score 4-5) patients switched to six cycles of BrECADD (brentuximab vedotin 1·8 mg/kg intravenously on day 1; etoposide 150 mg/m2 intravenously on days 2-4; cyclophosphamide 1250 mg/m2 intravenously on day 2; doxorubicin 40 mg/m2 intravenously on day 2; dexamethasone 40 mg orally on days 2-5; dacarbazine 250 mg/m2 intravenously on days 3-4). The primary endpoint was 2-year modified progression-free survival (mPFS), defined as the proportion of patients alive and free of progression, relapse, or death from treatment start, with initiation of new systemic therapy for persistent disease counted as an event. Analyses were prespecified and conducted in the evaluable population (registered and eligible patients, who commenced the allocated treatment according to PET1 results after 1 cycle of A-AVD). The safety population consists of all patients who started A-AVD treatment (ie, received at least one dose of study therapy). This is the primary analysis of a completed trial. This trial is registered on ClinicalTrials.gov (NCT03517137) and EudraCT 2017-000498-35).
From Aug 1, 2019, to Aug 31, 2021, we enrolled 150 patients (81 males [54%] and 69 females [46%]; median age 32 years [IQR 23-39]) who received one cycle of A-AVD, after which 90 (60%) of them had a negative PET1 and 60 (40%) a positive result. 145 were evaluable for efficacy; the median follow-up at the clinical cutoff (Sept 1, 2023; database lock Dec 11, 2023) was 30·1 months (IQR 24·6-36·4). 16 patients experienced an mPFS event. The estimated 2-year mPFS was 89·5% (80% CI 85·7-92·4). The most common grade 3-4 adverse event was neutropenia (53 [35%] of 150) followed by anaemia (18 [12%]) and peripheral sensory neuropathy (nine [6%]). Serious adverse events occurred in 45 (30%) of 150 patients. No deaths occurred.
Very early PET-guided intensification with BrECADD yields high activity in advanced-stage classic Hodgkin lymphoma while sparing most patients intensive chemotherapy.
Takeda Oncology.
Authors
Hutchings Hutchings, Diepstra Diepstra, Sureda Balari Sureda Balari, Carvalho Carvalho, Vranovsky Vranovsky, Noordzij Noordzij, Loft Loft, Arens Arens, Teesink Teesink, Visser Visser, Stevens Stevens, Aleman Aleman, Woei-A-Jin Woei-A-Jin, Viguria Viguria, Saevels Saevels, Te Boome Te Boome, Tonino Tonino, Meijnders Meijnders, Domingo Domènech Domingo Domènech, Hasselbalch Riley Hasselbalch Riley, Musekera Musekera, Nuyens Nuyens, Mallien Mallien, Sents Sents, Bührer Bührer, Fortpied Fortpied, Plattel Plattel
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