bay-80-6946 and Breast-Neoplasms

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

Activating mutations in. Patients received copanlisib (60 mg intravenous) once weekly on days 1, 8, and 15 in 28-day cycles until progression or toxicity. Patients with. The study met its primary end point with an ORR of 16% (

Topics: Breast Neoplasms; Class I Phosphatidylinositol 3-Kinases; Female; Humans; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Pyrimidines; Quinazolines

Inhibition of the PI3K/mTOR pathway suppresses breast cancer (BC) growth, enhances anti-tumor immune responses, and works synergistically with immune checkpoint inhibitors (ICI). The objective here was to identify a subclass of PI3K inhibitors that, when combined with paclitaxel, is effective in enhancing response to ICI.. C57BL/6 mice were orthotopically implanted with syngeneic luminal/triple-negative-like PyMT cells exhibiting high endogenous PI3K activity. Tumor growth in response to treatment with anti-PD-1 + anti-CTLA-4 (ICI), paclitaxel (PTX), and either the PI3Kα-specific inhibitor alpelisib, the pan-PI3K inhibitor copanlisib, or the broad spectrum PI3K/mTOR inhibitor gedatolisib was evaluated in reference to monotherapy or combinations of these therapies. Effects of these therapeutics on intratumoral immune populations were determined by multicolor FACS.. Treatment with alpelisib + PTX inhibited PyMT tumor growth and increased tumor-infiltrating granulocytes but did not significantly affect the number of tumor-infiltrating CD8. PI3K/mTOR inhibition plus PTX heightens response to ICI and may provide a viable therapeutic approach for treatment of metastatic BC.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cell Line, Tumor; Female; Granulocytes; Humans; Immune Checkpoint Inhibitors; Mice; Mice, Inbred C57BL; Molecular Targeted Therapy; Morpholines; Paclitaxel; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Pyrimidines; Quinazolines; Thiazoles; TOR Serine-Threonine Kinases; Treatment Outcome; Triazines; Tumor Microenvironment; Xenograft Model Antitumor Assays

The PI3K pathway is a key mechanism of trastuzumab resistance, but early attempts to indirectly target this pathway with mTOR inhibitors have had limited success. We present the results of a preclinical study of the selective alpha/delta isoform dominant PI3K inhibitor BAY 80-6946 tested alone and in combination with HER2-targeted therapies in HER2-positive cell lines, including models with acquired resistance to trastuzumab and/or lapatinib. A panel of HER2-positive breast cancer cells were profiled for their mutational status using Sequenom MassARRAY, PTEN status by Western blot, and anti-proliferative response to BAY 80-6946 alone and in combination with the HER2-targeted therapies trastuzumab, lapatinib and afatinib. Reverse phase protein array was used to determine the effect of BAY 80-6946 on expression and phosphorylation of 68 proteins including members of the PI3K and MAPK pathways. The Boyden chamber method was used to determine if BAY 80-6946 affected cellular invasion and migration. BAY 80-6946 has anti-proliferative and anti-invasive effects when used alone in our panel of cell lines (IC50s 3.9-29.4 nM). BAY 80-6946 inhibited PI3K signalling and was effective in cells regardless of their PI3K, P53 or PTEN status. The combination of HER2-targeted therapies and BAY 80-6946 inhibited growth more effectively than either therapy used alone (with clear synergism in many cases), and can restore sensitivity to trastuzumab and lapatinib in cells with acquired resistance to either trastuzumab and/or lapatinib. The addition of BAY 80-6946 to HER2-targeted therapy could represent an improved treatment strategy for patients with refractory metastatic HER2-positive breast cancer, and should be considered for clinical trial evaluation.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Breast Neoplasms; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Drug Synergism; Female; Humans; Inhibitory Concentration 50; Lapatinib; MAP Kinase Signaling System; Mutation; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; PTEN Phosphohydrolase; Pyrimidines; Quinazolines; Receptor, ErbB-2; Signal Transduction; TOR Serine-Threonine Kinases; Trastuzumab