^
    4d
    Fibroblast Growth Factor Receptor (FGFR) Inhibitors for the Treatment of Cholangiocarcinoma: Key Therapeutic Developments and Knowledge Gaps. (PubMed, Drug Des Devel Ther)
    Parallel translational work using cfDNA-based liquid biopsy has mapped a spectrum of secondary kinase-domain mutations that underlie acquired resistance, informing the development of next-generation FGFR2-selective inhibitors (eg, lirafugratinib) and combination strategies with EGFR/ERBB blockade. Collectively, these data underscore the need for comprehensive molecular profiling and innovative umbrella trial designs to optimise targeted therapy in this rare, biologically heterogeneous malignancy.
    Review • Journal • MSi-H Biomarker
    |
    EGFR (Epidermal growth factor receptor) • HER-2 (Human epidermal growth factor receptor 2) • BRAF (B-raf proto-oncogene) • MSI (Microsatellite instability) • FGFR2 (Fibroblast growth factor receptor 2) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • FGFR (Fibroblast Growth Factor Receptor)
    |
    BRAF V600E • MSI-H/dMMR • HER-2 amplification • BRAF V600 • IDH1 mutation • FGFR2 mutation • FGFR2 fusion • IDH mutation + BRAF V600E
    |
    lirafugratinib (RLY-4008)
    7d
    REFOCUS: A First-in-Human Study of Highly Selective FGFR2 Inhibitor, RLY-4008, in Patients With ICC and Other Advanced Solid Tumors (clinicaltrials.gov)
    P1/2, N=490, Completed, Elevar Therapeutics | Active, not recruiting --> Completed | Trial completion date: Dec 2027 --> Sep 2025
    Trial completion • Trial completion date • First-in-human
    |
    FGFR2 (Fibroblast growth factor receptor 2) • FGF23 (Fibroblast Growth Factor 23) • CA 19-9 (Cancer antigen 19-9)
    |
    FGFR2 mutation • FGFR2 fusion
    |
    lirafugratinib (RLY-4008)
    1m
    Recurrent resistance mutations to lirafugratinib inform treatment sequencing in FGFR2-driven tumors. (PubMed, Clin Cancer Res)
    The complementary activity of lirafugratinib and futibatinib against FGFR2 kinase domain mutations supports their sequential use, when precise resistance mutations are detected in patients.
    Journal
    |
    FGFR2 (Fibroblast growth factor receptor 2) • BICC1 (BicC Family RNA Binding Protein 1)
    |
    FGFR2 mutation
    |
    Lytgobi (futibatinib) • lirafugratinib (RLY-4008)
    1m
    ReFocus202: A Study of Lirafugratinib in Non-CCA Solid Tumors With FGFR2 Fusion or Rearrangement (clinicaltrials.gov)
    P2, N=30, Not yet recruiting, Elevar Therapeutics
    New P2 trial
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    FGFR2 (Fibroblast growth factor receptor 2) • FGF23 (Fibroblast Growth Factor 23) • CA 19-9 (Cancer antigen 19-9)
    |
    FGFR2 fusion
    |
    lirafugratinib (RLY-4008)
    1m
    Mechanisms of Clinical Resistance to Selective FGFR2 Inhibition by Lirafugratinib. (PubMed, Ann Oncol)
    Lirafugratinib retains activity against multiple mutations that confer clinical resistance to pan-FGFR inhibitors. However, diverse resistance mechanisms, including various kinase domain mutations and RTK-MAPK bypass alterations, remain challenges in the treatment of FGFR2-altered tumors, even with selective FGFR2 kinase inhibition.
    Journal
    |
    FGFR2 (Fibroblast growth factor receptor 2) • FGFR1 (Fibroblast growth factor receptor 1)
    |
    FGFR2 mutation
    |
    lirafugratinib (RLY-4008)
    2ms
    HMPL-453 Tartrate in Advanced Intrahepatic Cholangiocarcinoma (clinicaltrials.gov)
    P2/3, N=235, Recruiting, Hutchmed | Phase classification: P2 --> P2/3 | N=128 --> 235 | Trial completion date: Dec 2025 --> Feb 2030 | Trial primary completion date: Jun 2025 --> Jun 2028
    Phase classification • Enrollment change • Trial completion date • Trial primary completion date
    |
    FGFR2 (Fibroblast growth factor receptor 2)
    |
    FGFR2 fusion
    |
    fanregratinib (HMPL-453)
    2ms
    A Study of ABSK061 to Assess Safety, Tolerability, Pharmacokinetics, and Efficacy in Children With Achondroplasia (clinicaltrials.gov)
    P1/2, N=110, Not yet recruiting, Abbisko Therapeutics Co, Ltd
    New P1/2 trial
    |
    ABSK061
    3ms
    A Clinical Trial to Evaluate the Relative Bioavailability of New and Old ABSK-011 Capsules (clinicaltrials.gov)
    P1, N=40, Completed, Abbisko Therapeutics Co, Ltd | Recruiting --> Completed | N=73 --> 40 | Trial completion date: Dec 2024 --> Sep 2025 | Trial primary completion date: Dec 2024 --> Sep 2025
    Trial completion • Enrollment change • Trial completion date • Trial primary completion date
    |
    irpagratinib (ABSK011) • ABSK061
    6ms
    Oleandrin-mediated suppression of MELK induces apoptosis, autophagy, and ferroptosis in human non-small cell lung cancer cells. (PubMed, Phytomedicine)
    Oleandrin could potentially have therapeutic effects for NSCLC patients and possibly for other cancer types.
    Journal
    |
    MELK (Maternal Embryonic Leucine Zipper Kinase)
    |
    oleandrin (PBI-05204)
    8ms
    Rational Design and Identification of ISM7594 as a Tissue-Agnostic FGFR2/3 Inhibitor. (PubMed, J Med Chem)
    The compound demonstrated robust tumor growth suppression, favorable pharmacokinetic profile, and pharmacodynamic effects. This study supports the preclinical development of ISM7594 and demonstrates its potential in advancing tissue-agnostic therapy for advanced solid tumors with FGFR2/3 aberrations and mutation resistance.
    Journal • Pan tumor
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    FGFR2 (Fibroblast growth factor receptor 2) • FGFR1 (Fibroblast growth factor receptor 1)
    |
    FGFR2 mutation • FGFR2 fusion
    9ms
    Development of CPA-Catalyzed β-Selective Reductive Amination of Cardenolides for the Synthesis and Biological Evaluation of Hydrolytically Stable Analogs. (PubMed, Chemistry)
    The subsequent in vitro evaluation of digitoxigenin and oleandrin derivatives 13a, 13g, 15a, and 15gdemonstrated that these four analogs reduced steady-state ATP1A1 levels in T98G cells in the 12-96 nM range. Interestingly, only the oleandrin analog 15g also lowered also steady-state levels of the cellular prion protein (PrPC), the main therapeutic target for the treatment of prion diseases.
    Journal
    |
    ATP1A1 (ATPase Na+/K+ Transporting Subunit Alpha 1) • PRNP (Prion Protein)
    |
    oleandrin (PBI-05204)
    9ms
    A Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of ABSK061 Mini-tablets in Healthy Adult Participants (clinicaltrials.gov)
    P1, N=42, Recruiting, Abbisko Therapeutics Co, Ltd
    New P1 trial
    |
    ABSK061