roblitinib (FGF401) / Everest Medicines, Novartis - 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

Reactivation of the PI3K/mTOR Signaling Pathway Confers Resistance to the FGFR4 Inhibitor FGF401. (PubMed, Int J Mol Sci) - "The FGF401/everolimus combination effectively suppressed tumor cell proliferation; promoted apoptosis; reduced tumor hypoxia via blood vessel normalization; and downregulated key proteins involved in proliferation, survival, metastasis, and angiogenesis. These preclinical findings provide a strong rationale for clinical trials combining FGFR4 and mTOR inhibitors in HCC patients with FGF19/FGFR4/mTOR-dependent tumors."

Journal • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor • FGF19 • FGFR4

Targeting Drug Resistance in Hepatocellular Carcinoma: Uncovering Metabolic Vulnerabilities for Therapeutic Re-Sensitization (EACR 2025) - "Dose-response experiments in the presence of key growth factors were performed to determine sensitivities to five kinase inhibitors: Lenvatinib, Sorafenib, Regorafenib, Roblitinib, and Erdafitinib, the latter two being fibroblast growth factor receptor inhibitors currently in clinical trials. This study aims to provide a framework for targeting metabolic vulnerabilities in HCC, offering potential new therapies to enhance treatment efficacy and to break or delay drug resistance. By integrating physiologically relevant culture systems and metabolic reprogramming strategies, future findings could contribute to the development of more effective interventions for overcoming therapeutic resistance in HCC."

Hepatitis B • Hepatitis C • Hepatocellular Cancer • Hepatology • Infectious Disease • Liver Cancer • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Oncology • Solid Tumor • FGFR

PAX translocations remodel mitochondrial metabolism through altered leucine usage in rhabdomyosarcoma. (PubMed, Cell) - "We identify leucine usage as a key factor driving the growth of aggressive PAX-fusion tumors, as limiting its bioavailability impaired oxidative phosphorylation and mitochondrial metabolism, delaying tumor progression and improving survival in vivo. Our data provide a compelling list of actionable targets and suggest promising new strategies to treat this tumor."

Journal • Oncology • Rhabdomyosarcoma • Sarcoma • Solid Tumor • FGF • PAX3

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

SORL1-Mediated EGFR and FGFR4 Regulation Enhances Chemoresistance in Ovarian Cancer. (PubMed, Cancers (Basel)) - "Our data showed that a selective inhibitor of FGFR4, FGF401, can improve the therapeutic efficacy of carboplatin in a xenograft mouse model of ovarian cancer. This study has demonstrated the therapeutic potential of targeting the SORL1/FGFR4 pathway to improve the chemoresponse of patients with recurrent and/or resistant ovarian cancer."

Journal • Oncology • Ovarian Cancer • Solid Tumor • EGFR • FGFR4 • SORL1 • SORT1

SORL1-Mediated EGFR and FGFR4 Regulation Enhances Chemoresistance in Ovarian Cancer (Multidisciplinary Digital Publishing Institute) - "Our data showed that a selective inhibitor of FGFR4, FGF401, can improve the therapeutic efficacy of carboplatin in a xenograft mouse model of ovarian cancer. This study has demonstrated the therapeutic potential of targeting the SORL1/FGFR4 pathway to improve the chemoresponse of patients with recurrent and/or resistant ovarian cancer."

Preclinical • Ovarian Cancer

Fibroblast growth factor receptor four inhibitor FGF401 improves the efficacy of trastuzumab in FGFR4-overexpressing breast cancer cells. (PubMed, Int J Cancer) - "We believe that FGFR4 overexpression and complex formation with HER2 can serve as molecular markers to assist clinicians in identifying trastuzumab-resistant tumors. Our results suggest that FGF401 combined with trastuzumab as adjuvant therapy for patients with trastuzumab-resistant breast cancer may be a potential new treatment strategy."

Journal • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Inflammatory Arthritis • Oncology • Solid Tumor • FGFR4

Identification of FGFR4 as a regulator of myofibroblast differentiation in Pulmonary Fibrosis. (PubMed, Am J Physiol Lung Cell Mol Physiol) - "In vivo, we evaluated the development of bleomycin-induced lung fibrosis in Fgfr4-deficient (Fgfr4-/-) mice compared to Wild Type littermates (WT), and after FGF401 treatment in WT mice compared to a control group receiving the solvent only. Conclusion Our data suggest that FGFR4 exerts pro-fibrotic properties by enhancing TGF- β signaling in vitro. However, the inhibition of FGFR4 is not sufficient to prevent the development of pulmonary fibrosis in vivo."

Journal • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • ACTA2 • EDN1 • FGF19 • FGFR4 • TGFB1

Ferroptosis-Targeting Drugs in Breast Cancer. (PubMed, J Drug Target) - "For instance, roblitinib induces ferroptosis of trastuzumab-resistant human epidermal growth factor receptor 2 (HER2)-positive breast cancer cells by diminishing fibroblast growth factor receptor 4 (FGFR4) expression, thereby augmenting the susceptibility of these cells to HER2-targeted therapies. In tamoxifen-resistant breast cancer cells, Fascin exacerbates their resistance by repressing solute carrier family 7 member 11 (SLC7A11) expression, which in turn heightens their responsiveness to tamoxifen. In recent years, Chinese herbs extracts and therapeutic drugs have been demonstrated to elicit ferroptosis in breast cancer cells by modulating a spectrum of regulatory factors pertinent to ferroptosis, including SLC7A11, glutathione peroxidase 4 (GPX4), acyl-CoA synthetase long chain family member 4 (ACSL4), and heme oxygenase 1 (HO-1). Here, we review the roles and mechanisms of Chinese herbal extracts and therapeutic drugs in regulating ferroptosis in breast cancer,..."

Journal • Review • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Lung Cancer • Oncology • Solid Tumor • ACSL4 • Fascin • FGFR4 • GPX4 • HMOX1 • SLC7A11

The leukemia inhibitory factor regulates fibroblast growth factor receptor 4 transcription in gastric cancer. (PubMed, Cell Oncol (Dordr)) - "Together these data unreveal a previously unregnized regulatory mechanism of FGFR4 by LIF/LIFR and demonstrate that LIF and FGF19 converge on the regulation of oncogenic STAT3 in GC cells."

Journal • Gastric Adenocarcinoma • Gastric Cancer • Gastrointestinal Cancer • Hematological Malignancies • Infectious Disease • Leukemia • Oncology • Solid Tumor • FGF19 • FGFR4 • IL6 • JAK1 • LIF • LIFR

FGFR4 and EZH2 inhibitors synergistically induce hepatocellular carcinoma apoptosis via repressing YAP signaling. (PubMed, J Exp Clin Cancer Res) - "Collectively, our study highlighted the potential of the therapeutic combination of FGFR4 and EZH2 inhibitors, which would provide new references for the further development of clinical treatment strategies for HCC."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • EZH2 • FGFR4

Integrated Pharmacokinetic-Pharmacodynamic (PK-PD) and Exposure-Response (E-R) Analyses to Support the First-in-Human (FIH) Phase I/II Study of FGF401 (EORTC-NCI-AACR 2018) - P1/2; "This integrated analysis, covering PK, efficacy, safety and biomarkers, provides insights into the E-R relationships of FGF401, and demonstrates the utility of this methodology in early clinical development. These data support the FGF401 120 mg QD dose regimen."

P1/2 data • PK/PD data • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor

NVP-FGF401, a first-in-class highly selective and potent FGFR4 inhibitor for the treatment of HCC (AACR 2017) - P1/2; "...Sorafenib is the only targeted agent to show a marginal improvement in overall survival (OS) for patients with advanced HCC...The anti-tumor activity was confirmed across several xenograft animal models, as well as in patient-derived tumor xenografts (PDX) established in mice. The excellent drug-like properties of NVP-FGF401 drove us to test its efficacy in HCC patients in a PhI/II study, being the first selective FGFR4 inhibitor to ever enter into clinical trials (NCT02325739)."

Biosimilar • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology

Phase 1 dose escalation study of FGFR4 inhibitor in combination with pembrolizumab in advanced solid tumors patients. (PubMed, Cancer Med) - "Eighty milligrams BID was the MTD and RP2D for EVER4010001 plus pembrolizumab. Efficacy results were promising, and no new safety risks were reported, justifying the Phase 2 portion of this study."

Combination therapy • Journal • Metastases • P1 data • Oncology • Solid Tumor • FGFR4

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

Ph I/II study of FGF401 in adult pts with HCC or solid tumors characterized by FGFR4/KLB expression (AACR 2017) - P1/2; "Preliminary data suggest FGF401 has a manageable safety profile that is consistent with FGFR4 pathway inhibition. Promising clinical activity was observed in pts with advanced HCC in this dose escalation part of the study. Studies to further evaluate FGF401 as a single agent and in combination are ongoing."

Biomarker • Clinical • P1 data • Biosimilar • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology

Integration of pharmacokinetics, pharmacodynamics, safety, and efficacy into model-informed dose selection in oncology first-in-human study: a case of roblitinib (FGF401). (PubMed, Clin Pharmacol Ther) - "Simulations from an indirect PopPK/PD model established for alanine aminotransferase, including a chain of three precursor compartments, further supported that maximal target inhibition was achieved and a lack of safety-exposure relationship. This M&S framework supported a dose selection of 120 mg QD fasted or with low-fat meal and provides a practical example that might be applied broadly in oncology early clinical development."

Journal • P1 data • PK/PD data • Oncology • FGF19 • FGFR4

Strategies to inhibit FGFR4 V550L-driven rhabdomyosarcoma. (PubMed, Br J Cancer) - "Our results pave the way for precision medicine approaches against FGFR4 V550L-driven RMS."

Journal • Oncology • Pediatrics • Rhabdomyosarcoma • Sarcoma • Solid Tumor • FGFR4 • PAX3

Contribution of machine learning to tumor growth inhibition modeling for hepatocellular carcinoma patients under Roblitinib (FGF401) drug treatment. (PubMed, CPT Pharmacometrics Syst Pharmacol) - "The final PK/PD model was used to simulate effect of patients' characteristics on tumor growth inhibition profiles. The proposed methodology can be used to support drug development decisions, especially when large interpatient variability is observed."

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

A first-in-human phase 1/2 study of FGF401 and combination of FGF401 with spartalizumab in patients with hepatocellular carcinoma or biomarker-selected solid tumors. (PubMed, J Exp Clin Cancer Res) - P1/2 | "At biologically active doses, FGF401 alone or combined with spartalizumab was safe in patients with FGFR4/KLB-positive tumors including HCC. Preliminary clinical efficacy was observed. Further clinical evaluation of FGF401 using a refined biomarker strategy is warranted."

Biomarker • IO biomarker • Journal • P1 data • P1/2 data • P2 data • Gastrointestinal Cancer • Hepatocellular Cancer • Immune Modulation • Inflammation • Oncology • Solid Tumor • FGF19 • FGFR4

Highly Potent Immunotoxins Targeting the Membrane-distal N-lobe of GPC3 for Immunotherapy of Hepatocellular Carcinoma. (PubMed, J Cancer) - "Combination of J80A-PE24 with an angiogenesis inhibitor FGF401 showed additive effect, which dramatically shrank tumor growth. Our work demonstrated that, due to high affinity, excellent thermostability and potency, chicken mAbs targeting the N-lobe of GPC3 are appealing candidates to develop potent ADCs for immunotherapy of liver cancer."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • GPC3

Everest Medicines Announces Half-Year 2021 Interim Results (PRNewswire) - "Post-Reporting Period (expected) milestones and achievements: We plan to initiate a phase 2 clinical trial for FGF401 for the treatment of FGF19 amplified hepatocellular carcinoma patients in China in the second half of 2021."

New P2 trial • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor

Targeted inhibition of FGF19/FGFR cascade improves antitumor immunity and response rate in hepatocellular carcinoma. (PubMed, Hepatol Int) - "Our findings suggest that HCC patients with high FGFR2/3 or FGF19/FGFR4 expressing tumors might benefit from a combination infigratinib/FGF401; thus, supporting its evaluation in clinical trials."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • CD34 • CD8 • FGF19 • FGFR2 • FGFR4 • GZMB

Everest Medicines Announces Financial Results for Full Year Ended December 31, 2020 (PRNewswire) - "We plan to initiate Phase 2 clinical trial for FGF401 for the treatment of hepatocellular carcinoma in China in the second half of 2021."

New P2 trial • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology