Reference Detail

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 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 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 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 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 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 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
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 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 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 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	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 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 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 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 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 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 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 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