Background: Addition of brentuximab vedotin (BV) to conventional chemotherapy for classical Hodgkin lymphoma (cHL) improves outcomes. In cHL patients <60 years treated in the experimental arm of the ECHELON-1 study all patients received 6 x A-AVD (brentuximab vedotin, doxorubicin, vinblastine, dacarbazine) regardless of early PET results. Three-year PFS was 87.2% in PET2 negative patients and 69.2% in PET2 positive patients. The COBRA trial investigated early PET-response adapted treatment in BV-based first line therapy, by intensification to BrECADD (brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone) in patients PETpositive after 1 cycle of A-AVD.
Methods: The primary endpoint of this phase II study was modified progression-free survival rate at two years from start of treatment (2y mPFS). All patients received 1 cycle of A-AVD followed by an early interim real-time centrally reviewed PET/CT scan (PET1). PET results were interpreted according to the Lugano criteria and Deauville scores 1-3 were defined as negative and scores 4 and 5 as positive. PET1-negative patients received an additional 5 cycles of A-AVD and PET1-positive patients switched to 6 cycles of BrECADD. Radiotherapy was applied only to PET-positive residual lesions. PET images were quantified using 3D Slicer with MUST-segmenter with SUV4 method as threshold to determine the metabolic tumour volume (TMTV). Serum TARC was analyzed before and during treatment using standardized ELISA with a pre-defined cut-off at 1000 pg/ml.
Results: Among 150 enrolled patients, PET1 was negative in 90 (60%) and positive in 60 (40%) after one cycle of A-AVD. Safety was in line with prior reports of A-AVD and BrECADD. The estimated rate of mPFS at 2 years was 89.5% (80% 2-sided exact CI: 85.7-92.4%). Two-year mPFS was 88.3% in PET1 negative patients and 91.3% in PET1 positive patients. Quantified PET1 results showed a clear decrease in MTV in all PET1 negative patients but also in the majority of PET1 positive patients, in line with TARC1 results.
Conclusion: Treatment adaptation based on a very early FDG-PET/CT leads to very high efficacy in advanced stage HL patients receiving BV-containing first-line treatment while sparing most patients intensive chemotherapy. Semiquantitative assessment of interim PET and/or TARC analysis enhances the positive predictive value of the early response assessment and can potentially further help reduce the treatment burden.
Martin Hutchings, Sophie Teesink, Anna Sureda-Balari, Susana Carvalho, Andrej Vranovsky, Walter Noordzij, Annika Loft, Anne I. J. Aarens, Wendy Stevens, Arjan Diepstra, Berthe M.P. Aleman, Sherida Woei-A-Jin, Maria Viguria, Kirsten Saevels, Liane Te Boome, Sanne Tonino, Paul Meijnders, Eva Domingo-Domènech, Caroline Hasselbalch Riley, Sarah Nuyens, Cedric Mallien, Ward Sents, Emanuel Buhrer, Catherine Fortpied, Wouter J. Plattel