Ningshu Liu, Jose Garcia Vargas, Bertolt Kreft, Dominik Mumberg, Barrett H Childs and Karl Ziegelbauer
Bayer AG, Germany
Scientific Tracks Abstracts: Arch Cancer Res
Statement of the Problem: Follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) are two of the most common non-hodgkin lymphoma (NHL) worldwide with a high unmet medical need for relapsed or refractory disease represents from the frontline treatment. Despite the role of PI3K in NHL and solid tumors has been clinically validated, clinical development of PI3K inhibitors has been challenged with the therapeutic window of both pan- and isoform selective PI3K inhibitors. Methodology: Copanlisib is the first pan-PI3K inhibitor with intravenous intermittent dosing regimen developed in clinic. Copanlisib has been extensively studied in various preclinical tumor models in vitro and in vivo, as well as investigated in a series of clinical trials in both NHL and solid tumors. Findings: Investigation of FL and DLBCL patient samples indicates differential and redundant expression of PI3K isoforms. compared to PI3Kï¤ selective inhibition, copanlisib showed much stronger and broader anti-tumor activity in NHL by overcoming intrinsic resistance caused by multiple PI3K isoform expression and acquired resistance induced by rebound activation of PI3K/AKT and other oncogenic signaling molecules, such as NFï¤B. These findings have been translated into the significant clinical benefits in FL patients with durable objective responses (59%), which led to an accelerated FDA approval for treatment of relapsed or refractory FL. In addition, copanlisib has also demonstrated significant activity in DLBCL patients. Furthermore, recent preclinical study indicates that pulsatile inhibition of PI3K by copanlisib can also enhance anti-tumor immunity by inhibiting immune suppressive Tregs and M2-TAM and stimulating CD8+ T cells and M1 macrophages, and therefore overcome the resistance to immune checkpoint blocks. Conclusion & Significance: Pan-PI3K inhibitor copanlisib with intermittent dosing schedule has been successfully developed
as an effective and safe therapy for FL. Currently, copanlisib is being investigated in combination with rituximab (CHRONOS-3) or rituximab-chemotherapy (CHRONOS-4) in iNHL, as well as in combination with targeted therapies, such as immune checkpoint inhibitors, in solid tumors.
Recent Publications
1. Paul J, Soujon M, Wengner A M, et al. (2017) Simultaneous inhibition of PI3Kδ and PI3Kα induces ABC-DLBCL regression by blocking BCR-dependent and -independent activation of NF-κB and AKT. Cancer Cell doi: https://doi.org/10.1016/j.ccell.2016.12.003
2. Dreyling M, Santoro A, Mollica L, et al. (2017) Phosphatidylinositol 3-kinase inhibition by copanlisib in relapsed or refractory indolent lymphoma. Journal of Clinical Oncology 35(35):3898-3905.
3. Dreyling M, Morschhauser F, Bouabdallah K, et al. (2017) Phase II study of copanlisib, a PI3K inhibitor, in relapsed or refractory, indolent or aggressive lymphoma. Annals of Oncology 28(9):2169-2178.
Ningshu Liu has her research interests in evaluation and passion in improving the health and wellbeing. Her open and contextual evaluation model based on responsive constructivists creates new pathways for improving healthcare. She has built this model after years of experience in research, evaluation, teaching and administration both in hospital and education institutions. The foundation is based on fourth generation evaluation which is a methodology that utilizes the previous generations of evaluation: measurement, description and judgment. It allows for value-pluralism. This approach is responsive to all stakeholders and has a different way of focusing.
Email:ningshu.liu@bayer.com
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