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Ref Type Journal Article
PMID (37270847)
Authors Subbiah V, Sahai V, Maglic D, Bruderek K, Toure BB, Zhao S, Valverde R, O'Hearn PJ, Moustakas DT, Schonherr H, Gerami-Moayed N, Taylor AM, Hudson BM, Houde DJ, Pal D, Foster L, Gunaydin H, Ayaz P, Sharon DA, Goyal L, Schram AM, Kamath S, Sherwin CA, Schmidt-Kittler O, Jen KY, Ricard F, Wolf BB, Shaw DE, Bergstrom DA, Watters J, Casaletto JB
Title RLY-4008, the first highly selective FGFR2 inhibitor with activity across FGFR2 alterations and resistance mutations.
Journal Vol Issue Date Pages Journal Short Title
Cancer discovery 2023 Jun 04 Cancer Discov
URL
Abstract Text 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. While 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) 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 >5000-fold selectivity over FGFR1 and FGFR4, respectively, and targets primary alterations and resistance mutations. 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR2 N549D Advanced Solid Tumor predicted - sensitive Lirafugratinib Preclinical - Biochemical Actionable In a preclinical study, Lirafugratinib treatment inhibited Fgfr2 phosphorylation in cultured cells expressing FGFR2 N549D (PMID: 37270847). 37270847
FGFR2 V564F Advanced Solid Tumor predicted - sensitive Lirafugratinib Preclinical - Biochemical Actionable In a preclinical study, Lirafugratinib treatment inhibited Fgfr2 phosphorylation in cultured cells expressing FGFR2 V564F (PMID: 37270847). 37270847
FGFR2 V564L Advanced Solid Tumor predicted - sensitive Lirafugratinib Preclinical - Biochemical Actionable In a preclinical study, Lirafugratinib treatment inhibited Fgfr2 phosphorylation in cultured cells expressing FGFR2 V564L (PMID: 37270847). 37270847
FGFR2 V564L Advanced Solid Tumor predicted - sensitive Infigratinib Preclinical - Biochemical Actionable In a preclinical study, Truseltiq (infigratinib) failed to inhibit Fgfr2 phosphorylation in cultured cells expressing FGFR2 V564L (PMID: 37270847). 37270847
FGFR2 V564L Advanced Solid Tumor predicted - sensitive Pemigatinib Preclinical - Biochemical Actionable In a preclinical study, Pemazyre (pemigatinib) failed to inhibit Fgfr2 phosphorylation in cultured cells expressing FGFR2 V564L (PMID: 37270847). 37270847
FGFR2 V564F Advanced Solid Tumor resistant Pemigatinib Preclinical - Biochemical Actionable In a preclinical study, Pemazyre (pemigatinib) failed to inhibit Fgfr2 phosphorylation in cultured cells expressing FGFR2 V564F (PMID: 37270847). 37270847
FGFR2 E565A Advanced Solid Tumor predicted - sensitive Lirafugratinib Preclinical - Biochemical Actionable In a preclinical study, Lirafugratinib treatment inhibited Fgfr2 phosphorylation in cultured cells expressing FGFR2 E565A (PMID: 37270847). 37270847
FGFR2 C383R breast cancer sensitive Lirafugratinib Preclinical - Cell culture Actionable In a preclinical study, Lirafugratinib inhibited proliferation of a breast carcinoma cell line harboring FGFR2 C383R in culture (PMID: 37270847). 37270847
FGFR2 V564F Advanced Solid Tumor predicted - resistant Futibatinib Preclinical - Biochemical Actionable In a preclinical study, Lytgobi (futibatinib) failed to inhibit Fgfr2 phosphorylation in cultured cells expressing FGFR2 V564F (PMID: 37270847). 37270847
FGFR2 L617V Advanced Solid Tumor predicted - sensitive Lirafugratinib Preclinical - Biochemical Actionable In a preclinical study, Lirafugratinib treatment inhibited Fgfr2 phosphorylation in cultured cells expressing FGFR2 L617V (PMID: 37270847). 37270847
FGFR2 K310R FGFR2 N549K endometrial adenocarcinoma sensitive Futibatinib Preclinical - Cell line xenograft Actionable In a preclinical study, Lytgobi (futibatinib) treatment led to tumor regression in a cell line xenograft model of endometrial adenocarcinoma harboring FGFR2 N549K and FGFR2 K310R (PMID: 37270847). 37270847
FGFR2 V564F Advanced Solid Tumor predicted - resistant Erdafitinib Preclinical - Biochemical Actionable In a preclinical study, Balversa (erdafitinib) failed to inhibit Fgfr2 phosphorylation in cultured cells expressing FGFR2 V564F (PMID: 37270847). 37270847
FGFR2 K310R FGFR2 N549K endometrial adenocarcinoma sensitive Lirafugratinib Preclinical - Cell line xenograft Actionable In a preclinical study, Lirafugratinib inhibited proliferation of an endometrial adenocarcinoma cell line harboring FGFR2 N549K and FGFR K310R in culture, and led to tumor regression in a cell line xenograft model (PMID: 37270847). 37270847
FGFR2 amp colorectal adenocarcinoma sensitive Lirafugratinib Preclinical - Cell culture Actionable In a preclinical study, Lirafugratinib inhibited proliferation of a colorectal adenocarcinoma cell line with FGFR2 amplification in culture (PMID: 37270847). 37270847
FGFR2 amp stomach cancer sensitive Lirafugratinib Preclinical - Cell line xenograft Actionable In a preclinical study, Lirafugratinib treatment inhibited proliferation of gastric carcinoma cell lines with an FGFR2 amplification in culture, and led to tumor regression in a cell line xenograft model (PMID: 37270847). 37270847
FGFR2 K641N Advanced Solid Tumor predicted - sensitive Lirafugratinib Preclinical - Biochemical Actionable In a preclinical study, Lirafugratinib treatment inhibited Fgfr2 phosphorylation in cultured cells expressing FGFR2 K641N (PMID: 37270847). 37270847
FGFR2 V564I Advanced Solid Tumor predicted - sensitive Infigratinib Preclinical - Biochemical Actionable In a preclinical study, Truseltiq (infigratinib) failed to inhibit Fgfr2 phosphorylation in cultured cells expressing FGFR2 V564I (PMID: 37270847). 37270847
FGFR2 Y375C salivary gland carcinoma predicted - sensitive Lirafugratinib Case Reports/Case Series Actionable In a Phase I/II trial (ReFocus), Lirafugratinib treatment resulted in a partial response with near complete resolution of liver metastases, and regression of lung and adrenal metastases in a patient with metastatic carcinoma of the right parotid salivary gland harboring FGFR2 Y375C (PMID: 37270847; NCT04526106). 37270847
FGFR2 N549H Advanced Solid Tumor predicted - sensitive Lirafugratinib Preclinical - Biochemical Actionable In a preclinical study, Lirafugratinib treatment inhibited Fgfr2 phosphorylation in cultured cells expressing FGFR2 N549H (PMID: 37270847). 37270847
FGFR2 K659M Advanced Solid Tumor predicted - sensitive Lirafugratinib Preclinical - Biochemical Actionable In a preclinical study, Lirafugratinib treatment inhibited Fgfr2 phosphorylation in cultured cells expressing FGFR2 K659M (PMID: 37270847). 37270847