Reference Detail

Ref Type

Journal Article

PMID

(39226398)

Authors

Facchinetti F, Loriot Y, Braye F, Vasseur D, Bahleda R, Bigot L, Barbé R, Nobre C, Combarel D, Michiels S, Italiano A, Smolenschi C, Tselikas L, Scoazec JY, Ponce-Aix S, Besse B, Andre F, Olaussen KA, Hollebecque A, Friboulet L

Title

Understanding and Overcoming Resistance to Selective FGFR inhibitors Across FGFR2-Driven Malignancies.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research			2024 Sep 03		Clin Cancer Res

URL

Abstract Text

Understanding resistance to selective FGFR inhibitors is crucial to improve the clinical outcomes of patients with FGFR2-driven malignancies.We analyzed sequential ctDNA, +/- WES or targeted NGS on tissue biopsies from patients with tumors harboring activating FGFR2 alterations progressing on pan-FGFR-selective inhibitors, collected in the prospective UNLOCK program. FGFR2::BICC1 Ba/F3 and patient-derived xenografts (PDX) models were used for functional studies.Thirty-six patients were included. 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). Tumors other than cholangiocarcinoma shared the same mutated FGFR2 residues, but polyclonality was rare (1/9 patients). At resistance to reversible inhibitors, 14 residues in the FGFR2 kinase domain were mutated; after futibatinib, only the molecular brake N550 and the gatekeeper V565. Off-target alterations in PI3K/mTOR and MAPK pathways were found in 11 patients, often together with on-target mutations. 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 benefitted from everolimus. In cell viability assays on Ba/F3 and in pharmacologic studies on PDX, irreversible inhibitors retained better activity against FGFR2 kinase domain mutations, with lirafugratinib active against the recalcitrant V565L/F/Y.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.

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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
FGFR2	D651H	missense	unknown	FGFR2 D651H (corresponds to D650H in the canonical isoform) lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). D651H has been identified in the scientific literature (PMID: 39226398), but has not been biochemically characterized and therefore, its effect on Fgfr2 protein function is unknown (PubMed, Sep 2024).
FGFR2	I549T	missense	unknown	FGFR2 I549T (corresponds to I548T in the canonical isoform) lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). I549T has been identified in the scientific literature (PMID: 39226398), but has not been biochemically characterized and therefore, its effect on Fgfr2 protein function is unknown (PubMed, Sep 2024).
FGFR2	K527E	missense	unknown	FGFR2 K527E (corresponds to K526E in the canonical isoform) lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). K527E has been identified in the scientific literature (PMID: 39226398), but has not been biochemically characterized and therefore, its effect on Fgfr2 protein function is unknown (PubMed, Sep 2024).
FGFR2	N550D	missense	unknown	FGFR2 N550D (corresponds to N549D in the canonical isoform) lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). N550D has been identified in the scientific literature (PMID: 37843855, PMID: 39226398), but has not been biochemically characterized and therefore, its effect on Fgfr2 protein function is unknown (PubMed, Nov 2024).
FGFR2	V565Y	missense	unknown	FGFR2 V565Y (corresponds to V564Y in the canonical isoform) lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). V565Y has been identified in the scientific literature (PMID: 39226398), but has not been biochemically characterized and therefore, its effect on Fgfr2 protein function is unknown (PubMed, Sep 2024).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FGFR2 C382R	intrahepatic cholangiocarcinoma	predicted - sensitive	Futibatinib	Case Reports/Case Series	Actionable	In a clinical case study, Lytgobi (futibatinib) treatment resulted in a partial response with a progression-free survival of 17.3 months and a best objective response of -53% in a patient with intrahepatic cholangiocarcinoma harboring FGFR2 C382R (reported as C383R) (PMID: 39226398).	39226398
FGFR2 C382R	triple-receptor negative breast cancer	predicted - sensitive	Erdafitinib	Case Reports/Case Series	Actionable	In a clinical case study, Balversa (erdafitinib) treatment resulted in a partial response with a progression-free survival of 24.3 months and best objective response of -59% in a patient with a triple-negative breast cancer harboring FGFR2 C382R (reported as C383R) (PMID: 39226398).	39226398
FGFR2 C382R	intrahepatic cholangiocarcinoma	predicted - sensitive	Erdafitinib	Case Reports/Case Series	Actionable	In a clinical case study, Balversa (erdafitinib) treatment resulted in a partial response with a progression-free survival of 9.3 months and best objective response of -67% in a patient with intrahepatic cholangiocarcinoma harboring FGFR2 C382R (reported as C383R) (PMID: 39226398).	39226398
FGFR2 Y375C	intrahepatic cholangiocarcinoma	predicted - sensitive	Futibatinib	Case Reports/Case Series	Actionable	In a clinical case study, Lytgobi (futibatinib) treatment resulted in a partial response with a progression-free survival of 35.5 months and a best objective response of -45% in a patient with intrahepatic cholangiocarcinoma harboring FGFR2 Y375C (reported as Y376C) (PMID: 39226398).	39226398
FGFR2 C383R FGFR2 N550D	intrahepatic cholangiocarcinoma	sensitive	Lirafugratinib	Preclinical - Pdx	Actionable	In a preclinical study, Lirafugratinib inhibited tumor growth in a patient-derived xenograft (PDX) model of intrahepatic cholangiocarcinoma harboring FGFR2 C383R and FGFR2 N550D (PMID: 39226398).	39226398
FGFR2 C382R FGFR2 N549D	intrahepatic cholangiocarcinoma	conflicting	Futibatinib	Case Reports/Case Series	Actionable	In a clinical case study, a patient with intrahepatic cholangiocarcinoma harboring FGFR2 C382R (reported as C383R) and FGFR2 N549D (reported as N550D) experienced progressive disease on treatment with Lytgobi (futibatinib), however, treatment in the patient-derived xenograft (PDX) model resulted in tumor growth inhibition (PMID: 39226398).	39226398
FGFR2 C382R FGFR2 N549D	intrahepatic cholangiocarcinoma	predicted - resistant	Erdafitinib	Case Reports/Case Series	Actionable	In a clinical case study, FGFR2 N550D (reported as N549D) was identified in the post-progression tissue biopsy of a patient with intrahepatic cholangiocarcinoma harboring FGFR2 C382R (reported as C383R) who previously responded to treatment with Balversa (erdafitinib) (PMID: 39226398).	39226398
FGFR2 S267P	Cancer of Unknown Primary	predicted - sensitive	Erdafitinib	Case Reports/Case Series	Actionable	In a clinical case study, Balversa (erdafitinib) treatment resulted in a partial response with a progression-free survival of 7 months and best objective response of -40% in a patient with cancer of unknown primary harboring FGFR2 S267P (PMID: 39226398).	39226398