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

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

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

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

Elevar Therapeutics…announced it submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for its investigational drug lirafugratinib as a second-line treatment option for cholangiocarcinoma (CCA) patients with FGFR2 fusion or rearrangement (GlobeNewswire) - "The NDA is supported by positive clinical data from the phase 1/2 ReFocus trial (NCT04526106), in which lirafugratinib demonstrated clinically meaningful anti-tumor activity, measured by objective response rate (ORR), duration of response (DOR), and progression-free survival (PFS), as well as manageable and tolerable safety in patients with advanced/metastatic CCA and other solid tumors with fibroblast growth factor receptor 2 (FGFR2) alterations."

FDA filing • Cholangiocarcinoma

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

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

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

Mechanisms of Clinical Resistance to Selective FGFR2 Inhibition by Lirafugratinib. (PubMed, Ann Oncol) - P1/2 | "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 • Biliary Cancer • Biliary Tract Cancer • Cholangiocarcinoma • Oncology • Solid Tumor • FGFR1 • 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

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

New P2 trial • Biliary Cancer • Cholangiocarcinoma • Oncology • Solid Tumor • CA 19-9 • FGF23 • 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

HLB Discloses Phase 2 Clinical Trial Details for FGFR2-Targeted Anticancer Drug Lirafugratinib as a Tumor-Agnostic Therapy (Financial Economy Plus) - "The study is a global, single-arm Phase 2 clinical trial without a control group, to be conducted at 18 clinical sites across five countries, including the United States, France, South Korea, Spain, and the United Kingdom. Patient enrollment is scheduled to begin in February 2026, with primary endpoint data expected in 2027 and final study completion targeted for 2028....Through ReFocus202, HLB aims to build the clinical evidence required for a tumor-agnostic development strategy and plans to pursue a new drug application (NDA) for a tumor-agnostic indication of lirafugratinib by 2028."

FDA filing • P2 data • Trial completion date • Trial status • Solid Tumor

HLB releases lirafugratinib clinical trial abstract in cholangiocarcinoma, confirming best-in-class (BioNews) - "HLB's cholangiocarcinoma treatment candidate, 'lirafugratinib,' which is scheduled for submission to the US Food and Drug Administration (FDA) in January, demonstrated an objective response rate (ORR) of 47% in a global Phase 2 clinical trial...In addition, the secondary endpoint, median duration of response (mDOR), was reported as 11.8 months (95% CI, 7.5–13.0)...HLB further emphasized that the findings demonstrated favorable clinical outcomes across key efficacy endpoints assessed by the IRC when compared with competing therapies....In addition, the company reported that no treatment-related deaths were observed, highlighting a favorable tolerability profile for the candidate."

FDA filing • P2 data • Cholangiocarcinoma

Next-generation isoform-selective fibroblast growth factor receptor inhibitors. (PubMed, Trends Pharmacol Sci) - "Pan-FGFR-selective inhibitors (erdafitinib, pemigatinib, and futibatinib) have been developed in clinical practice...FGFR2-selective inhibitor lirafugratinib, FGFR3-selective inhibitors LOXO-435 and TYRA-300, FGFR2/3-selective inhibitor ABSK061, and FGFR4-selective inhibitors are in clinical development. Additionally, novel isoform-selective FGFR-targeting degraders, FGFR2b/FGFR3-selective antibodies, and de novo-designed 'c' isoform-selective proteins provide novel treatment strategies. This review provides an overview of the current FGFR-targeted therapeutics and limitations and evaluates next-generation inhibitor development to guide future research."

Journal • Review • Oncology • FGFR • FGFR2 • FGFR3 • FGFR4

Recurrent resistance mutations to lirafugratinib delineate treatment sequences for FGFR2-driven tumors (ESMO 2025) - P1/2 | "Conclusions The complementary activity of lirafugratinib and futibatinib against FGFR2 kinase domain mutations supports their sequential use as irreversible FGFR inhibitors, poised for clinical implementation. Legal entity responsible for the study Gustave Roussy Cancer Campus."

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

Elevar reported that the Phase 2 clinical trial (ReFocus) of lirafugratinib in cholangiocarcinoma demonstrated superior results compared to existing treatments in key efficacy metrics, including objective response rate (ORR) and duration of response (DOR). (BioNews) - "The company plans to present the final Phase 2 data at the 2026 American Society of Clinical Oncology Gastrointestinal Cancers (ASCO GI) Symposium."

P2 data • Cholangiocarcinoma

A pan-cancer map of paralog dependencies reveals novel synthetic lethal targets and biomarker-defined vulnerabilities (AACR-NCI-EORTC 2025) - "We further uncovered strong dependency on KRAS/NRAS activity in FGFR-fusion cancers, which exhibit marked sensitivity to the pan-RAS inhibitor RMC-6236 and to the combination of RMC-6236 and the FGFR2 inhibitor RLY-4008 which synergistically enhanced antiproliferative effects in these models. This study presents a systematic and high-resolution map of paralog dependencies across cancer, uncovering novel synthetic lethal interactions and biomarker-associated vulnerabilities. By expanding functional genomic screens to paralog pairs, we unveil a new dimension of cancer dependencies. These insights provide a valuable foundation for the rational development of next-generation therapeutic strategies that harness genetic redundancy and synthetic lethality – offering new precision oncology opportunities for tumors currently lacking effective targeted therapies."

Biomarker • Pan tumor • Synthetic lethality • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • FGFR2 • KRAS • NRAS • RB1

HLB Group's second major commercialization initiative is 'lirafugratinib,' for which a New Drug Application (NDA) submission to the FDA is planned for January of next year. (BioNews) - "Lirafugratinib received Breakthrough Therapy Designation from the FDA in October 2023 for the treatment of cholangiocarcinoma, enabling the possibility of accelerated approval based solely on Phase 2 clinical trial results."

FDA filing • Cholangiocarcinoma

A pan-cancer map of paralog dependencies reveals novel synthetic lethal targets and biomarker-defined vulnerabilities (AACR-NCI-EORTC 2025) - "We further uncovered strong dependency on KRAS/NRAS activity in FGFR-fusion cancers, which exhibit marked sensitivity to the pan-RAS inhibitor RMC-6236 and to the combination of RMC-6236 and the FGFR2 inhibitor RLY-4008 which synergistically enhanced antiproliferative effects in these models. This study presents a systematic and high-resolution map of paralog dependencies across cancer, uncovering novel synthetic lethal interactions and biomarker-associated vulnerabilities. By expanding functional genomic screens to paralog pairs, we unveil a new dimension of cancer dependencies. These insights provide a valuable foundation for the rational development of next-generation therapeutic strategies that harness genetic redundancy and synthetic lethality – offering new precision oncology opportunities for tumors currently lacking effective targeted therapies."

Biomarker • Pan tumor • Synthetic lethality • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • FGFR2 • KRAS • NRAS • RB1

The tyrosine kinase inhibitor RLY4008 prevents premature coronal suture fusion and restores spatial memory impairment in a mouse model of Crouzon syndrome (ASBMR 2025) - No abstract available

Preclinical • Alzheimer's Disease • CNS Disorders

HLB heads back to FDA with new bile duct cancer drug after liver cancer rejection (Korea Biomedical Review) - "HLB is seeking feedback from the FDA on its experimental bile duct cancer drug lirafugratinib, a targeted treatment for patients with FGFR2 gene alterations, as it tries to secure its first U.S. approval following a series of regulatory setbacks. The Korean biotech said Wednesday that its U.S. affiliate, Elevar Therapeutics, has formally asked the FDA to review its clinical and manufacturing plans for lirafugratinib ahead of a formal approval application. HLB expects the meeting to take place by late September, in line with the agency’s typical 60-day window for such requests....The meeting is intended to align the company and the agency on the drug’s data and filing strategy, a step HLB said could 'increase the likelihood of approval'."

FDA event • Biliary Tract Cancer • Cholangiocarcinoma

HLB Aims to Commercialize Liver Cancer Drug in 2025, Bile Duct Cancer Drug in 2026 (Business Korea) - "'We are focusing our company-wide capabilities on the goal of successfully commercializing the liver cancer drug combination therapy of rivoceranib and camrelizumab this year, followed by the bile duct cancer drug lirafugratinib next year, and ensuring that the thyroid cancer drug is prescribed to patients'."

Launch • Biliary Tract Cancer • Cholangiocarcinoma • Hepatocellular Cancer • Thyroid Gland Carcinoma

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 | Active, not recruiting | Sponsor: Elevar Therapeutics | Trial primary completion date: Sep 2024 ➔ Sep 2025

Trial primary completion date • Biliary Cancer • Cholangiocarcinoma • Oncology • Solid Tumor • CA 19-9 • FGF23 • FGFR2

FGFR2 residence in primary cilia is necessary for epithelial cell signaling. (PubMed, J Cell Biol) - "We also show that the pathogenic FGFR2 variants have minimal cilium presence, which can be rescued for the p.P253R variant associated with the Apert syndrome by using the RLY-4008 kinase inhibitor. Finally, we determine the molecular regulators of FGFR2 trafficking to cilia, including IFT144, BBS1, and the conserved T429V430 motif within FGFR2."

Journal • FGFR1 • FGFR2 • FGFR3 • FGFR4

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 | Active, not recruiting | Sponsor: Elevar Therapeutics | Trial completion date: Aug 2025 ➔ Dec 2027

Trial completion date • Biliary Cancer • Cholangiocarcinoma • Oncology • Solid Tumor • FGFR2