Aliqopa (copanlisib) / Bayer - LARVOL DELTA

THE BTK DEGRADER BGB-16673 AND THE BCL2 INHIBITOR SONROTOCLAX SHOWS ANTI-TUMOR ACTIVITY AS SINGLE AGENTS AND IN COMBINATION IN MARGINAL ZONE LYMPHOMA MODELS (ICML 2025) - "The activity did not differ from the BTK inhibitor zanubrutinib and, accordingly, was limited in cells resistant to ibrutinib (n. = 2), idelalisib (n...= 1), and copanlisib/venetoclax (n...Karpas1718, SSK41, VL51 and HC1 were exposed to BGB-16673 plus lenalidomide, selinexor, venetoclax, sonrotoclax (BGB-11417), bendamustine, tazemetostat and rituximab... Its ability to degrade BTK protein, combined with its synergistic effects with other targeted therapies, positions BGB-16673 as a promising candidate for further development in MZL patients. The 2nd generation BCL2 inhibitor sonrotoclax appears as another drug to be explored in the same patient populations, possibly combining the two molecules."

B Cell Lymphoma • Hematological Malignancies • Lymphoma • Marginal Zone Lymphoma • Oncology • BCL2L1 • CRBN • MCL1

COMBINATION OF THE INTRAVENOUS PI3K INHIBITOR COPANLISIB IN COMBINATION WITH OBINUTUZUMAB IN PATIENTS WITH PREVIOUSLY UNTREATED FOLLICULAR LYMPHOMA AND HIGH TUMOR BURDEN (ICML 2025) - "Copanlisib plus Obinutuzumab did not achieve the prespecified PFS improvement but demonstrated durable responses and manageable toxicity, suggesting potential benefit for selected patients."

Clinical • Combination therapy • IO biomarker • Follicular Lymphoma • Hematological Malignancies • Indolent Lymphoma • Lymphoma • Oncology • BCL2

A PROSPECTIVE MULTICENTER PHASE 2 STUDY OF THE CHEMOTHERAPY-FREE COMBINATION OF THE INTRAVENOUS PHOSPHATIDYLINOSITOL-3-KINASE (PI3K) INHIBITOR COPANLISIB IN COMBINATION WITH OBINUTUZUMAB IN PATIENTS WITH PREVIOUSLY UNTREATED FOLLICULAR LYMPHOMA (FL) AND A HIGH TUMOR BURDEN (ALTERNATIVE-C) (EHA 2025) - "Copanlisib plus obinutuzumab did not achieve the prespecified PFS improvement but demonstrated durable responses and manageable toxicity, suggesting potential benefit for selected patients."

Clinical • Combination therapy • IO biomarker • P2 data • Cardiovascular • Diabetes • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Hypertension • Indolent Lymphoma • Infectious Disease • Lymphoma • Neutropenia • Oncology • Pneumonia • Respiratory Diseases • Septic Shock • BCL2

Copanlisib in combination with rituximab and bendamustine for transplant-ineligible relapsed/refractory diffuse large B-cell lymphoma patients: Results from the phase II multicentre FIL Copa-BR trial from Fondazione Italiana Linfomi (FIL). (PubMed, Br J Haematol) - "Due to limited efficacy, poor tolerability and emerging alternative treatments, the trial was terminated prematurely. Copa-BR showed limited activity and an unfavourable safety profile, discouraging further investigation of this combination in ASCT- and CAR-T-ineligible R/R DLBCL."

Journal • P2 data • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Infectious Disease • Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Novel Coronavirus Disease • Oncology • Thrombocytopenia • Transplantation

Copanlisib and Avelumab as a Maintenance Therapy for Advanced Bladder Cancer (clinicaltrials.gov) - P1/2 | N=0 | Withdrawn | Sponsor: VA Office of Research and Development | N=29 ➔ 0 | Trial completion date: Jun 2029 ➔ Jun 2025 | Not yet recruiting ➔ Withdrawn | Trial primary completion date: Dec 2028 ➔ Jun 2025

Enrollment change • Trial completion date • Trial primary completion date • Trial withdrawal • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer

Digital spatial profiling of advanced solid tumors and lymphomas from a phase 1 trial of copanlisib and nivolumab. (ASCO 2025) - P1 | "As part of the exploratory objectives in the Phase 1B trial (NCT03502733) evaluating adult patients(pts) with solid tumors and lymphomas copanisib (C), nivolumab (N) + ipilumumab (I), we employed the NanoString-Bruker GeoMx DSP platform to evaluate spatial heterogeneity in differentially regulated biomarkers... GeoMx DSP demonstrated its capability to investigate phospho-signaling and immune profiles in tumor and stromal compartments of small biopsies, highlighting its potential to enhance the understanding of TMEs in clinical studies. Further applications may provide critical insights for clinical cancer trials."

IO biomarker • Metastases • P1 data • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • CD20 • CD8 • CD80 • CTLA4 • FOXP3 • PD-1 • PD-L1 • PIK3IP1 • PTPRC

Industry promotion of oncology drugs with accelerated approval that failed confirmatory trials. (ASCO 2025) - "Pepaxto was excluded from our analysis as it had no reported payments on OpenPayments...Following announcement of negative postapproval confirmatory study results, average monthly payments received by all physicians increased for Marqibo (vinCRIStine sulfate) from $138 in the year preceding announcement to $164 during the period between announcement of negative results and market withdrawal, but decreased for Farydak (panobinostat) ($12,317 to $4,916), Blenrep (belantamab mafodotin) ($152,417 to $119,394), and Ukoniq (umbralisib) ($23,139 to $14,130). Lartruvo (olaratumab) and Aliqopa (copanlisib) had almost no payments after announcement of negative confirmatory study results. Industry payments for oncology drugs with accelerated approvals mostly decreased after announcement of negative confirmatory trial results; however, there was evidence of continued promotion for certain drugs until a request for voluntary withdrawal was made by FDA. This suggests that regulatory..."

Oncology

Direct Tumor Microinjection and FDG-PET in Testing Drug Sensitivity in Patients With Relapsed or Refractory Non-Hodgkin Lymphoma, Hodgkin Lymphoma, or Stage IV Breast Cancer (clinicaltrials.gov) - P1 | N=17 | Terminated | Sponsor: Mayo Clinic | N=39 ➔ 17 | Suspended ➔ Terminated; funding - sponsor filing Chapter 11 bankruptcy

Enrollment change • Trial termination • Breast Cancer • Cutaneous T-cell Lymphoma • Dermatology • Hematological Malignancies • Hodgkin Lymphoma • Lymphoma • Marginal Zone Lymphoma • Mycosis Fungoides • Nodal Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • T Cell Non-Hodgkin Lymphoma

Combinatorial screen with standard of care and selected anticancer agents identifies multiple combinations with activity against a panel of patient-derived colorectal organoids (AACR 2025) - "Following compound addition, organoid growth was measured by live bright field imaging every 24 h and cell viability was determined by CellTiter-Glo 3D at 48 h and 168 h. Modest responses were observed in most models from the combination of leucovorin with 5-FU; however, >1 log of cytotoxicity was observed in only several models. The panel was more responsive to FOLFOX, which was consistent with the sensitivity of models to oxaliplatin. Responses to TAS-102 varied and >1 log of cytotoxicity was observed in several models...Combination of the BCL-2/BCL-xL inhibitor pelcitoclax plus cobimetinib achieved >1 log of cytotoxicity in most organoid models. Combinations of cobimetinib with the EGFR inhibitors erlotinib, afatinib or cetuximab demonstrated synergy in many organoids according to the Bliss independence model and frequently achieved ≥1 log of cytotoxicity...The combination of cobimetinib and MRTX1133 had synergistic activity by Bliss independence in multiple..."

Clinical • Oncology • BCL2 • BCL2L1 • BRAF • KRAS • PIK3CA

Development of anti-CD21 Chimeric Antigen Receptor (CAR)-T Cells for T-Cell Acute Lymphoblastic Leukemia (T-ALL) - CAR engineering for a complex antigen. (ASGCT 2025) - "The dual αδ PI3K inhibitor copanlisib upregulated CD21 in T-ALL cell lines and PDX both in vitro and in vivo. Anti-CD21 Fab-CAR-T cells, targeting membrane-proximal epitopes, showed potent anti-CD21 activity. Pharmacological upregulation of CD21 can enhance efficacy in low antigen density. This novel approach avoids fratricide and T-cell aplasia, offering promise for treating T-ALL Disease Focus of Abstract:Leukemia"

IO biomarker • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • T Acute Lymphoblastic Leukemia • T-cell Acute Lymphoblastic Lymphoma • CD21 • CD7

Testing the Addition of Copanlisib to Eribulin in Metastatic Triple Negative Breast Cancer (clinicaltrials.gov) - P1/2 | N=28 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Completed ➔ Active, not recruiting | Trial completion date: Mar 2024 ➔ May 2026

Enrollment closed • Trial completion date • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Negative Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ER • PGR • PIK3CA • PTEN

Phosphatidylinositol 3-Kinase Inhibition and Allogeneic Stem Cell Transplantation Can Overcome Chemotherapy Resistance in Refractory Burkitt Lymphoma. (PubMed, J Hematol) - "Our report demonstrates that targeting B-cell receptor signaling via the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway with copanlisib can overcome chemotherapy resistance and achieve complete remission in relapsed Burkitt lymphoma. This novel approach, followed by consolidation with allogeneic hematopoietic stem cell transplantation can provide durable complete remission by harnessing the immune graft-versus-lymphoma effect in chemoresistant Burkitt lymphoma."

Journal • Bone Marrow Transplantation • Burkitt Lymphoma • Hematological Malignancies • Lymphoma • Oncology • Transplantation

Co-alterations in PIK3CA and ARID1A lead to greater sensitivity to PI3K pathway inhibition (AACR 2025) - "Previously we have shown that patients with mutations in both genes are more sensitive to copanlisib (cop) treatment than those with just PIK3CA(PK) mutation...An enhanced response was observed with some other PI3K inhibitors, including sapanisertib (PK=0.13; PKAD=0.014; p < 0.005) everolimus (PK=0.66, PKAD=0.36; p < 0.005) and capivasertib (PK=0.85; PKAD=0.47; p < 0.05). Cancers with PK and AD alterations have enhanced efficacy to PI3K pathway inhibition, especially those inhibitors with downstream activity against AKT or MTOR. Further mechanistic and in vivo studies are warranted in addition to further clinical validation."

Colorectal Cancer • Endometrial Cancer • Oncology • Solid Tumor • ARID1A • IFNG • IL6 • PIK3CA

Copanlisib and Venetoclax for the Treatment of Relapsed or Refractory Mantle Cell Lymphoma (clinicaltrials.gov) - P1/2 | N=8 | Active, not recruiting | Sponsor: City of Hope Medical Center | Trial completion date: Mar 2025 ➔ Feb 2026 | Trial primary completion date: Mar 2025 ➔ Feb 2026

Trial completion date • Trial primary completion date • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Oncology • BCL2 • CCND1 • CD20 • CD5 • PAX5

Retraction Note: Copanlisib promotes growth inhibition and apoptosis by modulating the AKT/FoxO3a/PUMA axis in colorectal cancer. (PubMed, Cell Death Dis) - No abstract available

Journal • Colorectal Cancer • Oncology • Solid Tumor • FOXO3

Efficacy of ATR kinase inhibitor elimusertib monotherapy or combination in tumors with DNA damage response pathway and other genomic alterations. (PubMed, Mol Cancer Ther) - "The combination of the PI3K inhibitor copanlisib with elimusertib enhanced EFS-2 compared to monotherapy in 3 of 11 models tested. The combination of elimusertib with the poly (ADP-ribose) polymerase (PARP) inhibitor niraparib enhanced antitumor activity compared to single agents in PARP-resistant PDX models. Our study shows that ATR inhibition has antitumor activity, including in models with both intrinsic and acquired PARP inhibitor resistance. Further work is needed to better refine patient selection for ATR-based therapies."

Journal • Monotherapy • Ataxia • Immunology • Movement Disorders • Oncology • Primary Immunodeficiency • ATM • BRCA1 • BRCA2

Validation of genetically defined Oncopig hepatocellular carcinoma cell lines for in vitro evaluation of targeted therapeutic efficacy (AACR 2025) - "Therapeutic susceptibility of the established Oncopig WT, PTENKO, AXIN1KO, and ARID1KO HCC cell lines was assessed for PI3K inhibitors (GSK2636771, BAY 80-6946, and BKM120). These results validate the utility of the Oncopig HCC model for preclinical evaluation of novel targeted therapeutics in vitro. Future work demonstrating consistent results in vivo will enable the genetically defined Oncopig HCC model to be an ideal animal system to test precision medicine therapeutics prior to entry into the clinic.Therapeutic Susceptibility (Log IC50 (µM))PI3K InhibitorOncopig WT HCCOncopig AXIN1KO HCCOncopig ARID1KO HCCOncopig PTENKO HCCHuman PTEN Null CellsGSK26367711.461.170.660.07ResponsiveBAY80-694611.55.64.52.38ResponsiveBKM1202.050.95NA2.3Non-Responsive"

Preclinical • Hepatocellular Cancer • Oncology • Solid Tumor • ARID1A • KRAS • PTEN

CDK9 pharmacological inhibition has antitumor activity in marginal zone lymphoma models and can improve the effects of BTK, PI3K, and BCL2 inhibitors (AACR 2025) - P1 | "PRT2527 has shown favorable tolerability, with manageable toxicity in a phase 1 study for solid tumor patients (Patel et al, ENA 2023), and it is now in phase 1 as a single agent and in combination with the BTK inhibitor zanubrutinib for hematological cancers patients (NCT05665530)...The combination of PRT2527 with the PI3K inhibitor idelalisib, with the BTK inhibitor ibrutinib, or triple combination with the PI3K inhibitor copanlisib and the BCL2 inhibitor venetoclax was beneficial in all parental cells, and the benefit was maintained, although reduced, in derivatives with acquired resistance to PI3K and BTK inhibitors. CDK9 inhibition with PRT2527 has in vitro antitumor activity in MZL models, which is maintained in models with acquired resistance to PI3K, BTK, or BCL2 inhibitors. CDK9 inhibition with PRT2527 can improve the sensitivity of MZL cells to BTK, PI3K, and BCL2 inhibitors."

B Cell Lymphoma • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • CDK9 • MCL1

Identifying novel vulnerabilities in clear cell sarcoma through functional and genomic screening (AACR 2025) - "These findings offer new insights into actionable vulnerabilities in CCSA, with PI3K/mTOR inhibitors showing potential for therapeutic development. Future studies will investigate synergistic combinations to further optimize treatment efficacy and validate further vulnerabilities identified by our dual screening approach."

IO biomarker • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • ATF1 • CHEK1 • CREB1 • EWSR1 • HSPA5 • MCL1 • SOX10

A chemoradiation platform for evaluating multimodal therapy effects on tumor viability and invasion ex vivo (AACR 2025) - "Proof-of-concept experiments with HPV-negative HNSCC lines (HN30 and HN31, established from primary and metastatic disease from the same patient) and HPV-positive HNSCC cells (SCC154) revealed that treatment with cetuximab and ibrutinib enhances radiosensitivity in HN31 cells. The PI3K inhibitor copanlisib radio-sensitized both HN30 and HN31, while alpelisib sensitized SCC154 cells. Additionally, copanlisib, afatinib, and ibrutinib were shown to limit ECM invasion of HN31, while the AKT inhibitor ipatasertib and the mTOR-targeting rapamycin promote invasion of HN30 cells, as observed in previous studies (Brolih et al., 2018). Our pilot experiments using bioprinted patient-derived HNSCC organoids confirmed the feasibility of performing sensitivity screening by integrating bioprinting, conventional viability assays, and advanced image analysis techniques. Our goal is to establish a personalized therapeutic pipeline for patients with advanced HNSCC, maximizing responses to..."

Preclinical • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Profiling protein-protein interactions to predict sensitivity to drugs targeting BCL2 family members in lymphoma models (AACR 2025) - "Drug sensitivity parameters were integrated with protein data using Spearman Correlation and Multiple Linear Regression (MLR, Lasso). We exposed MCL (n=10, JVM2, REC1, JEKO1, UPN1, SP49, SP53, MAVER1, GRANTA519, Z138, MINO), MZL (n=6, VL51, SSK41, Karpas1718, HC1, HAIRM, ESKOL) cell lines and MZL models of secondary resistance (MZL-RES) to idelalisib (n=2), copanlisib (n=2), ibrutinib (n=2), venetoclax (n=1) and copanlisib/venetoclax (n=2), to BCL2i (venetoclax, sonrotoclax), BCL2/BCXLi (navitoclax), and MCL1i (S63845). Anti-apoptotic inhibitors show variable heterogeneous activity in MCL and MZL models, including those resistant to PI3Ki and BTKi, which could be predicted quantifying the BCL2-family members levels and interactions using the SPID. Such an approach might have a clinical potential to predict the sensitivity of patients with mature B cell lymphomas to this class of agents."

IO biomarker • Acute Myelogenous Leukemia • B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2 • BCL2L1

Selective degradation of SMARCA2 and dual degradation of SMARCA2 and SMARCA4 has strong antitumor activity in marginal zone lymphoma (MZL) (AACR 2025) - "PRT3789 is currently in phase 1 as a single agent or in combination with docetaxel for patients with solid tumors with loss of SMARCA4...None of the models had mutations in the coding regions of ARID1A or SMARCA4.Adding individual degraders to the BTK inhibitor ibrutinib, the PI3Kδ inhibitor idelalisib, or to the combination of the PI3K inhibitor copanlisib with the BCL2 inhibitor venetoclax led to additivity/synergism... The single SMARCA2 degrader PRT3789 and the dual SMARCA2/4 degrader showed strong dose-dependent cytotoxic activity in MZL cells, showing activity in the low nM range. Both compounds induced apoptosis as single agents and improved the activity of a BTK inhibitor in the two cell lines tested. Interestingly, the antitumor activity was maintained in MZL cell lines with acquired resistance to BTK, PI3K, and BCL2 inhibitors."

IO biomarker • Hematological Malignancies • Lymphoma • Marginal Zone Lymphoma • Oncology • Solid Tumor • ARID1A • PIK3CD • SMARCA2 • SMARCA4

The BTK degrader BGB-16673 shows anti-tumor activity in marginal zone lymphoma models (AACR 2025) - "Effect on cell viability was assessed by MTT assay after 5 days of exposure to increasing concentrations of compounds or DMSO (control) in MZL cell lines and in cell lines with secondary resistance to idelalisib (n.=2), copanlisib (n.=1), ibrutinib (n.=2), and copanlisib/venetoclax. Oxidative phosphorylation, commonly associated with resistance to multiple therapies, was repressed by BGB-16673 but upregulated by zanubrutinib.Conclusions. Its ability to degrade BTK protein and its antitumor activity position the BTK degrader BGB-16673 as a promising candidate for further development in MZL patients."

B Cell Lymphoma • Hematological Malignancies • Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CRBN

Co-existent PIK3CA and ARID1A mutations lead to enhanced sensitivity to PI3K inhibition through PUMA induction by FOXO3a and p53/p21 (AACR 2025) - "The Z1F arm of the NCI MATCH clinical trial demonstrated an improved response rate for the pan-PI3K inhibitor, copanlisib (cop) in subjects with PK and AD mutant cancers... Co-alterations in PIK3CA and ARID1A lead to enhanced sensitivity to PI3K inhibition through PUMA induction by FOXO3a due to aberrant expression of p53/p21 caused by ARID1A loss. Further validation studies are underway utilizing PK and AD altered patient-derived cancer organoids."

Colorectal Cancer • Oncology • Solid Tumor • ANXA5 • ARID1A • BBC3 • CDKN1A • FOXO3 • MCL1 • MYC • PIK3CA

Targeting the phosphatidylinositol-3-kinase (PI3K) and mitogen activated protein kinase (MAPK) signalling pathways to enhance chemoradiotherapy in locally advanced rectal cancer. (PubMed, Cancer Treat Res Commun) - "A panel of colorectal cancer (CRC) cell lines (n = 10) with varying PI3K and MAPK mutational backgrounds were treated with combinations of 5-Flourouracil (5-FU), radiation, the PI3K inhibitor copanlisib, and/or the MEK inhibitor refametinib, and their effects on proliferation in vitro were measured...Our results suggest that activation of the kinase signalling pathway may modulate PI3K/MEK inhibitor responsiveness in colorectal cancer. Furthermore, the addition of copanlisib to 5-FU chemoradiotherapy resulted in an enhanced anti-proliferative cytotoxic effect compared to 5-FU chemoradiotherapy alone, regardless of the background mutational status, and supports further clinical development of this regimen."

Journal • Colorectal Cancer • Oncology • Rectal Cancer • Solid Tumor • KRAS • PIK3CA