AZD5069 / AstraZeneca - LARVOL DELTA

CXCR2+ Neutrophils Drive Neutrophil Extracellular Traps Formation and Exacerbate Pulpitis in Rats: An In Vitro and In Vivo Laboratory Investigation. (PubMed, Int Endod J) - "CXCR2+ neutrophils act as a pro-inflammatory subset in pulpitis, driving NETs release through macrophage-derived signals. Inhibition of CXCR2 attenuates inflammation and enhances dentine repair, supporting CXCR2 as a promising therapeutic target for immune modulation in pulpitis."

Journal • Preclinical • Dental Disorders • Immune Modulation • Immunology • Inflammation • CXCL8 • CXCR2

Platelets hijack neutrophils for pro-tumour polarisation in MASH-HCC (LCS 2026) - "Conclusion These observations have implications for an ongoing clinical trial (CUBIC) examining the efficacy of a combination of AZD5069, an antagonist of CXCR2-mediated neutrophil trafficking, and durvalumab. We have previously hypothesised that this combination therapy re-programmes neutrophils to anti-tumour phenotype. In the light of our discovery that PD-L1 is almost exclusively found on platelets associated with pro-tumour neutrophils we need to reassess the mechanism by which immune checkpoint interactions modulate neutrophil phenotype in liver disease and further investigate the role of platelet- neutrophil aggregates in tumour immunology."

IO biomarker • Gastrointestinal Cancer • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor • CXCR2 • ITGB3

A phase (Ph) I/II trial of the CXCR2 antagonist AZD5069 in combination with enzalutamide (ENZA) in patients (pts) with metastatic castration resistant prostate cancer (mCRPC) (ESMO 2022) - P1/2 | "Conclusions The combination of AZD5069 and ENZA is tolerable and has antitumor activity in mCRPC. We provide clinical evidence for direct targeting of myeloid chemotaxis as a therapeutic strategy in mCRPC."

Clinical • Combination therapy • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CXCR2 • CYP3A4 • IL23A • NRG1

Challenges in recruiting patients (pts) to clinical trials of systemic therapy in advanced hepatocellular carcinoma (HCC) (LCS 2026) - "Method With Caldicott Guardian approval, we retrospectively analysed records of pts approached at a single (lead) centre (Glasgow; July 2022–Sept 2025) for participation in a phase I/II study of AZD5069 in combination with durvalumab in pts with HCC (EudraCT 2020-003346-36)...74 (of 90; 82%) received non-trial systemic therapy, most commonly atezolizumab + bevacizumab (n=43)...Conclusion Only 11% of HCC pts approached entered this clinical trial, 27% declined to participate, 10% were ineligible due to requirement for biopsy +/- histological diagnosis. These data have implications for clinical trial design and patient eligibility criteria to make clinical trials more inclusive and representative of real- world pts."

Clinical • Metastases • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor

CXCR2 antagonism as a promising therapeutic approach for pulmonary fibrosis therapy. (PubMed, Biomed Pharmacother) - "In this study, we evaluated and compared the anti-inflammatory effects of four CXCR2 antagonists - DF2755A, AZD-5069, SX-682, and SCH527123 - in a murine model of bleomycin-induced lung injury. Importantly, DF2755A and SX-682 were particularly effective in mitigating fibrosis and chronic inflammatory changes when administered in both preventive and therapeutic schedules, even at later stages of disease progression. These findings underscore the potential of CXCR2 antagonism, especially with DF2755A, as a promising strategy to limit inflammation and fibrosis in experimental lung injury."

Journal • Fibrosis • Immunology • Inflammation • Pneumonia • Pulmonary Disease • Respiratory Diseases • CXCR2 • MPO

Study to Assess MEDI4736 With Either AZD9150 or AZD5069 in Advanced Solid Tumors & Relapsed Metastatic Squamous Cell Carcinoma of Head & Neck (clinicaltrials.gov) - P1/2 | N=340 | Completed | Sponsor: AstraZeneca | Active, not recruiting ➔ Completed

IO biomarker • Monotherapy • Trial completion • Head and Neck Cancer • Oncology • Prostate Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Trajectory-Based Clustering to Identify Asthma Subgroups Responsive to the Selective CXCR2 Antagonist, AZD5069. (PubMed, Allergy) - No abstract available

Journal • Asthma • Immunology • Pulmonary Disease • Respiratory Diseases • CXCR2

The Interleukin-8-CXCR1/2 Axis as a Therapeutic Target in Peritoneal Carcinomatosis. (PubMed, Curr Oncol) - "IL-8 targeting agents such as monoclonal antibodies (BMS-986253) and small-molecule inhibitors (SX-682, AZD5069, navarixin) have shown efficacy in mitigating tumor growth and improving the efficacy of immune checkpoint inhibitors. In this review, we discuss the influence of the IL-8/CXCR1/CXCR2 axis within the peritoneal immune environment in PC and highlight recent work using IL-8 or CXCR1/CXCR2 blockade as a therapeutic strategy for PC. Continued research into the peritoneal immune microenvironment and the development of targeted therapies are essential for improving the management and prognosis of PC, potentially enhancing antitumor immunity and patient outcomes."

Journal • Review • Oncology • Peritoneal Cancer • CXCL8 • CXCR1 • CXCR2 • IL6

Targeting Myeloid Trem2 Reprograms the Immunosuppressive Niche and Potentiates Checkpoint Immunotherapy in NASH-Driven Hepatocarcinogenesis. (PubMed, Cancer Immunol Res) - "These therapeutic effects were further amplified when combined with the CXCR2 inhibitor AZD5069. Our findings identify Trem2 as a central regulator of the NASH-driven HCC immunosuppressive niche, and suggest a combinatorial therapeutic strategy that targets both myeloid reprogramming and NETosis to overcome immunotherapy resistance in metabolic liver cancer progression."

IO biomarker • Journal • Addiction (Opioid and Alcohol) • Hepatocellular Cancer • Hepatology • Liver Cancer • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Oncology • Solid Tumor • CD8 • CX3CR1 • CXCR2 • CXCR4 • SYK • TGFB1 • TREM2

Cell-specific nanoengineering strategy to disrupt tolerogenic signaling from myeloid-derived suppressor cells and invigorate antitumor immunity in pancreatic cancer. (PubMed, Cancer Immunol Immunother) - "We chemically modified a small-molecule CXCR2 inhibitor AZD5069 by conjugating it with polyethylene glycol (PEG) to enhance aqueous solubility. Treatment of orthotopic tumor-bearing KPC mice with CXCR2-NPRuxo reduced tumor burden compared with vehicle, free Ruxolitinib, or non-drug-loaded CXCR2-NP treatments, without causing appreciable neutropenia. Taken together, cell-specific delivery of payloads via CXCR2-homing immunonanoparticles represents a novel strategy to disrupt MDSC-mediated immunosuppression and invigorate antitumor immunity in PDAC."

Journal • Hematological Disorders • Neutropenia • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CXCR2 • JAK2 • KRAS • STAT3

The CXCL1-CXCR2 Axis as a Component of Therapy Resistance, a Source of Side Effects in Cancer Treatment, and a Therapeutic Target. (PubMed, Cancers (Basel)) - "It discusses anti-CXCL1 antibodies and CXCR2 antagonists, including AZD5069, SB225002, SCH-479833, navarixin/SCH-527123, ladarixin/DF2156A, and reparixin, as well as strategies to enhance CXCR2 expression in lymphocytes during adoptive cell therapy to improve immunotherapy outcomes. CXCR2 inhibitors are well tolerated by patients in clinical trials. However, the limited number of studies evaluating these agents in combination with standard chemotherapy precludes any definitive conclusions."

Adverse events • IO biomarker • Journal • Review • Cardiovascular • Oncology • Pain • CXCL1 • CXCL8 • CXCR2

Study to Assess MEDI4736 With Either AZD9150 or AZD5069 in Advanced Solid Tumors & Relapsed Metastatic Squamous Cell Carcinoma of Head & Neck (clinicaltrials.gov) - P1/2 | N=340 | Active, not recruiting | Sponsor: AstraZeneca | Trial completion date: Mar 2025 ➔ Aug 2025

IO biomarker • Monotherapy • Trial completion date • Head and Neck Cancer • Oncology • Prostate Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Overcoming Immunotherapy Resistance in Hepatocellular Carcinoma by Targeting Myeloid IL-8/ CXCR2 Signaling. (PubMed, Mol Ther) - "Single-cell RNA sequencing (scRNA-seq) were performed in advanced HCC patients with baseline and on-treatment biopsy after pembrolizumab in a Phase II clinical trial cohort...This myeloid IL-8/CXCR2 pathway was further elucidated in our ICB-resistant orthotopic mouse model using AZD5069, a clinically available CXCR2 antagonist...The association between myeloid IL-8 and ICB therapeutic outcome also extended to multiple cancer types. Collectively, our study not only suggests a potential non-invasive biomarker for patient stratification and monitoring of ICB response, but also provides a proof-of-concept for combinational immunotherapy to benefit patients who are non-responsive to ICB monotherapy."

IO biomarker • Journal • Hepatocellular Cancer • Oncology • Solid Tumor • CXCL8 • CXCR2

Convergent signaling via C/EBPβ regulates MDSC-intrinsic NLRP3 inflammasomes to drive inflammatory CAF polarization (AACRPanCa 2024) - "This was corroborated in vivo where ASC speck formation in intratumoral Ly6G+ gMDSCs was diminished in mice treated with CXCR2i AZD5069 and p38i peximetinib... CXCR2-p38 and TLR4 signaling converge on C/EBPβ to regulate gMDSC-intrinsic NLRP3 inflammasomes, which drives iCAF polarization in PDAC. The role of C/EBPβ activation as a central node in imparting myeloid checkpoint function in gMDSCs warrants further exploration."

Myeloid-derived suppressor cells • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • ACTA2 • CAFs • CEBPB • CXCR2 • IL1B • IL1R1 • IL6 • MYD88 • NLRP3

Cell-specific nanoengineering strategy disrupts tolerogenic signaling from myeloid-derived suppressor cells to invigorate antitumor immunity in pancreatic cancer. (PubMed, bioRxiv) - "We conjugate a chemically modified small-molecule inhibitor of MDSC-surface receptor CXCR2 (AZD5069) with polyethylene glycol (PEG) and chemically graft AZD5069-PEG constructs onto amphiphilic polysaccharide derivatives to engineer CXCR2-homing nanoparticles (CXCR2-NP). Encapsulation of JAK2/STAT3i Ruxolitinib (CXCR2-NP Ruxo ) resulted in more durable attenuation in STAT3-regulated arginase activity from PMN-MDSCs and induction of cytolytic T-cell activity vs. free Ruxolitinib in-vitro and in-vivo . Cell-specific delivery of payloads via CXCR2-homing immunonanoparticles represents a novel strategy to disrupt MDSC-mediated immunosuppression and invigorate antitumor immunity in PDAC."

Journal • Myeloid-derived suppressor cells • Gastrointestinal Cancer • Hematological Disorders • Hepatology • Neutropenia • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CXCR2 • JAK2 • STAT3

Selective anti-CXCR2 receptor blockade by AZD5069 inhibits CXCL8-mediated pro-tumorigenic activity in human thyroid cancer cells in vitro. (PubMed, J Endocrinol Invest) - "Our findings confirm the involvement of the CXCL8/CXCR2-axis in promoting pro-tumorigenic effects in TC cells, further demonstrating its immunotherapeutic significance in human cancer."

Journal • Preclinical • Endocrine Cancer • Oncology • Solid Tumor • Thyroid Gland Carcinoma • CXCL8 • CXCR2 • TNFA

A microphysiological system reveals neutrophil contact-dependent attenuation of pancreatic tumor progression by CXCR2 inhibition-based immunotherapy. (PubMed, Sci Rep) - "Interestingly, treatment with AZD-5069, a CXCR2 inhibitor, attenuates invasion and proliferation of tumor spheroids by blocking direct contact with neutrophils. Our findings also show that CXCR2 inhibition reduces neutrophil migration toward tumor spheroids. These results shed new light on the tumor-promoting mechanisms of human neutrophils and the tumor-suppressive mechanisms of CXCR2 inhibition in pancreatic cancer and may aid in the design and optimization of novel immunotherapeutic strategies based on neutrophils."

Journal • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • CXCR2

CXCR2 perturbation promotes Staphylococcus aureus implant-associated infection. (PubMed, J Med Microbiol) - "To assess the role of CXCR2 induction or inhibition during infection, treatment groups received daily intraperitoneal doses of either Lipocalin-2 (Lcn2) or AZD5069, respectively...Interestingly, however, perturbation of CXCR2 expression or signalling both resulted in enhanced Cxcr2 transcription and elevated implant-associated bacterial burdens. Thus, CXCR2 appears finely tuned to efficiently recruit effector cells and mediate control of S. aureus biofilm-mediated infection."

Journal • Immune Modulation • Immunology • Infectious Disease • CXCR2 • LCN2

Study to Assess MEDI4736 With Either AZD9150 or AZD5069 in Advanced Solid Tumors & Relapsed Metastatic Squamous Cell Carcinoma of Head & Neck (clinicaltrials.gov) - P1/2 | N=340 | Active, not recruiting | Sponsor: AstraZeneca | Phase classification: P1b/2 ➔ P1/2 | Trial completion date: Dec 2023 ➔ Mar 2025

Combination therapy • Metastases • Monotherapy • Phase classification • Trial completion date • Head and Neck Cancer • Oncology • Prostate Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Targeting myeloid chemotaxis to reverse prostate cancer therapy resistance. (PubMed, Nature) - "To determine whether myeloid cells fuel resistance to androgen receptor signalling inhibitors, and whether inhibiting CXCR2 to block myeloid chemotaxis reverses this, we conducted an investigator-initiated, proof-of-concept clinical trial of a CXCR2 inhibitor (AZD5069) plus enzalutamide in patients with metastatic CRPC that is resistant to androgen receptor signalling inhibitors. This study provides the first clinical evidence that senescence-associated myeloid inflammation can fuel mCRPC progression and resistance to AR blockade. Targeting myeloid chemotaxis merits broader evaluation in other cancers."

Journal • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Metastatic Castration-Resistant Prostate Cancer • Oncology • Prostate Cancer • Solid Tumor

A Comparative Inflammation-On-A-Chip with A Complete 3D Interface: Pharmacological Applications in COPD-Induced Neutrophil Migration. (PubMed, Adv Healthc Mater) - "We used the IoC model to evaluate the pharmacological effects of CXCR2 inhibitors (MK-7123, AZD5069, and SB225002) on the migration of neutrophil-like cells in the presence of plasma samples from patients with COPD. This is the first study to evaluate inhibitors of CXCR2-dependent NTEM in a comparative IoC model that mimics the physiological 3D microenvironment, consisting of an endothelial barrier, extracellular compartment, and inflammatory conditions. This IoC model will be useful to investigate COPD severity using patient samples, and will aid basic and translational research involving NTEM."

Journal • Chronic Obstructive Pulmonary Disease • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases

Combination Study of AZD5069 and Enzalutamide. (clinicaltrials.gov) - P1/2 | N=30 | Terminated | Sponsor: Institute of Cancer Research, United Kingdom | N=86 ➔ 30 | Trial completion date: Oct 2023 ➔ Nov 2022 | Active, not recruiting ➔ Terminated | Trial primary completion date: Jan 2023 ➔ Sep 2022; Discontinuation of production of IMP

Combination therapy • Enrollment change • Metastases • Trial completion date • Trial primary completion date • Trial termination • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Myeloid IL-8 enrichment associates with immunotherapy resistance in advanced hepatocellular carcinoma (EASL-ILC 2023) - "In this study, we analyzed the immune contexture of advanced HCC patients before and after pembrolizumab treatment to investigate the role of myeloid IL-8 in ICB-resistance mechanism and aim to intervene the IL-8 pathway through inhibition of its receptor by a clinical in-use CXCR2 antagonist...Therapeutic efficacy of CXCR2 pathway inhibition by AZD5069 in potentiating ICB response was evaluated in our ICB-resistant orthotopic mouse model which is generated by serial in vivo passaging of anti-PD-L1 residual tumor... We demonstrated the importance of myeloid IL-8/CXCR2 pathway in ICB-resistance from our advanced HCC cohort which paved way for IL-8 to become a novel prognostic target for immunotherapy. Blocking CXCR2 could reduce MDSC trafficking and overcome ICB-resistance in our pre-clinical HCC model, suggesting a promising combination regimen in future development."

IO biomarker • Metastases • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Immune Modulation • Oncology • Solid Tumor • CXCL8 • CXCR2

REDUCED EXPRESSION OF THE CHEMOKINES CXCL2, CXCL3 AND CXCL8 PROVIDES A POTENTIAL MECHANISM PROMOTING IMMUNE EVASION FACILITATING AML RELAPSE FOLLOWING ALLOGENEIC HSCT (EHA 2023) - "Conversely, CXCR2 inhibition with AZD5069 led to reduced CD4 proliferation and PD-1 expression.Summary/ This study further highlights the importance of immune evasion in mediating AML relapse following AHSCT. This study further highlights the importance of immune evasion in mediating AML relapse following AHSCT. The chemokines CXCL2 and CXCL8 were identified as potential mediators of this process and may provide prospective targets to enhance the GvL effect to prevent or treat post-AHSCT relapse. Diagram Description automatically generated Chemokine, Acute myeloid leukemia, Allogeneic hematopoietic stem cell transplant"

IO biomarker • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Hematological Malignancies • Leukemia • Oncology • Transplantation • CD4 • CD8 • CXCL3 • CXCL8 • CXCR2 • PD-1

Gastric cancer mesenchymal stem cells via the CXCR2/HK2/PD-L1 pathway mediate immunosuppression. (PubMed, Gastric Cancer) - "Our findings reveal that blocking GCMSCs-derived IL-8/CXCR2 pathway decreasing PD-L1 expression and lactate production, improving antitumor efficacy of anti-PD-1 immunotherapy, may be of value for the treatment of advanced gastric carcinoma."

IO biomarker • Journal • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CD8 • CXCL8 • CXCR1 • CXCR2 • HIF1A