fexagratinib (ABSK091) / AstraZeneca, Abbisko - LARVOL DELTA

Targeting FGFR Attenuates Tumor Growth in an Anal Squamous Cell Carcinoma Patient Derived Xenograft Model. (PubMed, Mol Carcinog) - "Fourier-transform infrared (FTIR) spectroscopy of post-treatment residual tumors revealed significant differences in the Amide I and Amide II regions between AZD4547-treated and control groups. These findings demonstrate that FGFR inhibition effectively attenuates ASCC tumor growth and highlights the promise of precision medicine in managing this rare cancer."

Journal • Preclinical • Anal Carcinoma • Oncology • Squamous Cell Carcinoma • CASP3 • FGFR

BISCAY: Open-Label, Randomised, Multi-Drug, Biomarker-Directed, Phase 1b Study in Pts w/ Muscle Invasive Bladder Cancer (clinicaltrials.gov) - P1 | N=117 | Active, not recruiting | Sponsor: AstraZeneca | Trial completion date: Mar 2025 ➔ Jan 2026

Biomarker • Trial completion date • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • CCNE1 • CDKN2A • HRD • MYCL • MYCN • RB1

Fibroblast growth factor 8 (FGF8) induces mitochondrial remodeling in chondrocytes via ERK/AMPK signaling pathway. (PubMed, FASEB J) - "In contrast, both AZD4547 and U0126 inhibitors abolished mitochondrial elongation as well as the alteration of fusion-fission proteins induced by FGF8, and U0126 also inhibited the FGF8-triggered activation of AMPK. This study is the first to reveal that FGF8 remodels mitochondria through ERK/AMPK signaling in chondrocytes, offering novel insights into the potential role of FGF8 in OA."

Journal • Immunology • Ocular Inflammation • Osteoarthritis • Pain • Rheumatology • FGF8 • FGFR • MFN2 • OPA1

FGFR3 signaling is essential for gastric cancer cell triggering the transition of BM-MSCs into tumor-associated MSCs. (PubMed, Differentiation) - "Suppression of FGFR3 signaling by AZD4547 or siRNA against FGFR3 notably blocked the miR-99a-5p inhibitor-induced BM-MSCs transition and the oncogenic roles of GC-MSCs...Taken together, although manipulating miR-99a-5p to mimic its levels in GC-MSCs promotes the transition of BM-MSCs into GC-MSCs-like cells, FGFR3 signaling, rather than miR-99a-5p, is unexpectedly essential for the education of BM-MSCs by gastric cancer cells. This discovery provides a novel mechanism underlying the transition of BM-MSCs into tumor-associated MSCs and identifies potential therapeutic targets for gastric cancer."

Journal • Gastric Cancer • Oncology • Solid Tumor • FGFR3 • MIR99A

Human-induced pluripotent stem cell-derived exosomes promote skin wound healing through activating FGF2-mediated p38 pathway. (PubMed, Mol Cell Biochem) - "In addition, fibroblast growth factor 2 (FGF-2) was existent in hiPSC-Exos, and hiPSC-Exos could upregulate the p-p38/p38 level, which could be significantly reversed by AZD4547, but not affect the p-ERK/ERK and p-JNK/JNK levels in wound model tissues and cells. In conclusion, hiPSC-Exos may have the potential to promote wound healing by inhibiting cell inflammation as well as promoting cell proliferation and migration based on inherent FGF-2 targeting to FGFR3 to activate p38 pathway, which may serve as a promising candidate for skin healing."

Journal • Inflammation • Mood Disorders • CCL2 • CXCL5 • FGF2 • FGFR3 • IL1B • PCNA

Effect of electroacupuncture on regulation of the basic fibroblast growth factor/glycogen synthase kinase-3β pathway in Parkinson's disease mice. (PubMed, Zhen Ci Yan Jiu) - "EA at GV16, LR3 and ST36 can alleviate motor disorders, reduce cell apoptosis, protect dopaminergic neurons in mice with PD, which may be related to its effect in regulating the BFGF/GSK-3β pathway."

IO biomarker • Journal • Preclinical • CNS Disorders • Hematological Malignancies • Lymphoma • Movement Disorders • Oncology • Parkinson's Disease • BAX • BCL2 • FGFR • PI3K

Extrachromosomal DNA dynamics contribute to intratumoural receptor tyrosine kinase genetic heterogeneity and drug resistance in gastric cancer. (PubMed, Mol Cancer Res) - "Conversely, when resistant clone cells were cultured under conditions that excluded AZD4547, the ecDNA status became similar to that of the original clone cells, and the inhibitory effect on cell growth was restored. Implications: Our results show that dynamic quantitative and qualitative changes in ecDNA can drive the intratumoural genetic heterogeneity of RTKs and resistance to RTK inhibitors."

Heterogeneity • Journal • Gastric Cancer • Oncology • Solid Tumor • FGFR2 • HER-2

Efficacy and safety of fexagratinib (Fexa) in Chinese patients (pts) with metastatic or unresectable urothelial carcinoma (mUC) harboring FGF receptor (FGFR) genetic alterations. (ASCO-GU 2025) - P1b/2 | "Fexa was generally well tolerated in previously treated Chinese mUC pts, with no new safety signals identified. The efficacy observed was consistent with that previously reported in western populations, with notable benefits seen in pts with FGFR alterations who had experienced disease progression following PD-(L)1 treatment."

Clinical • Metastases • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • FGFR • FGFR3

Efficacy and safety of fexagratinib (Fexa) in combination with tislelizumab (T) in a phase II study of patients (pts) with locally advanced or metastatic urothelial carcinoma (mUC) harboring FGFR alterations (FGFRa). (ASCO-GU 2025) - P2 | "1st-line Tx with Fexa plus T were tolerable with a safety profile consistent with previously reported for both agents. The toxicity was overall manageable. Encouraging efficacy was observed in pts with FGFR3 overexpression, regardless of PD-L1 expression or FGFR3 mutations/fusions.Further exploration of these findings is warranted."

Clinical • Combination therapy • IO biomarker • Metastases • P2 data • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • FGFR • FGFR3 • PD-L1

Orphan Drug Designations and Approvals g (FDA) - Generic Name: Small molecular inhibitor of fibroblast growth factor receptor (FGFR)-1,2 and 3 tyrosine kinases, Date Designated: 03/01/2022, Orphan Designation: Treatment of gastric cancer, Orphan Designation Status: Designated.

Orphan drug • Gastric Cancer

Design, synthesis, and biological evaluation of a potent and orally bioavailable FGFRs inhibitor for fibrotic treatment. (PubMed, Eur J Med Chem) - "Through scaffold hopping, bioisosteric replacement design, and structure-activity relationship optimization, we developed a series of highly potent FGFRs inhibitors, and the indazole-containing candidate compound A16 showed potent kinase activity comparable to that of AZD4547...Moreover, in models of pulmonary fibrosis, A16 ameliorated (in the prevention model) and reversed (in the treatment model) bleomycin-induced lung fibrosis, as well as mitigated inflammatory immune response in the lung. Furthermore, in the CCl4-induced liver fibrosis model, when A16 was administrated orally at a dose of 30 mg/kg/day for 3 weeks, it effectively improved liver function, restored damaged liver structures, and reduced collagen deposition. Taken together, these results suggest that A16 could be a potential drug candidate for the treatment of organ fibrosis."

Journal • Fibrosis • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Pulmonary Disease • Respiratory Diseases • TGFB1

SAFIR02_Breast - Efficacy of Genome Analysis as a Therapeutic Decision Tool for Patients With Metastatic Breast Cancer (clinicaltrials.gov) - P2 | N=1460 | Active, not recruiting | Sponsor: UNICANCER | Trial completion date: Dec 2024 ➔ Dec 2025

IO biomarker • Trial completion date • Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor

BISCAY: Open-Label, Randomised, Multi-Drug, Biomarker-Directed, Phase 1b Study in Pts w/ Muscle Invasive Bladder Cancer (clinicaltrials.gov) - P1 | N=117 | Active, not recruiting | Sponsor: AstraZeneca | Trial completion date: Jun 2024 ➔ Mar 2025

Biomarker • Trial completion date • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • CCNE1 • CD8 • CDKN2A • FGFR • HRD • IFNG • IL10 • IL2 • IL6 • MYCL • MYCN • RB1

Systematic Analysis of Disulfidptosis-Related lncRNAs in Hepatocellular Carcinoma with Vascular Invasion Revealed That AC131009.1 Can Promote HCC Invasion and Metastasis through Epithelial-Mesenchymal Transition. (PubMed, ACS Omega) - "Additionally, we identified valuable chemical drugs (AZD4547, BMS-536924, BPD-00008900, dasatinib, and YK-4-279) for high-risk VI+ HCC patients. Immunohistochemical analysis and hematoxylin-eosin staining (HE) staining provided preliminary evidence that AC131009.1 may promote the invasion and metastasis of HCC cells by inducing epithelial-mesenchymal transition (EMT) in both subcutaneous xenograft models and orthotopic HCC models within nude mice. To summarize, we developed a risk assessment model founded on DRLRs and explored the potential mechanisms by which hub DRLRs promote HCC invasion and metastasis."

IO biomarker • Journal • Hepatocellular Cancer • Oncology • Solid Tumor • LUCAT1

FGFR SIGNALING POTENTIATES CHOLESTATIC LIVER FIBROSIS (AASLD 2024) - "FGFR signaling was inhibited in vivo by a small molecule inhibitor AZD4547... FGFR signaling is activated in human liver fibrosis. FGFR inhibition ameliorates fibrosis progression in fibrosis models, suggesting that targeting FGFR signaling may be a potential therapeutic strategy to manage liver fibrosis"

Fibrosis • Hepatology • Immunology • Liver Cirrhosis • ABCB4 • FGFR1 • MMP7 • MMP9 • S100A4 • TGFB1 • TIMP1 • TIMP3

Anti-inflammatory and remyelinating effects of fexagratinib in experimental multiple sclerosis. (PubMed, Br J Pharmacol) - "Multi-kinase inhibition by fexagratinib in a well-tolerated dose of 1 mg·kg-1 in humans may be a promising approach to reduce inflammation and neurodegeneration, to slow down disease progression and support remyelination in patients."

Journal • CNS Disorders • Immunology • Inflammation • Multiple Sclerosis • Solid Tumor • CSF1R

The efficacy and mechanism of pan-FGFR inhibitor (AZD4547) combined with immunoagonists or immunosuppressants in FGFR-positive tumors (ESMO 2024) - "Pan-FGFR inhibitor (AZD4547) combined with 4-1BB antibody have synergistic anti-tumor effects, which not only directly inhibit tumor cell proliferation, but also enhance anti-tumor immunity, further inhibit tumor growth, and significantly prolong survival."

Clinical • IO biomarker • Breast Cancer • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Hematological Malignancies • Oncology • Solid Tumor • CD8 • IFNG • ITGAM • ITGAX

FGF23-Mediated Hypertension via Augmented Calcium Entry in Vascular Smooth Muscle Cells (ERA-EDTA 2024) - "To elucidate the in vitro pro-hypertensive mechanisms of FGF23, studies were conducted with the administration of inhibitors targeting FGF Receptors 1-3 (AZD4547, 150 nM), FGF Receptor-4 (BLU9931, 10 nM), and Erk1/2 phosphorylation (PD98059, 10 M)...The addition of Thapsigargin in a Ca2+-free culture medium to VSMCs incubated with recombinant FGF23 for 9 days led to increased Ca2+ efflux from endoplasmic reticulum... Elevated levels of FGF23 directly enhanced calcium entry in VSMCs. This effect is mediated by FGFR1-3 receptors, Erk1/2 phosphorylation, and the upregulation of related protein to cell contraction such as SERCA2a, PKD1 or AGTR1. These modifications could be responsible of FGF23-associated hypertension in the experimental model."

Cardiovascular • Hypertension • FGF23 • FGFR4 • PKD1 • PRKD1 • STIM1

Macrophage-derived FGFR1 drives atherosclerosis through PLCγ-mediated activation of NF-κB inflammatory signaling pathway. (PubMed, Cardiovasc Res) - "Our study provides evidence of a new FGFR1-PLCγ- NF-κB axis in macrophages in inflammatory atherosclerosis, supporting FGFR1 as a potentially therapeutic target for atherosclerosis-related diseases."

Journal • Atherosclerosis • Cardiovascular • Dyslipidemia • Inflammation • APOE • FGFR1 • FRS2

TARGET: A phase I/II open-label multicenter study to assess safety and efficacy of fexagratinib in patients with relapsed/refractory FGFR fusion-positive glioma. (PubMed, Neurooncol Adv) - P1/2 | "Fexagratinib exhibited acceptable toxicity but limited efficacy in recurrent FGFR3-TACC3 + HGGs. Patients treated at first recurrence appeared more likely to benefit, yet additional evidence is required."

Clinical • Journal • P1/2 data • Brain Cancer • CNS Tumor • Dental Disorders • Diabetes • Glioblastoma • Glioma • Oncology • Solid Tumor • Stomatitis • FGFR • FGFR3 • TACC3

National Lung Matrix Trial: Multi-drug Phase II Trial in Non-Small Cell Lung Cancer (clinicaltrials.gov) - P2 | N=423 | Active, not recruiting | Sponsor: University of Birmingham | Trial completion date: Sep 2023 ➔ Sep 2024 | Trial primary completion date: Sep 2023 ➔ Sep 2024

IO biomarker • Trial completion date • Trial primary completion date • Lung Cancer • Lung Non-Small Cell Squamous Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • NKX2-1 • TP63

THE CLINICAL SIGNIFICANCE OF FGFR2 AS A THERAPEUTIC TARGET FOR ESCAPING TRASTUZUMAB RESISTANCE (GBCC 2024) - "To prevent FGF2/FGFR2 signaling pathway, we treated with specific FGFR inhibitors, BGJ398 and AZD4547, in TR cells...Accordingly, a specific MEK1/2 inhibitor, binimetinib, enhanced cellular senescence, suggesting that FGFR2 inhibitors induce cellular senescence through regulation of the ERK/p27/cyclinD1 axis. Taken together, these findings reveal that trastuzumab resistance is mediated through the activation of novel signaling pathways including the FGF2/FGFR2 signaling pathway. Therefore, we cautiously suggest that combination therapy with FGFR2 targeting drugs and trastuzumab will be more effective in overcoming trastuzumab resistance."

Clinical • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • CCND1 • FGF2 • FGFR1 • FGFR2 • HER-2

Fibroblast growth factor receptor inhibitors mitigate the neuropathogenicity of Borrelia burgdorferi or its remnants ex vivo. (PubMed, Front Immunol) - "Inhibition of FGFR1-3 by AZD4547 similarly downregulated both inflammation and apoptosis in both FC and DRG in response to live bacteria, while with sonicated remnants, this effect was seen in one of the two FC tissues and 2 of 3 DRG tissues tested...We show here that FGFR inhibition can be an effective anti-inflammatory treatment in antibiotic refractive neurological Lyme. Alternatively, two biologics may be needed to effectively curb neuroinflammation and pathology in the CNS and PNS."

Journal • Preclinical • Inflammation • Inflammatory Arthritis • Lyme Disease • CCL2 • CXCL8 • FGFR • FGFR2 • FGFR3 • IL6

Analysis of the effect of FGFR inhibitor and cannabidiol in colorectal cancer (AACR 2024) - "It was confirmed that the combined effect of FGFR inhibitor and cannabidiol was effective in colorectal cancer cells, and it was assumed to be related to the ER stress pathway."

Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • FGFR2

Hyperglycemia activates FGFR1 via TLR4/c-Src pathway to induce inflammatory cardiomyopathy in diabetes. (PubMed, Acta Pharm Sin B) - "Pharmacological inhibition of FGFR1 by a selective inhibitor, AZD4547, also prevents cardiac inflammation, fibrosis, and dysfunction in both type 1 and type 2 diabetic mice. These studies have identified FGFR1 as a new player in driving DCM and support further testing of FGFR1 inhibitors for possible cardioprotective benefits."

Journal • Cardiomyopathy • Cardiovascular • Diabetes • Fibrosis • Immunology • Inflammation • Metabolic Disorders • Type 2 Diabetes Mellitus • FGFR1 • TLR4