fisogatinib (BLU-554) / CStone Pharma, Sanofi - LARVOL DELTA

A multicenter, open-label, first-in-human study of TYRA-430 in advanced hepatocellular carcinoma and other solid tumors with activating FGF/FGFR pathway aberrations (SURF431) (ESMO 2025) - P1 | "FGF19 signals through FGF receptor 4 (FGFR4), however, selective investigational FGFR4 inhibitors, such as fisogatinib and roblitinib have shown limited clinical efficacy. Part B Cohort 1 dose expansion will enroll approximately 40 patients with advanced HCC at RP2D(s), focusing on FGF19-positive patients; approximately 20 patients with FGFR3/4 altered solid tumors will be enrolled in Part B Cohort 2. The study is planned for approximately 25 centers in North America, Asia, and Europe."

Clinical • First-in-human • Metastases • P1 data • Brain Cancer • Hepatocellular Cancer • Lung Cancer • Lung Non-Small Cell Squamous Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • FGF19 • FGFR3 • FGFR4

TYRA-430: First reversible FGFR4/3 inhibitor designed to overcome current challenges in FGF19-driven hepatocellular carcinoma treatment. (ASCO-GI 2025) - "In vitro data showed that TYRA-430 displayed superior potency over the reversible multi-kinase inhibitors sorafenib and lenvatinib, and the covalent FGFR4 inhibitors fisogatinib (BLU-554) and roblitinib (FGF401) in KLB/FGF-19/FGFR3/4 driven models of HCC (Hep3B, HuH-7, and JHH-7 cells). TYRA-430 was active and potent in multiple KLB/FGF-19/FGFR3/4 models of human hepatocellular carcinoma in vitro and in vivo. Moreover, TYRA-430 displayed potent activity against known FGFR4 resistance mutations compared to covalent FGFR4-specific inhibitors in the clinic. TYRA-430 will be investigated in a Phase 1 clinical trial in hepatocellular carcinoma and other advanced solid tumors."

Gastric Cancer • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • FGF19 • FGFR3 • FGFR4

Fibroblast Growth Factor Receptor 4 Promotes Triple-Negative Breast Cancer Progression via Regulating Fatty Acid Metabolism Through the AKT/RYR2 Signaling. (PubMed, Cancer Med) - "Dysregulated FGFR4 activates the AKT/RYR2 axis, leading to tumor proliferation, invasion, and altered lipid metabolism in TNBC. FGFR4 inhibition could potentially serve as a novel therapeutic strategy for TNBC treatment."

Journal • Breast Cancer • Metabolic Disorders • Oncology • Solid Tumor • Triple Negative Breast Cancer • FGFR4

Orphan Drug Designations and Approvals (FDA) - Generic Name: fisogatinib, Date Designated: 09/14/2015, Orphan Designation: Treatment of hepatocellular cancer (HCC), Orphan Designation Status: Designated

Orphan drug • Hepatocellular Cancer

Bromocriptine sensitivity in bromocriptine-induced drug-resistant prolactinomas is restored by inhibiting FGF19/FGFR4/PRL. (PubMed, J Endocrinol Invest) - "Overall, our study revealed FGF19/FGFR4 as a new mechanism involved in the drug resistance of prolactinomas, and combination therapy targeting the pathway could be helpful for the treatment of BRC-induced drug-resistant prolactinomas."

Journal • Oncology • Pituitary Gland Carcinoma • FGF19 • FGFR4 • PRL

Genome-wide identification of Fgfr genes and function analysis of Fgfr4 in myoblasts differentiation of Lateolabrax maculatus. (PubMed, Gene) - "By treating differentiating myoblasts cultured in vitro with BLU-554, the mRNA expressions of myogenin (myog) and the numbers of myotubes formed by myoblasts increased significantly compared to negative control group. These results indicated that Fgfr4 inhibits the differentiation of myoblasts in spotted sea bass. Our findings contributed to filling a research gap on fgfr4 in bony fish myogenesis and the theoretical understanding of growth trait regulation of spotted sea bass."

Journal • FGFR2 • FGFR3 • FGFR4 • Myogenin

Discovery of 2,6-Naphthyridine Analogues as Selective FGFR4 Inhibitors for Hepatocellular Carcinoma. (PubMed, J Med Chem) - "Compound 11 displayed a nanomolar potency against Huh7 cell lines and high selectivity over FGFR1-3 that were comparable to that of fisogatinib (8) as a reference standard. Additionally, compound 11 demonstrated remarkable antitumor efficacy in the Huh7 and Hep3B HCC xenograft mouse model. Moreover, bioluminescence imaging experiments with the orthotopic mouse model support that compound 11 can be considered a promising candidate for treating HCC."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • FGF19 • FGFR1 • FGFR4

A Phase 1 Study of Fisogatinib (BLU-554) in Patients With Hepatocellular Carcinoma (clinicaltrials.gov) - P1 | N=146 | Completed | Sponsor: Blueprint Medicines Corporation | Active, not recruiting ➔ Completed

Trial completion • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • FGF19

Dual inhibition of FGFR4 and HER2/EGFR with Lapatinib improves targeting of Erk and Akt signaling in HER2+ breast cancer cells (SABCS 2023) - "Ridaforolimus (mTOR inhibitor) was used in combination with either BLU554 or Lapatinib to assess MAPK/ERK and PI3K/AKT pathway crosstalk in MB-453 cells. Dual treatment simultaneously blocks MAPK/ERK and PI3K/AKT signaling and yields decreases of mTOR downstream effectors pS6RP and p4EBP1. These effects are maintained even when challenged with FGF19, suggesting that dual inhibition of FGFR4 and HER2 could prevent pathway activation from external stimuli."

Breast Cancer • HER2 Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • EGFR • EIF4EBP1 • FGF19 • FGFR4 • HER-2

FGF19-Induced Inflammatory CAF Promoted Neutrophil Extracellular Trap Formation in the Liver Metastasis of Colorectal Cancer. (PubMed, Adv Sci (Weinh)) - "Importantly, targeting FGF19 signaling with fisogatinib efficiently suppresses FGF19-induced liver metastasis in a mouse model. In summary, this study describes the mechanism by which FGF19 regulates CRLM, thereby providing a novel target for CRLM intervention."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Hepatology • Immune Modulation • Oncology • Solid Tumor • CAFs • FGF19 • FGFR4 • IL1B

FGF19-MEDIATED ELF4 OVEREXPRESSION PROMOTES COLORECTAL CANCER METASTASIS THROUGH FGFR4 AND SRC (DDW 2023) - "Furthermore, the combination treatment of FGFR4 inhibitor BLU-554 and SRC inhibitor KX2-391 dramatically suppressed ELF4-induced CRC metastasis. We demonstrated that FGF19-FGFR4 upregulated ELF4 expression through the ERK1/2/SP1 pathway, and ELF4 promotes CRC metastasis through upregulating FGFR4 and SRC expression, which formed a FGF19-ELF4-FGFR4 positive feedback loop. Targeting the FGF19-ELF4 pathway might represent a novel therapeutic strategy to inhibit CRC metastasis."

Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • FGF19 • FGFR4 • SRC

Discovery & characterization of a next-generation FGFR4 inhibitor overcoming resistant mutations (AACR 2023) - "Efficacy studies were conducted in HCC xenograft models and mutant FGFR4-dependent xenograft models including a RMS PDX model harboring FGFR4 V550L mutation. ABSK012 demonstrated strong potency over multiple FGFR4 mutants that are insensitive to a first generation FGFR4 inhibitor BLU-554. ABSK012, presented here by Abbisko Therapeutics, is a highly potent, selective, and next-generation small molecule FGFR4 inhibitor overcoming FGFR4 mutations resistant to first-generation inhibitors. Its superior preclinical profile supports its fast-track development into clinic."

Late-breaking abstract • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Rhabdomyosarcoma • Sarcoma • Solid Tumor • AVEN • FGF19 • FGFR4

FGF19/FGFR4-mediated elevation of ETV4 facilitates hepatocellular carcinoma metastasis by upregulating PD-L1 and CCL2. (PubMed, J Hepatol) - "ETV4 is a prognostic biomarker, and anti-PD-L1 combined with FGFR4 inhibitor BLU-554 or MAPK inhibitor trametinib may be effective strategies to inhibit HCC metastasis."

IO biomarker • Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • CCL2 • CCR2 • ETV4 • FGF19 • FGFR4 • HGF • MET • PD-L1

FGF19-mediated ELF4 overexpression promotes colorectal cancer metastasis through transactivating FGFR4 and SRC. (PubMed, Theranostics) - "Furthermore, the combination of the FGFR4 inhibitor BLU-554 and the SRC inhibitor KX2-391 dramatically suppressed ELF4-mediated CRC metastasis. We demonstrated the essentiality of ELF4 in the metastatic process of CRC, and targeting the ELF4-relevant positive feedback circuit might represent a novel therapeutic strategy."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • FGF19 • FGFR4 • SRC

Phase 1 safety and clinical activity of BLU-554 in advanced hepatocellular carcinoma (HCC) (ESMO 2017) - P1; "48 (79%) pts had metastatic disease, 54 (89%) had failed ≥1 prior systemic therapy (48 (79%) sorafenib; 11 (18%) nivolumab) and 29 (48%) had pathway activation (IHC+). BLU-554 is well tolerated at the recommended dose of 600 mg and demonstrates important clinical activity in FGF19 IHC+ advanced HCC pts who have failed prior systemic therapy."

Clinical • P1 data • Hepatocellular Cancer

Identification of resistance mechanisms to FGFR4 targeted therapy in hepatocellular carcinoma (AACR-NCI-EORTC 2019) - P1; "In this study, we validate for the first time a driver of disease in the FGF19 expressing subset of HCC through the identification of Fisogatinib resistance mutations in FGFR4. Using a gatekeeper-agnostic pan-FGFR inhibitor we show, in preclinical models, continued FGF19/FGFR4 pathway dependence. These results validate FGF19/FGFR4 as an oncogenic driver and inform the profile of potential next-generation inhibitors designed to facilitate improved patient outcomes."

A phase Ib/II study of BLU-554, a fibroblast growth factor receptor 4 inhibitor in combination with CS1001, an anti-PD-L1, in patients with locally advanced or metastatic hepatocellular carcinoma. (PubMed, Invest New Drugs) - "Preliminary data showed that BLU-554 in combination with CS1001 is safe and effective for treatment of patients with locally advanced or metastatic HCC."

Combination therapy • Journal • Metastases • P1/2 data • Dermatology • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • FGF19 • FGFR4

A Phase 1 Study of Fisogatinib (BLU-554) in Patients With Hepatocellular Carcinoma (clinicaltrials.gov) - P1 | N=150 | Active, not recruiting | Sponsor: Blueprint Medicines Corporation | Trial completion date: Dec 2022 ➔ Dec 2023

Trial completion date • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • FGF19

A Phase Ib/II Study of Fisogatinib(BLU-554) in Subjects With Hepatocellular Carcinoma (clinicaltrials.gov) - P1/2 | N=26 | Completed | Sponsor: CStone Pharmaceuticals | Unknown status ➔ Completed | N=52 ➔ 26

Combination therapy • Enrollment change • Metastases • Trial completion • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • PD-L1

Mechanisms of resistance toward FGFR4 inhibition in hepatocellular carcinoma (AACR-NCI-EORTC 2022) - "Materials and We established resistant cell lines following long-term exposure of Huh7 with BLU-554...In addition, the cells were also resistant to other FGFR4 inhibitors including FGF-401, H3B-6527 and erdafitinib... These data suggest the bypass activation of other RTK may contribute to acquired resistance of FGFR4 inhibition and potential combination strategy to overcome resistance. No"

Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • FGF19 • FGFR4

A Phase 1 Study of Fisogatinib (BLU-554) in Patients With Hepatocellular Carcinoma (clinicaltrials.gov) - P1 | N=150 | Active, not recruiting | Sponsor: Blueprint Medicines Corporation | Trial completion date: Mar 2022 ➔ Dec 2022

Trial completion date • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • FGF19

Predictiveness of the Human-CYP3A4-Transgenic Mouse Model (Cyp3aXAV) for Human Drug Exposure of CYP3A4-Metabolized Drugs. (PubMed, Pharmaceuticals (Basel)) - "Population pharmacokinetic models based on wild-type (WT) and Cyp3aXAV mouse pharmacokinetic data of oral lorlatinib, brigatinib, ribociclib and fisogatinib were allometrically scaled and compared to human exposure. Due to the lack of a human population pharmacokinetic model for fisogatinib, only median maximum concentration ratios were calculated, resulting in ratios of 1.0 and 0.6 for WT and Cyp3aXAV mice extrapolations, respectively. The more accurate predictions of human exposure in preclinical research based on the Cyp3aXAV mouse model can ultimately result in FIH doses associated with improved safety and efficacy and in higher success rates in drug development."

Journal • Preclinical • CYP3A4

Fisogatinib: Expiry of patents in US/ex-US related to composition-of-matter analogs and method of use between 2033 and 2040 (Blueprint Medicines) - Annual Report 2021

Patent • Oncology

BLU-554, A selective inhibitor of FGFR4, exhibits anti-tumour activity against gastric cancer in vitro. (PubMed, Biochem Biophys Res Commun) - "BLU-554 inhibited the mitogen-activated protein kinase (RAS-RAF-MEK-ERK) pathway by inhibiting FGFR4, ultimately impeding the proliferation and invasion of gastric cancer cells and promoting cell apoptosis and cell cycle arrest."

Journal • Preclinical • Gastric Cancer • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • FGFR4

A Phase 1 Study of Fisogatinib (BLU-554) in Patients With Hepatocellular Carcinoma (clinicaltrials.gov) - P1; N=150; Active, not recruiting; Sponsor: Blueprint Medicines Corporation; Trial completion date: Dec 2021 ➔ Mar 2022

Clinical • Trial completion date • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • FGF19