Australasian Leukaemia & Lymphoma Group NHL35-Pacific: An Open Label Phase II Study of Pembrolizumab and Chemo-Immunotherapy As First-Line Therapy for Primary Mediastinal B-Cell Lymphoma - Trial in Progress

• Published in: Blood 2023-11, Vol.142 (Supplement 1), p.3103-3103
• Main Authors: Lewis, Katharine L., Blombery, Piers, Sungala, Nagendra Prasad, Ma, Chun Kei Kris, Giri, Pratyush, Vanguru, Vinay, Cochrane, Tara, Czerwinski, Joanna Katarzyna, Lee, Denise, Hamad, Nada, Francis, Roslyn, Walia, Mannu, Carlson, Julia, Butcher, Belinda E, Cheah, Chan Y.
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2023-185160

Background: Primary Mediastinal B-cell Lymphoma (PMBL) comprises 10% of Diffuse large B-cell lymphoma (DLBCL), primarily affecting young adults. Combination chemoimmunotherapy with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisolone (R-CHOP) is effective, however up to 10-20% of patients may have either refractory disease or experience relapse within 12 months of completing treatment. Consolidative radiotherapy has often been used following R-CHOP, with retrospective data suggesting a survival benefit compared with R-CHOP alone. However, mediastinal radiotherapy increases risk of breast cancer and cardiovascular disease and the recently reported randomised IELSG37 study demonstrated no improvement in progression free survival (PFS) with the use of consolidative radiotherapy following chemoimmunotherapy. Dose-adjusted Etoposide, Prednisolone, Vincristine, Cyclophosphamide, Doxorubicin and Rituximab (DA-EPOCH-R) without radiotherapy has demonstrated excellent activity in a small phase II study but with increased chemotherapy toxicity. In IELSG37, PFS was inferior for patients treated with R-CHOP-21 compared with other chemoimmunotherapy regimens, supporting intensification of therapy beyond R-CHOP-21 in this entity. The outcome for patients with relapsed/refractory PMBL is poor, with response rates of around 25% to second line therapy, and a 2-year overall survival of 15%. Therefore, there remains a need to improve initial therapy for patients with PMBL. Programmed-Death-1 (PD-1) ligands PD-L1/PD-L2 are commonly upregulated in PMBL. The PD-1 inhibitor Pembrolizumab blocks the interaction of PD-1 and PD-L1/2, and subsequent signalling, and has encouraging activity in relapsed/refractory PMBL, with an overall response rate of 43% (complete response 23%) and modest toxicity in a phase II study. ‘Window’ induction treatment involving delivery of checkpoint inhibitor therapy to patients with lymphoma, prior to initiation of chemotherapy has been investigated in phase II studies, showing encouraging efficacy and no safety concerns with this ‘chemotherapy-free’ initial treatment approach. The combination of Pembrolizumab and Rituximab is predicted to be synergistic, and in non-randomised trials in other B-cell lymphoma histologies, has demonstrated superior response rates to those expected with Rituximab monotherapy, suggesting synergism of the combination. There is therefore compelling rationale for combining R-CHOP and Pembrolizumab as first-li