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 | "Funded by Elevar Therapeutics, Relay Therapeutics Clinical Trial Registration Number: NCT04526106 The full, final text of this abstract will be available on Jan 05 at 05:00 PM EST."

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

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

Elevar Therapeutics Announces the Formation and Members of Scientific Advisory Board (GlobeNewswire) - "Scientific Advisory Board formed with internationally recognized liver and biliary tract cancer physicians to support the advancement of solid tumor pipeline programs. Elevar plans for major 2025 oncology regulatory milestones: (i)...Launch preparation for unresectable hepatocellular carcinoma; (ii) NDA Submission for lirafugratinib in second half 2025 for FGFR2 driven cholangiocarcinoma."

Clinical • FDA filing • Launch US • Cholangiocarcinoma • Hepatocellular Cancer

Elevar Therapeutics and Relay Therapeutics Announce Exclusive Global Licensing Agreement for Lirafugratinib in FGFR2-Driven Cholangiocarcinoma and Other Solid Tumors (GlobeNewswire) - "Relay Therapeutics has potential to receive up to $500 million in upfront, regulatory and commercial milestone payments, including $75 million in upfront and regulatory milestones, plus up to double digit royalties on global sales...Relay Therapeutics...and Elevar Therapeutics...today announced an exclusive global licensing agreement for lirafugratinib (RLY-4008). Lirafugratinib is a selective oral small molecule inhibitor of fibroblast growth factor receptor 2 (FGFR2) that is being developed for patients with FGFR2-driven cholangiocarcinoma (CCA) and other FGFR2-altered solid tumors. The announcement of the partnership follows Relay’s recent positive FDA interaction and previously reported differentiated data in cholangiocarcinoma and data across other solid tumors."

Licensing / partnership • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor

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

Lirafugratinib Update (GlobeNewswire) - "Updated FGFR2 fusion tumor agnostic data...will be presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, taking place October 23-25, 2024; The company met with the FDA regarding the lirafugratinib regulatory path. The FDA suggested that the company first file a new drug application (NDA) in cholangiocarcinoma, followed by a tumor agnostic supplemental NDA for FGFR2 fusions with data from more patients and more follow up; The company plans to seek a global commercialization partner for lirafugratinib in order to maintain focus on the remainder of the portfolio."

Clinical • Commercial • FDA event • Biliary Cancer • Biliary Tract Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor

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: Relay Therapeutics, Inc. | Trial completion date: Oct 2024 ➔ Aug 2025 | Trial primary completion date: Jun 2024 ➔ Sep 2024

Metastases • Trial completion date • Trial primary completion date • Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • FGFR2

Understanding and overcoming resistance to selective FGFR inhibitors across FGFR2-driven tumors (ESMO 2024) - "In cholangiocarcinoma, at resistance to both reversible inhibitors (e.g. pemigatinib, erdafitinib) and the irreversible inhibitor futibatinib, polyclonal FGFR2 kinase domain mutations were frequent (14/27 patients)...At progression to a first FGFR inhibitor, 12 patients received futibatinib or lirafugratinib (irreversible inhibitors), with variable clinical outcomes depending on previous resistance mechanisms. Two patients with TSC1 or PIK3CA mutations had prolonged benefit from everolimus... Resistance to FGFR inhibitors in FGFR2-driven tumors is complex and heterogeneous. We unveiled similarities and differences between cholangiocarcinoma vs other tumors, between reversible vs irreversible agents. Our work suggests strategies for overcoming resistance in patients progressing on selective FGFR inhibitors."

Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • BICC1 • FGFR2 • PIK3CA • TSC1

Understanding and Overcoming Resistance to Selective FGFR inhibitors Across FGFR2-Driven Malignancies. (PubMed, Clin Cancer Res) - "At progression to FGFR inhibitors, FGFR2-driven malignancies are characterized by high intra- and inter-patient molecular heterogeneity, particularly in cholangiocarcinoma. Resistance to FGFR inhibitors can be overcome by sequential, molecularly-oriented treatment strategies across FGFR2-driven tumors."

Journal • Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • BICC1 • FGFR2 • PIK3CA • TSC1

Relay Therapeutics Reports Second Quarter 2024 Financial Results and Corporate Highlights (GlobeNewswire) - "Anticipated Upcoming Milestones: (i) Breast Cancer: RLY-2608 + fulvestrant data update in the fourth quarter of 2024; RLY-2608 + fulvestrant + ribociclib initial safety data in the fourth quarter of 2024; RLY-2608 + fulvestrant + atirmociclib clinical trial initiation by the end of 2024; RLY-2608 + fulvestrant potential Phase 3 trial initiation in 2025; (ii) Lirafugratinib: tumor agnostic data and regulatory update in the second half of 2024; (iii) Pre-clinical:...NRAS: clinical start in the second half of 2025."

New P3 trial • New trial • P1 data • Regulatory • Breast Cancer • Cholangiocarcinoma

Relay Therapeutics Reports First Quarter 2024 Financial Results and Corporate Highlights (GlobeNewswire) - "Anticipated 2024 Milestones: (i) RLY-2608: RLY-2608 + fulvestrant data update in the second half of 2024; RLY-2608 + fulvestrant + ribociclib initial safety data in the second half of 2024; (ii) Lirafugratinib: tumor agnostic data and regulatory update in the second half of 2024; (iii) Pre-clinical: disclose new program(s) in 2024."

P1 data • P1/2 data • Pipeline update • Regulatory • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer

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

FGFR-targeted therapeutics: clinical activity, mechanisms of resistance and new directions. (PubMed, Nat Rev Clin Oncol) - "Various agents, including pan-FGFR inhibitors (erdafitinib and futibatinib), FGFR1/2/3 inhibitors (infigratinib and pemigatinib), as well as a range of more-specific agents, have been developed and several have entered clinical use. The next generation of small-molecule inhibitors, such as lirafugratinib and LOXO-435, and the FGFR2-specific antibody bemarituzumab are expected to have a reduced risk of hyperphosphataemia and the ability to overcome certain resistance mutations. In this Review, we describe the development and current clinical role of FGFR inhibitors and provide perspective on future research directions including expansion of the therapeutic indications for use of FGFR inhibitors, combination of these agents with immune-checkpoint inhibitors and the application of novel technologies, such as artificial intelligence."

Journal • Review • Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Renal Disease • Solid Tumor • Urothelial Cancer • FGFR • FGFR2 • TP53

RLY-4008-101: 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=540 | Active, not recruiting | Sponsor: Relay Therapeutics, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Metastases • Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • FGFR2