lirafugratinib (RLY-4008) / Relay Therap, HLB Bio Group, Elevar Therapeutics - LARVOL DELTA

FGFR2 Modulates T-Cell Cytotoxicity Through Regulation of PD-L1 Expression in cSCC1 Cell Line (AAO-HNSF 2026) - "Complementary in vivo studies utilized a short-term murine UVB-irradiation model to determine the acute impact of FGFR inhibition (AZD4547) on the recruitment and PD-1 expression of tumor-infiltrating immune cells. RLY4008-mediated FGFR2 inhibition significantly downregulated PD-L1 expression in cSCC1 cells (p = 0.0017). These findings suggest that FGFR2 activity is a requisite for the PD-L1-mediated immune evasion that characterizes cSCC. By reversing the acute immunosuppressive effects of UVB and enhancing T-cell cytotoxic potential, FGFR2 inhibition represents a potent therapeutic strategy. This data provides a strong mechanistic rationale for targeting FGFR signaling to prevent the progression of UV-damaged skin into invasive, immune-evasive cSCC."

IO biomarker • Preclinical • Genetic Disorders • Non-melanoma Skin Cancer • Skin Cancer • Squamous Cell Carcinoma • Squamous Cell Skin Cancer • CD4 • CD8 • FGFR2 • GZMB • IFNG • PD-1 • PD-L1 • TNFA

ReFocus: A phase 1/2 study of the highly selective FGFR2 inhibitor, RLY-4008, in patients with advanced solid tumors including breast cancer (SABCS 2022) - P1/2 | "US enrollment began September 2020 and has expanded into Europe and Asia. Clinical trial information: NCT04526106."

Clinical • P1/2 data • Biliary Cancer • Breast Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • FGFR2 • FGFR3 • FGFR4

Immune Checkpoint Inhibitors (ICI) and Risk of Mucocutaneous Adverse Events (mcAEs) on FGFR2 Inhibition: Post-Hoc Analysis of the Lirafugratinib (Lira) ReFocus Trial (ESMO 2026) - No abstract available

Adverse events • Checkpoint inhibition • Retrospective data • Oncology • FGFR2

RLY-4008, the first highly selective FGFR2 inhibitor with activity across FGFR2 alterations and resistance mutations. (PubMed, Cancer Discov) - "In vivo, RLY-4008 induces regression in multiple xenograft models - including models with FGFR2 resistance mutations that drive clinical progression on current pan-FGFRi - while sparing FGFR1 and FGFR4. In early clinical testing, RLY-4008 induced responses without clinically significant off-isoform FGFR toxicities, confirming the broad therapeutic potential of selective FGFR2 targeting."

Journal • Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Metabolic Disorders • Nephrology • Oncology • Solid Tumor • FGFR1 • FGFR2 • FGFR4

Efficacy and safety of lirafugratinib in FGFRi-naïve cholangiocarcinoma (CCA) patients harboring FGFR2 fusions/rearrangements (FGFR2 f/r). (ASCO-GI 2026) - P1/2 | "Background: Outcomes remain poor for patients with advanced/metastatic CCA treated with first-line gemcitabine-cisplatin +/- anti-PD(L)1. Lirafugratinib demonstrated clinically meaningful anti-tumor activity (ORR, DOR, and PFS), manageable and tolerable safety in CCA FGFR2 f/r patients. aORR defined as proportion achieving confirmed response of complete response or partial response per RECIST v1.1. bDCR defined as proportion with confirmed response of complete response, partial response, or stable disease per RECIST v1.1."

Clinical • Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • FGFR2

Identifying FGFR2 fusions/rearrangements in cholangiocarcinoma patients using a novel cfDNA algorithm for treatment with RLY-4008, a highly selective irreversible FGFR2 inhibitor (AACR-NCI-EORTC 2022) - P1/2 | "ConclusionsIn this study, FGFR2 f/r detection using a novel fusion partner-agnostic cfDNA approach has an acceptable performance and is a feasible noninvasive option for screening CCA patients. These encouraging results suggest a utility of cfDNA in FGFR2 f/r profiling, which will be prospectively validated in the RLY-4008-101 pivotal study."

Clinical • Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • BICC1 • FGFR2

HLB…said on the 15th that it has begun the European Union (EU) approval process for its cholangiocarcinoma drug candidate "lirafugratinib" following the United States. (Chosun Biz) - "This EU filing was based on results from global phase 1 and 2 clinical trials. In a study of patients with advanced or metastatic cholangiocarcinoma with FGFR2 fusions who had received one or more prior systemic therapies, the objective response rate (ORR) for lirafugratinib was 46.5%."

EMA filing • Cholangiocarcinoma

Tumor-agnostic efficacy and safety of lirafugratinib, a highly selective FGFR2 inhibitor, in patients (pts) with advanced solid tumors with FGFR2 fusions or rearrangements (f/r): the ReFocus study (EORTC-NCI-AACR 2024) - P1/2 | "Conclusion Lirafugratinib demonstrates rapid and durable responses in heavily pretreated pts with high tumor burden, across multiple refractory solid tumor types harboring an FGFR2 f/r. Together with robust efficacy previously reported in CCA and with a differentiated safety profile (minimal off-isoform toxicity) across tumor types, these data validate FGFR2 f/r as a tumor-agnostic target sensitive to selective FGFR2 inhibition."

Clinical • Metastases • Pan tumor • Biliary Cancer • Breast Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • FGFR1 • FGFR2 • FGFR4

Recurrent resistance mutations to lirafugratinib inform treatment sequencing in FGFR2-driven tumors. (PubMed, Clin Cancer Res) - P1/2 | "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 • Biliary Cancer • Cholangiocarcinoma • Oncology • Solid Tumor • BICC1 • FGFR2

Efficacy of RLY-4008, a highly selective FGFR2 inhibitor in patients (pts) with an FGFR2-fusion or rearrangement (f/r), FGFR inhibitor (FGFRi)-naïve cholangiocarcinoma (CCA): ReFocus trial (ESMO 2022) - P1/2 | "Table: 000LBA12 Conclusions RLY-4008 is a promising next-generation inhibitor with potential to transform the treatment of FGFR2 f/r, FGFRi-naïve CCA. Pivotal testing continues in ReFocus."

Clinical • Late-breaking abstract • Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • FGFR2

Updated dose escalation results for ReFocus, a first-in-human study of highly selective FGFR2 inhibitor RLY-4008 in cholangiocarcinoma and other solid tumors. (ASCO 2023) - P1/2 | "These encouraging dose escalation data confirm the broad therapeutic potential of highly selective FGFR2 targeting with RLY-4008 by demonstrating encouraging initial efficacy across FGFR2-altered solid tumors and genomic alterations, with a differentiated safety profile that avoids FGFR1- and FGFR4-related toxicity. Phase 2 of ReFocus continues across solid tumors and with registrational intent in FGFRi-naïve, FGFR2 f/r CCA. Clinical trial information: NCT04526106."

P1 data • Alopecia • Biliary Cancer • Cholangiocarcinoma • Dental Disorders • Dry Eye Disease • Gastrointestinal Cancer • Oncology • Ophthalmology • Solid Tumor • Stomatitis • Xerostomia • FGFR1 • FGFR2 • FGFR4

Futibatinib, pemigatinib, or lirafugratinib for patients with biliary tract cancers and FGFR Alterations (ESMO 2026) - No abstract available

Clinical • Biliary Cancer • Biliary Tract Cancer • Oncology • Solid Tumor • FGFR

Virtual screening of natural product libraries for selective FGFR2 inhibitors across the FGFR kinase family | Poster Board #1153 (ACS-Fall 2026) - "Compound libraries are sourced from the Comprehensive Marine Natural Products Database (CMNPD), Indian Medicinal Plants, Phytochemistry and Therapeutics (IMPPAT), LOTUS, Medicinal Fungi Secondary Metabolites and Therapeutics (MeFSAT), and Traditional Chinese Medicine (TCM). These compounds are computationally docked against all four FGFR kinase domains, using the binding pockets and poses of lirafugratinib as references to identify compounds with selective activity toward FGFR2 over other family members."

Biliary Cancer • Cholangiocarcinoma • Metabolic Disorders • Nephrology • Renal Disease • Solid Tumor • FGFR2 • FGFR3 • FGFR4

Elevar Therapeutics Announces Three Abstracts Accepted for Presentation at ESMO Congress 2026 (The Manila Times) - "Rivoceranib: A rapid oral presentation detailing Phase 2 results in pretreated metastatic thymic epithelial tumors; Camrelizumab + Rivoceranib: A poster sub-analysis of the CARES-310 study evaluating the impact of early antibiotic exposure on treatment efficacy in unresectable hepatocellular carcinoma (uHCC); Lirafugratinib: An ePoster post-hoc analysis from the ReFocus trial examining prior immunotherapy exposure and mucocutaneous adverse event risks."

P1/2 data • P2 data • P3 data • Cholangiocarcinoma • Hepatocellular Cancer • Thymic Epithelial Tumor

Fibroblast growth factor 2 (FGF2) modulates the excitability of brain noradrenergic and serotonergic neurons: possible involvement of FGFR1 and FGFR4 receptors. (PubMed, Front Pharmacol) - "Adult male Wistar rats, weighing 250-350 g, were treated with the recombinant FGF2, selective inhibitors of FGFR1 (PD173074), FGFR2 (lirafugratinib), FGFR4 (BLU9931), or corresponding vehicle. The FGF2-catecholaminergic interactions are putatively mediated via FGFR1, and FGF2-5-HT-crosstalk-via FGFR4. These two receptors can be thus potential targets for the future CNS drugs."

Journal • Addiction (Opioid and Alcohol) • Anesthesia • FGF2 • FGFR1 • FGFR2 • FGFR4

HLB…said on the 24th that it completed a late-cycle meeting with the U.S. Food and Drug Administration (FDA) for the cholangiocarcinoma drug candidate ’lirafugratinib’ without any particular issues (Chosun Biz) - "HLB's U.S. subsidiary Elevar Therapeutics discussed postmarketing requirements (PMR) and postmarketing commitments (PMC) in a meeting with the FDA on the 23rd (local time). According to the company, there have been no particular differences of opinion with the FDA in the review process so far, and no new review items that could affect approval were raised....Whether the FDA would conduct a pre-approval inspection (PAI) of the active pharmaceutical ingredient (API) and drug product (DP) manufacturing sites for lirafugratinib was not separately mentioned at this meeting....FDA set to rule by sept. 25 on prioritized cholangiocarcinoma drug lirafugratinib after uneventful final review talk."

FDA event • Cholangiocarcinoma

Conversion to surgery after FGFR2 inhibitor therapy in FGFR2 fusion–positive intrahepatic cholangiocarcinoma: Multicentre case series (ESMO-GI 2026) - "All received cisplatin–gemcitabine (± durvalumab) (median 5 months). FGFRi included lirafugratinib (n=1), futibatinib (n=4) and pemigatinib (n=3), with median duration 11,86 months (range 2,92–31,27 months)...All patients were alive at last follow-up. Conclusions FGFRi therapy may enable surgical resection in selected patients with initially unresectable FGFR2 fusion–positive iCCA."

Clinical • Surgery • Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • BICC1 • FGFR2

FGF-2 modulates serotonergic neuron activity via FGFR4 signaling (CINP 2026) - "Based on our current results and previous findings, we conclude that FGF-2 modulates burst activity of serotonergic neurons in the dorsal raphe nucleus (DRN). Whereas recombinant FGF-2 strongly inhibited burst firing in these neurons, neither FGFR1 blockade with PD173074 nor selective FGFR2 inhibition with RLY-4008 produced significant effects on their electrophysiological activity. Published evidence indicates that FGFR3 expression in the central nervous system is minimal and functionally insignificant, making it an unlikely mediator of FGF-2 action."

Addiction (Opioid and Alcohol) • CNS Disorders • FGF2 • FGFR1 • FGFR2 • FGFR3 • FGFR4

Elevar Therapeutics Announces First Patients Dosed in Phase 2 Study of Lirafugratinib Among Non-CCA Solid Tumors With FGFR2 Fusion or Rearrangement (GlobeNewswire) - "The trial, known as ReFocus202 (Protocol ID ELE-4008-202; NCT07359820), is an open-label, single-arm study evaluating the efficacy and safety among a broad scope of tumors containing an FGFR2 fusion or rearrangement. The primary endpoint is objective response rate. The first patient was dosed at Samsung Medical Center in Seoul, South Korea, and a second patient at Moffitt Cancer Center in Tampa, Florida. The multi-site study is set to take place in the U.S., Korea, the UK, Spain, and France."

Trial status • Solid Tumor

HLB Subsidiary Elevar Therapeutics Begins Global Phase 2 Trial of Lirafugratinib - "This Phase 2 trial will evaluate the efficacy and safety of lirafugratinib in patients with unresectable, locally advanced, or metastatic solid tumors who have confirmed FGFR2 fusions or rearrangements....The trial will be conducted across five countries: the United States, South Korea, the United Kingdom, Spain, and France, with the primary endpoint being the objective response rate (ORR)."

New P2 trial • Cholangiocarcinoma

Co-targeting FGFR and PI3K signaling as a strategy to overcome resistance to alpelisib/fulvestrant treatment in PIK3CA-mutant luminal A breast cancer (EACR 2026) - "To elucidate the functional impact of FGFR-dependent resistance mechanisms, resistant cells, 3D tumor spheroids, in vivo xenografts, and PDX models were treated with combinations of alpelisib and FDA-approved pan-FGFR inhibitors, erdafitinib and pemigatinib, or the FGFR2-specific inhibitor lirafugratinib.Result and Transcriptomic analysis revealed overactivation of FGFR signaling as a key bypass mechanism of resistance. Overall, our study identifies FGFR signaling as a key mediator of resistance to combined alpelisib and fulvestrant treatment in PIK3CA-mutant luminal A breast cancer. These findings suggest that targeting the FGFR pathway in combination with PI3K inhibition may represent a potential strategy to overcome drug resistance in advanced-stage refractory luminal A breast cancer."

Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • FGFR • FGFR2 • HER-2 • PIK3CA

A phase 2, open-label, single-arm study of lirafugratinib in patients with previously treated, unresectable, locally advanced, or metastatic solid tumors (excluding cholangiocarcinoma) with FGFR2 fusion or rearrangement. (ASCO 2026) - P1/2, P2 | "With 65 subjects, observing at least 21 subjects with a complete response (CR) or partial response (PR) (ORR ≥32%), will result in a 95% CI (lower bound >20%) with the probability of observing ≥21 responders assuming a true ORR of 40% is approximately 92%. The results of this analysis will determine whether the pooled evaluable data from RLY-4008-101 and ELE-4008-202 meet regulatory requirements to support a tissue-agnostic indication for FGFR2 f/r non-CCA solid tumors."

Clinical • Metastases • P2 data • Biliary Cancer • Cholangiocarcinoma • Oncology • Solid Tumor • FGFR2

Comparative biochemical kinase activity analysis identifies lirafugratinib as a highly selective FGFR2 inhibitor (AACR 2026) - "A KINOMEscan Profiling Service scanMAX and TREEspot™ interaction maps were used for evaluation and visualization of inhibition of kinases: a panel of 468 human target kinases and disease-relevant kinase mutant variants were tested at a concentration of 500 nM for lirafugratinib and four other pan-FGFR inhibitors (futibatinib, pemigatinib, erdafitinib, and AZD4547). The head-to-head kinome analysis of lirafugratinib and four other FGFR inhibitors revealed that lirafugratinib inhibited FGFR2 with high selectivity, suggesting minimal off-target and off-isoform-related toxicities compared to pan-FGFR inhibitors used in clinical practice."

Biliary Cancer • Cholangiocarcinoma • Oncology • Solid Tumor • FGFR2 • FGFR3 • FGFR4 • MKNK2

Discovery and preclinical characterization of ISM8001, a covalent and selective FGFR2/FGFR3 dual inhibitor with strong monotherapy anti-tumor activity against advanced solid tumors (AACR 2024) - "The second generation of FGFR inhibitors currently undergoing clinical evaluation such as RLY-4008 and LOXO-435 are primarily focused on achieving selectivity against either the FGFR2 or FGFR3 isoform, which may narrow their clinical potential. Results of 28-day non-clinical toxicology studies in rat and dog showed a safety window of approximately 2-5 fold based on efficacious exposure in different models. Taken together, these data support the clinical development of ISM8001 as a novel, selective FGFR2/FGFR3 dual inhibitor for the potential tissue-agnostic therapy of advanced solid tumors with FGFR2/3 aberrations."

Metastases • Monotherapy • Preclinical • Biliary Cancer • Bladder Cancer • Cholangiocarcinoma • Endometrial Cancer • Gastric Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • FGFR1 • FGFR2 • FGFR3 • FGFR4

ReFocus202: A Study of Lirafugratinib in Non-CCA Solid Tumors With FGFR2 Fusion or Rearrangement (clinicaltrials.gov) - P2 | N=30 | Recruiting | Sponsor: Elevar Therapeutics | Not yet recruiting ➔ Recruiting

Enrollment open • Biliary Cancer • Cholangiocarcinoma • Oncology • Solid Tumor • CA 19-9 • FGF23 • FGFR2