bay-80-6946 and Lymphoma--Large-B-Cell--Diffuse

On the occasion of its recent approval for relapsed follicular lymphoma, we review the design and development of the pan-class I PI3K inhibitor copanlisib as a drug for the treatment of B-cell malignancies in comparison with other kinase inhibitors targeting B-cell-receptor signaling, in particular with strictly isoform-δ-selective idelalisib. In agreement with previously defined PI3K-inhibitor chemotypes, the 2,3-dihydroimidazo[1,2-

Topics: Animals; Antineoplastic Agents; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Large B-Cell, Diffuse; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Purines; Pyrimidines; Quinazolines; Quinazolinones

Bayer are developing copanlisib (Aliqopa™)-a pan-class I phosphoinositide 3-kinase (PI3K) inhibitor-as a treatment for various haematological and solid malignancies. The US FDA has granted copanlisib accelerated approval for the treatment of adults with relapsed follicular lymphoma who have received at least two prior systemic therapies based on the results of a phase II trial. Phase III trials are underway evaluating copanlisib as treatment for relapsed/refractory diffuse large B-cell lymphoma and in combination with rituximab or rituximab-based chemotherapy or standard immunochemotherapy in patients with relapsed indolent B-cell non-Hodgkin's lymphoma. Phase I/II studies are underway in relapsed or refractory peripheral T-cell or NK/T-cell lymphoma, advanced cholangiocarcinoma, hormone receptor-positive HER2-negative stage I-IV breast cancer, HER2-positive breast cancer and recurrent and/or metastatic head and neck squamous cell carcinomas harbouring a PI3KCA mutation/amplification and/or a PTEN loss. This article summarizes the milestones in the development of copanlisib leading to this first approval for relapsed follicular lymphoma.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cholangiocarcinoma; Class I Phosphatidylinositol 3-Kinases; Drug Approval; Humans; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Pyrimidines; Quinazolines; Rituximab; United States; United States Food and Drug Administration

Patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) have adverse outcomes. We evaluated the efficacy and safety of the phosphatidylinositol 3-kinase inhibitor copanlisib in patients with relapsed/refractory DLBCL and assessed the relationship between efficacy and DLBCL cell of origin (COO; activated B-cell like [ABC] and germinal center B-cell like [GCB]) and other biomarkers. The primary endpoint was objective response rate (ORR) in DLBCL COO subgroups (ABC, GCB, and unclassifiable) and by CD79B mutational status (NCT02391116). Sixty-seven patients received copanlisib (ABC DLBCL, n = 19; GCB DLBCL, n = 30; unclassifiable, n = 3; missing, n = 15). The ORR was 19.4%; 31.6% and 13.3% in ABC and GCB DLBCL patients, respectively. ORR was 22.2%/20.0% for patients with/without CD79B mutations (wild type, n = 45; mutant, n = 9; missing, n = 13). Overall median progression-free survival and duration of response were 1.8 and 4.3 months, respectively. Adverse events included hypertension (40.3%), diarrhea (37.3%), and hyperglycemia (32.8%). Aberrations were detected in 338 genes, including BCL2 (53.7%) and MLL2 (53.7%). A 16-gene signature separating responders from nonresponders was identified. Copanlisib treatment demonstrated a manageable safety profile in patients with relapsed/refractory DLBCL and a numerically higher response rate in ABC vs. GCB DLBCL patients.

Topics: Adult; Aged; Aged, 80 and over; CD79 Antigens; Female; High-Throughput Nucleotide Sequencing; Humans; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Mutation; Phosphoinositide-3 Kinase Inhibitors; Pyrimidines; Quinazolines; Recurrence

Inhibition of the B-cell receptor (BCR) signaling pathway is a promising treatment strategy in multiple B-cell malignancies. However, the role of BCR blockade in diffuse large B-cell lymphoma (DLBCL) remains undefined. We recently characterized primary DLBCL subsets with distinct genetic bases for perturbed BCR/phosphoinositide 3-kinase (PI3K) signaling and dysregulated B-cell lymphoma 2 (BCL-2) expression. Herein, we explore the activity of PI3K inhibitors and BCL-2 blockade in a panel of functionally and genetically characterized DLBCL cell line models. A PI3K inhibitor with predominant α/δ activity, copanlisib, exhibited the highest cytotoxicity in all BCR-dependent DLBCLs. The proapoptotic effect of copanlisib was associated with DLBCL subtype-specific dysregulated expression of BCL-2 family members including harakiri (HRK) and its antiapoptotic partner BCL extra large (BCL-xL), BCL2 related protein A1, myeloid cell leukemia 1 (MCL-1), and BCL2 interacting mediator of cell death. Using functional BH3 profiling, we found that the cytotoxic activity of copanlisib was primarily mediated through BCL-xL and MCL-1-dependent mechanisms that might complement BCL-2 blockade. For these reasons, we evaluated single-agent activity of venetoclax in the DLBCLs and identified a subset with limited sensitivity to BCL-2 blockade despite having genetic bases of BCL-2 dysregulation. As these were largely BCR-dependent DLBCLs, we hypothesized that combined inhibition of PI3Kα/δ and BCL-2 would perturb BCR-dependent and BCL-2-mediated survival pathways. Indeed, we observed synergistic activity of copanlisib/venetoclax in BCR-dependent DLBCLs with genetic bases for BCL-2 dysregulation in vitro and confirmed these findings in a xenograft model. These results provide preclinical evidence for the rational combination of PI3Kα/δ and BCL-2 blockade in genetically defined DLBCLs.

Topics: Animals; Antineoplastic Agents; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Cell Proliferation; Class I Phosphatidylinositol 3-Kinases; Drug Synergism; Female; Humans; Lymphoma, Large B-Cell, Diffuse; Mice; Mice, Inbred NOD; Mice, SCID; Proto-Oncogene Proteins c-bcl-2; Pyrimidines; Quinazolines; Sulfonamides; Tumor Cells, Cultured; Xenograft Model Antitumor Assays