RLY-4008, the First Highly Selective FGFR2 Inhibitor - Activity across FGFR2 Alterations and Resistance Mutations

Sep 24, 2026

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Oncogenic activation of fibroblast growth factor receptor 2 (FGFR2) drives multiple cancers and offers a therapeutic opportunity, yet selective FGFR2 targeting has remained unmet. Pan-FGFR inhibitors validate FGFR2 as a driver in FGFR2 fusion–positive intrahepatic cholangiocarcinoma, but benefit is restricted by FGFR1- and FGFR4-mediated toxicities and by acquired FGFR2 resistance mutations. RLY-4008 is a highly selective, irreversible FGFR2 inhibitor showing strong in vitro selectivity and tumor regression in vivo, including models with resistance mutations, while sparing FGFR1 and FGFR4. Early clinical testing reports responses without clinically significant off-isoform FGFR toxicities.

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CategoryHealthcare

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Introduction

RESEARCH ARTICLE RLY-4008, the First Highly Selective FGFR2 Inhibitor with Activity across FGFR2 Alterations and Resistance Mutations Vivek Subbiah1, Vaibhav Sahai2, Dejan Maglic3, Kamil Bruderek3, B. Barry Touré3, Songping Zhao3, Roberto Valverde3, Patrick J. O’Hearn3, Demetri T. Moustakas3, Heike Schönherr3, Nastaran Gerami-Moayed3, Alexander M. Taylor3, Brandi M. Hudson3, Damian J. Houde3, Debjani Pal3, Lindsey Foster3, Hakan Gunaydin3, Pelin Ayaz4, Dina A. Sharon4, Lipika Goyal5, Alison M. Schram6, Suneel Kamath7, Cori Ann Sherwin3, Oleg Schmidt-Kittler3, Kai Yu Jen3, Fabien Ricard3, Beni B. Wolf3, David E. Shaw4,8, Donald A. Bergstrom3, James Watters3, and Jessica B. Casaletto3 ABSTRACT Oncogenic activation of fibroblast growth factor receptor 2 (FGFR2) drives multiple cancers and represents a broad therapeutic opportunity, yet selective targeting of FGFR2 has not been achieved. Although the clinical efficacy of pan-FGFR inhibitors (pan-FGFRi) validates FGFR2 driver status in FGFR2 fusion–positive intrahepatic cholangiocarcinoma, their benefit is limited by incomplete target coverage due to FGFR1-and FGFR4-mediated toxicities (hyperphosphatemia and diarrhea, respectively) and the emergence of FGFR2 resistance mutations. RLY-4008 is a highly selective, irreversible FGFR2 inhibitor designed to overcome these limitations. In vitro, RLY-4008 demonstrates >250-and >5,000-fold selectivity over FGFR1 and FGFR4, respectively, and targets primary alterations and resistance mutations. In vivo, RLY-4008 induces regression in multiplexenograft 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. SIGNIFICANCE: Patients with FGFR2-driven cancers derive limited benefit from pan-FGFRi due to multiple FGFR1–4-mediated toxicities and acquired FGFR2 resistance mutations. RLY-4008 is a highly selective FGFR2 inhibitor that targets primary alterations and resistance mutations and induces tumor regression while sparing other FGFRs, suggesting it may have broad therapeutic potential. See related commentary by Tripathi et al., p. 1964. INTRODUCTION FGFR2 is a member of the fibroblast growth factor receptor (FGFR) family and plays a key role in cell survival and proliferation (1, 2). FGFR2 genetic alterations have been reported in many solid tumors, most commonly in intrahepatic cholangiocarcinoma (iCCA; 10%–16%; refs. 3, 4), endometrial cancer (7.5%–11%), and gastric/gastroesophageal junction cancer (3.7%–7.9%; refs. 5, 6). Oncogenic activation of FGFR2 can occur via gene amplification, activating mutation, or chromosomal rearrangement (1). FGFR2 fusions are the most common FGFR2 alteration in iCCA, occurring in 10% to 15% of cases (7), but are also found in a variety of other tumor types (5, 6). These oncogenic fusions typically consist ofFGFR2 exons 1 to 17—encoding the intact extracellular and kinase domains—fused toa 3′ partner gene that permits protein dimerization, resulting 1The University of Texas MD Anderson Cancer Center, Houston, Texas. 2University of Michigan, Ann Arbor, Michigan. 3Relay Therapeutics, Inc., Cambridge, Massachusetts. 4D. E. Shaw Research, New York, New York. 5Massachusetts General Hospital, Boston, Massachusetts. 6Memorial Sloan Kettering Cancer Center, New York, New York. 7The Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio. 8Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York. Note: V. Subbiah and V. Sahai are co–first authors of this article. B.B. Touré, B.M. Hudson, D.A. Sharon, and L. Goyal conducted this research while employed by the institutions noted in their respective affiliations. Corresponding Author: Jessica B. Casaletto, Relay Therapeutics, Inc., 399 Binn

FAQs

Why has selective FGFR2 targeting been difficult compared with pan-FGFR inhibitors?

FGFR1–4 kinase domains share high sequence and structural homology, so traditional structure-based design often yields inhibitors that are not selective.

What limitations reduce the clinical benefit of pan-FGFR inhibitors for FGFR2-driven cancers?

Benefit is limited by incomplete target coverage due to FGFR1- and FGFR4-mediated toxicities (hyperphosphatemia and diarrhea) and by the emergence of FGFR2 resistance mutations.

What does RLY-4008 demonstrate in preclinical and early clinical settings?

RLY-4008 shows strong in vitro selectivity over FGFR1 and FGFR4, induces regression in vivo including in resistance-driven models, and in early clinical testing produces responses without clinically significant off-isoform FGFR toxicities.

Sep 24, 2026

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