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Ref Type Journal Article
PMID (31109923)
Authors Goyal L, Shi L, Liu LY, Fece de la Cruz F, Lennerz JK, Raghavan S, Leschiner I, Elagina L, Siravegna G, Ng RWS, Vu P, Patra KC, Saha SK, Uppot RN, Arellano R, Reyes S, Sagara T, Otsuki S, Nadres B, Shahzade HA, Dey-Guha I, Fetter IJ, Baiev I, Van Seventer EE, Murphy JE, Ferrone CR, Tanabe KK, Deshpande V, Harding JJ, Yaeger R, Kelley RK, Bardelli A, Iafrate AJ, Hahn WC, Benes CH, Ting DT, Hirai H, Getz G, Juric D, Zhu AX, Corcoran RB, Bardeesy N
Title TAS-120 Overcomes Resistance to ATP-Competitive FGFR Inhibitors in Patients with FGFR2 Fusion-Positive Intrahepatic Cholangiocarcinoma.
Journal Cancer discovery
Vol 9
Issue 8
Date 2019 Aug
URL
Abstract Text ATP-competitive fibroblast growth factor receptor (FGFR) kinase inhibitors, including BGJ398 and Debio 1347, show antitumor activity in patients with intrahepatic cholangiocarcinoma (ICC) harboring activating FGFR2 gene fusions. Unfortunately, acquired resistance develops and is often associated with the emergence of secondary FGFR2 kinase domain mutations. Here, we report that the irreversible pan-FGFR inhibitor TAS-120 demonstrated efficacy in 4 patients with FGFR2 fusion-positive ICC who developed resistance to BGJ398 or Debio 1347. Examination of serial biopsies, circulating tumor DNA (ctDNA), and patient-derived ICC cells revealed that TAS-120 was active against multiple FGFR2 mutations conferring resistance to BGJ398 or Debio 1347. Functional assessment and modeling the clonal outgrowth of individual resistance mutations from polyclonal cell pools mirrored the resistance profiles observed clinically for each inhibitor. Our findings suggest that strategic sequencing of FGFR inhibitors, guided by serial biopsy and ctDNA analysis, may prolong the duration of benefit from FGFR inhibition in patients with FGFR2 fusion-positive ICC. SIGNIFICANCE: ATP-competitive FGFR inhibitors (BGJ398, Debio 1347) show efficacy in FGFR2-altered ICC; however, acquired FGFR2 kinase domain mutations cause drug resistance and tumor progression. We demonstrate that the irreversible FGFR inhibitor TAS-120 provides clinical benefit in patients with resistance to BGJ398 or Debio 1347 and overcomes several FGFR2 mutations in ICC models.This article is highlighted in the In This Issue feature, p. 983.

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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
Futibatinib Futibatinib 32 4
Infigratinib Infigratinib 99 12
Drug Name Trade Name Synonyms Drug Classes Drug Description
Futibatinib TAS-120 FGFR Inhibitor (Pan) 18 Futibatinib (TAS-120) is a third-generation pan-FGFR inhibitor, which result in the inhibition of FGFR-mediated signal transduction pathways and tumor cell proliferation (PMID: 31109923).
Infigratinib BGJ398|BGJ-398|BGJ 398 FGFR Inhibitor (Pan) 18 Infigratinib (BGJ398) is pan-FGFR inhibitor, which inhibits tumor angiogenesis and tumor cell proliferation (PMID: 31109923, PMID: 30101387).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
FGFR2 E566A missense gain of function FGFR2 E566A (corresponds to E565A in the canonical isoform) lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). E566A results in increased Fgfr2 autophosphorylation and substrate phosphorylation in in vitro kinase assays (PMID: 17803937, PMID: 28166054) and is also associated with resistance to FGFR inhibitors (PMID: 31109923). Y
FGFR2 INA FGFR2 - INA fusion gain of function FGFR2-INA results from the fusion of FGFR2 and INA, leading to activation of Mapk and Pi3k signaling pathways and transformation in cell culture (PMID: 29767381). FGFR2-INA has been identified in mixed neuronal-glial tumors (PMID: 29767381) and intrahepatic cholangiocarcinoma (PMID: 31109923).
FGFR2 KIAA1217 FGFR2 - KIAA1217 fusion unknown FGFR2-KIAA1217 results from the fusion of FGFR2 and KIAA1217 (PMID: 30745300). FGFR2-KIAA1217 has been identified in cholangiocarcinoma (PMID: 30745300, PMID: 31109923), but has not been biochemically characterized and therefore, the effect on protein function is unknown (PubMed, Aug 2020).
FGFR2 NRAP FGFR2 - NRAP fusion unknown FGFR2-NRAP results from the fusion of FGFR2 and NRAP (PMID: 31109923). FGFR2-NRAP has been identified in intrahepatic cholangiocarcinoma (PMID: 31109923), but has not been biochemically characterized and therefore, the effect on protein function is unknown (PubMed, May 2020).
FGFR2 OPTN FGFR2 - OPTN fusion gain of function - predicted FGFR2-OPTN results from the fusion of FGFR2 and OPTN (PMID: 28034880), and leads to constitutive FRS2 phosphorylation on Y196 cultured cells (PMID: 31109923), and therefore, is predicted to lead to gain of function. FGFR2-OPTN fusions have been identified in intrahepatic cholangiocarcinoma (PMID: 28034880).
FGFR2 SORBS1 FGFR2 - SORBS1 fusion unknown FGFR2-SORBS1 results from the fusion of FGFR2 and SORBS1 (PMID: 31109923). FGFR2-SORBS1 has been identified in intrahepatic cholangiocarcinoma (PMID: 31109923), but has not been biochemically characterized and therefore, the effect on protein function is unknown (PubMed, Aug 2020).
FGFR2 ZMYM4 FGFR2 - ZMYM4 fusion unknown FGFR2-ZMYM4 results from the fusion of FGFR2 and ZMYM4 (PMID: 28034880). FGFR2-ZMYM4 has been identified in intrahepatic cholangiocarcinoma (PMID: 28034880, PMID: 31109923), but has not been biochemically characterized and therefore, the effect on fusion protein function is unknown (PubMed, Aug 2020).
FGFR2 H683L missense unknown FGFR2 H683L (corresponds to H682L in the canonical isoform) lies within the protein kinase domain of the FGFR2 protein (UniProt.org). H683L has been associated with resistance to Fgfr inhibitors in the context of an FGFR2 fusion in culture (PMID: 31109923), but has not been biochemically characterized and therefore, its effect on Fgfr2 protein function is unknown (PubMed, Jun 2020). Y
FGFR2 K660M missense unknown FGFR2 K660M (corresponds to K659M in the canonical isoform) lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). K660M has been associated with resistance to Fgfr inhibitors in the context of an FGFR2 fusion (PMID: 31109923), but has not been biochemically characterized and therefore, its effect on Fgfr2 protein function is unknown (PubMed, Jun 2020). Y
FGFR2 K714R missense unknown FGFR2 K714R (also referred to as K715R from the FGFR2IIIb isoform) lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). K714R has been associated with resistance to Fgfr inhibitors in the context of an FGFR2 fusion (PMID: 31109923), but has not been biochemically characterized and therefore, its effect on Fgfr2 protein function is unknown (PubMed, Jun 2020). Y
FGFR2 K715R missense unknown FGFR2 K715R (corresponds to K714R in the canonical isoform) lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). K715R has been associated with resistance to Fgfr inhibitors in the context of an FGFR2 fusion (PMID: 31109923), but has not been biochemically characterized and therefore, its effect on Fgfr2 protein function is unknown (PubMed, Jun 2020). Y
FGFR2 V563L missense gain of function - predicted FGFR2 V563L (corresponds to V562L in the canonical isoform) lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). V563L is predicted to confer a gain of function to the Fgfr2 protein as indicated by increased Fgfr2 kinase activity in cell culture, and has been shown to be associated with secondary resistance to FGFR inhibitors (PMID: 25169980, PMID: 31109923). Y
FGFR2 V565F missense gain of function - predicted FGFR2 V565F (corresponds to V564F in the canonical isoform) lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). V565F is predicted to confer a gain of function as demonstrated by increased Fgfr2 kinase activity in cell culture (PMID: 25169980), and has been shown to be associated with secondary resistance to FGFR inhibitors (PMID: 28034880, PMID: 31109923). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR2 fusion FGFR2 N550H intrahepatic cholangiocarcinoma sensitive Futibatinib Preclinical - Cell culture Actionable In a preclinical study, TAS-120 treatment of intrahepatic cholangiocarcinoma cells with an FGFR2 fusion in context with FGFR2 N550H were sensitive to treatment as demonstrated by decreased cell viability and decreased activation of downstream signaling (PMID: 31109923). 31109923
FGFR2 - NRAP intrahepatic cholangiocarcinoma sensitive Futibatinib Case Reports/Case Series Actionable In a Phase I trial, a patient with intrahepatic cholangiocarcinoma, harboring an FGFR2-NRAP fusion responded to TAS-120 for 17.2 months before progressing due to an acquired FGFR2 N550K mutation, detected in cell-free DNA and the tumor biopsy (PMID: 31109923; NCT02052778). 31109923
FGFR2 - ZMYM4 FGFR2 N550H FGFR2 N550K FGFR2 V565F FGFR2 E566A FGFR2 K660M intrahepatic cholangiocarcinoma sensitive Futibatinib Case Reports/Case Series Actionable In a Phase I trial, a patient with intrahepatic cholangiocarcinoma, harboring an FGFR2-ZMYM4 fusion with FGFR2 V565F, K660M E566A, N550H, and N550K mutations, responded to TAS-120 for 7.2 months before progressing due to an acquired FGFR2 V563L mutation, detected in cell-free DNA (PMID: 31109923; NCT02052778). 31109923
FGFR2 fusion FGFR2 N550H intrahepatic cholangiocarcinoma decreased response Debio 1347 Preclinical - Cell culture Actionable In a preclinical study, Debio 1347 treatment of intrahepatic cholangiocarcinoma cells with an FGFR2 fusion in context with FGFR2 N550H had weakened sensitivity, as demonstrated by cell viability and downstream signaling assays (PMID: 31109923). 31109923
FGFR2 fusion FGFR2 L618V intrahepatic cholangiocarcinoma sensitive Futibatinib Preclinical - Cell culture Actionable In a preclinical study, TAS-120 treatment of intrahepatic cholangiocarcinoma cells with an FGFR2 fusion in context with FGFR2 L618V were sensitive to treatment as demonstrated by decreased cell viability and decreased activation of downstream signaling (PMID: 31109923). 31109923
FGFR2 fusion FGFR2 V565F intrahepatic cholangiocarcinoma resistant Futibatinib Preclinical - Cell culture Actionable In a preclinical study, TAS-120 treatment of intrahepatic cholangiocarcinoma cells with an FGFR2 fusion in context with FGFR2 V565F were resistant to treatment, as demonstrated by cell viability and downstream signaling assays (PMID: 31109923). 31109923
FGFR2 - ZMYM4 FGFR2 N550H FGFR2 N550K FGFR2 V565F FGFR2 E566A FGFR2 K660M intrahepatic cholangiocarcinoma resistant Infigratinib Case Reports/Case Series Actionable In a clinical case study, a patient with intrahepatic cholangiocarcinoma harboring an FGFR2-ZMYM4 fusion developed progressive disease after initial response to Infigratinib (BGJ398) for 5.6 months and FGFR2 V565F, K660M E566A, N550H, and N550K mutations were identified in the post-progression cell-free DNA (PMID: 31109923). 31109923
FGFR2 fusion FGFR2 H683L intrahepatic cholangiocarcinoma decreased response Debio 1347 Preclinical - Cell culture Actionable In a preclinical study, Debio 1347 treatment of intrahepatic cholangiocarcinoma cells with an FGFR2 fusion in context with FGFR2 H683L had weakened sensitivity, as demonstrated by cell viability and downstream signaling assays (PMID: 31109923). 31109923
FGFR2 - INA intrahepatic cholangiocarcinoma sensitive Debio 1347 Case Reports/Case Series Actionable In a clinical case study, a patient with intrahepatic cholangiocarcinoma, harboring an FGFR2-INA fusion responded to Debio 1347 for 11.4 months before progressing due to acquired FGFR2 H683L, L618V, N550H, N550T, and M538I mutations (PMID: 31109923). 31109923
FGFR2 fusion FGFR2 K715R intrahepatic cholangiocarcinoma sensitive Futibatinib Preclinical - Cell culture Actionable In a preclinical study, TAS-120 treatment of intrahepatic cholangiocarcinoma cells with an FGFR2 fusion in context with FGFR2 K715R were sensitive to treatment as demonstrated by decreased cell viability and decreased activation of downstream signaling (PMID: 31109923). 31109923
FGFR2 fusion FGFR2 N550K intrahepatic cholangiocarcinoma resistant Infigratinib Preclinical - Cell culture Actionable In a preclinical study, Infigratinib (BGJ398) treatment of intrahepatic cholangiocarcinoma cells with an FGFR2 fusion in context with FGFR2 N550K were resistant to treatment as demonstrated by cell viability and downstream signaling assays (PMID: 31109923). 31109923
FGFR2 fusion FGFR2 K660M intrahepatic cholangiocarcinoma sensitive Futibatinib Preclinical - Cell culture Actionable In a preclinical study, TAS-120 treatment of intrahepatic cholangiocarcinoma cells with an FGFR2 fusion in context with FGFR2 K660M were sensitive to treatment as demonstrated by decreased cell viability and decreased activation of downstream signaling (PMID: 31109923). 31109923
FGFR2 fusion FGFR2 N550K intrahepatic cholangiocarcinoma sensitive Futibatinib Preclinical - Cell culture Actionable In a preclinical study, TAS-120 treatment of intrahepatic cholangiocarcinoma cells with an FGFR2 fusion in context with FGFR2 N550K were sensitive to treatment as demonstrated by decreased cell viability and decreased activation of downstream signaling (PMID: 31109923). 31109923
FGFR2 - ZMYM4 FGFR2 V563L intrahepatic cholangiocarcinoma resistant Futibatinib Case Reports/Case Series Actionable In a Phase I trial, a patient with intrahepatic cholangiocarcinoma, harboring an FGFR2-SORBS1 fusion with FGFR2 V565F, K660M E566A, N550H, and N550K mutations, responded to TAS-120 for 7.2 months before progressing due to an acquired FGFR2 V563L mutation, detected in cell-free DNA and tumor biopsy (PMID: 31109923; NCT02052778). 31109923
FGFR2 fusion FGFR2 M538I intrahepatic cholangiocarcinoma decreased response Infigratinib Preclinical - Cell culture Actionable In a preclinical study, Infigratinib (BGJ398) treatment of intrahepatic cholangiocarcinoma cells with an FGFR2 fusion in context with FGFR2 M538I had weakened sensitivity, as demonstrated by cell viability and downstream signaling assays (PMID: 31109923). 31109923
FGFR2 fusion FGFR2 E566A intrahepatic cholangiocarcinoma decreased response Debio 1347 Preclinical - Cell culture Actionable In a preclinical study, Debio 1347 treatment of intrahepatic cholangiocarcinoma cells with an FGFR2 fusion in context with FGFR2 E566A had weakened sensitivity, as demonstrated by cell viability and downstream signaling assays (PMID: 31109923). 31109923
FGFR2 - SORBS1 FGFR2 V565F intrahepatic cholangiocarcinoma resistant Futibatinib Case Reports/Case Series Actionable In a Phase I trial, a patient with intrahepatic cholangiocarcinoma, harboring an FGFR2-SORBS1 fusion, responded to TAS-120 for 15.8 months before progressing due to an acquired FGFR2 V565F mutation, detected in cell-free DNA (PMID: 31109923; NCT02052778). 31109923
FGFR2 fusion FGFR2 N550K intrahepatic cholangiocarcinoma resistant Debio 1347 Preclinical - Cell culture Actionable In a preclinical study, Debio 1347 treatment of intrahepatic cholangiocarcinoma cells with an FGFR2 fusion in context with FGFR2 N550K were resistant to treatment, as demonstrated by cell viability and downstream signaling assays (PMID: 31109923). 31109923
FGFR2 - NRAP intrahepatic cholangiocarcinoma sensitive Infigratinib Case Reports/Case Series Actionable In a clinical case study, a patient with intrahepatic cholangiocarcinoma, harboring an FGFR2-NRAP fusion responded to Infigratinib (BGJ398) for 7.1 months before progressing (PMID: 31109923). 31109923
FGFR2 - SORBS1 intrahepatic cholangiocarcinoma sensitive Infigratinib Case Reports/Case Series Actionable In a clinical case study, a patient with intrahepatic cholangiocarcinoma, harboring an FGFR2-SORBS1 fusion responded to Infigratinib (BGJ398) for 12.6 months before progressing due to acquired FGFR2 K660M and K175R mutations, detected in cell-free DNA (PMID: 31109923). 31109923
FGFR2 fusion FGFR2 E566A intrahepatic cholangiocarcinoma sensitive Futibatinib Preclinical - Cell culture Actionable In a preclinical study, TAS-120 treatment of intrahepatic cholangiocarcinoma cells with an FGFR2 fusion in context with FGFR2 E566A were sensitive to treatment as demonstrated by decreased cell viability and decreased activation of downstream signaling (PMID: 31109923). 31109923
FGFR2 fusion FGFR2 K660M intrahepatic cholangiocarcinoma resistant Debio 1347 Preclinical - Cell culture Actionable In a preclinical study, Debio 1347 treatment of intrahepatic cholangiocarcinoma cells with an FGFR2 fusion in context with FGFR2 K660M were resistant to treatment, as demonstrated by cell viability and downstream signaling assays (PMID: 31109923). 31109923
FGFR2 - INA FGFR2 V565L FGFR2 E566A intrahepatic cholangiocarcinoma resistant Futibatinib Case Reports/Case Series Actionable In a Phase I trial, a patient with intrahepatic cholangiocarcinoma, harboring an FGFR2-INA fusion with FGFR2 H683L, L618V, N550H, N550T, M538I mutations, responded to TAS-120 for 5.1 months before progressing due to acquired FGFR2 V565L and E566A mutations, detected in cell-free DNA (PMID: 31109923; NCT02052778). 31109923
FGFR2 - ZMYM4 intrahepatic cholangiocarcinoma sensitive Infigratinib Case Reports/Case Series Actionable In a clinical case study, a patient with intrahepatic cholangiocarcinoma, harboring an FGFR2-ZMYM4 fusion responded to Infigratinib (BGJ398) for 5.6 months before progressing due to acquired FGFR2 V565F, K660M, E566A, N550H, and N550K mutations, detected in cell-free DNA (PMID: 31109923). 31109923
FGFR2 - KIAA1217 intrahepatic cholangiocarcinoma sensitive Futibatinib Preclinical - Pdx Actionable In a preclinical study, TAS-120 treatment of an intrahepatic cholangiocarcinoma patient-derived xenograft model, harboring an FGFR2-KIAA1217 fusion, decreased tumor growth and suppressed MEK/ERK signaling (PMID: 31109923). 31109923
FGFR2 - SORBS1 FGFR2 K660M FGFR2 K715R intrahepatic cholangiocarcinoma sensitive Futibatinib Case Reports/Case Series Actionable In a Phase I trial, a patient with intrahepatic cholangiocarcinoma, harboring an FGFR2-SORBS1 fusion with FGFR2 K660M and K175R mutations, responded to TAS-120 for 15.8 months before progressing due to an acquired FGFR2 V565F mutation, detected in cell-free DNA (PMID: 31109923; NCT02052778). 31109923
FGFR2 fusion FGFR2 K715R intrahepatic cholangiocarcinoma sensitive Infigratinib Preclinical - Cell culture Actionable In a preclinical study, Infigratinib (BGJ398) treatment of intrahepatic cholangiocarcinoma cells with an FGFR2 fusion in context with FGFR2 K715R were sensitive to treatment as demonstrated by decreased cell viability and decreased activation of downstream signaling, in in vitro assays (PMID: 31109923). 31109923
FGFR2 fusion FGFR2 V565F intrahepatic cholangiocarcinoma decreased response Debio 1347 Preclinical - Cell culture Actionable In a preclinical study, Debio 1347 treatment of intrahepatic cholangiocarcinoma cells with an FGFR2 fusion in context with FGFR2 V565F had weakened sensitivity, as demonstrated by cell viability and downstream signaling assays (PMID: 31109923). 31109923
FGFR2 fusion FGFR2 V565F intrahepatic cholangiocarcinoma resistant Infigratinib Preclinical - Cell culture Actionable In a preclinical study, Infigratinib (BGJ398) treatment of intrahepatic cholangiocarcinoma cells with an FGFR2 fusion in context with FGFR2 V565F were resistant to treatment as demonstrated by cell viability and downstream signaling assays (PMID: 31109923). 31109923
FGFR2 fusion FGFR2 E566A intrahepatic cholangiocarcinoma decreased response Infigratinib Preclinical - Cell culture Actionable In a preclinical study, Infigratinib (BGJ398) treatment of intrahepatic cholangiocarcinoma cells with an FGFR2 fusion in context with FGFR2 E566A had weakened sensitivity, as demonstrated by cell viability and downstream signaling assays (PMID: 31109923). 31109923
FGFR2 fusion FGFR2 M538I intrahepatic cholangiocarcinoma decreased response Debio 1347 Preclinical - Cell culture Actionable In a preclinical study, Debio 1347 treatment of intrahepatic cholangiocarcinoma cells with an FGFR2 fusion in context with FGFR2 M538I had weakened sensitivity, as demonstrated by cell viability and downstream signaling assays (PMID: 31109923). 31109923
FGFR2 - INA FGFR2 M538I FGFR2 N550H FGFR2 N550T FGFR2 L618V FGFR2 H683L intrahepatic cholangiocarcinoma sensitive Futibatinib Case Reports/Case Series Actionable In a Phase I trial, a patient with intrahepatic cholangiocarcinoma, harboring an FGFR2-INA fusion with FGFR2 H683L, L618V, N550H, N550T, M538I mutations, responded to TAS-120 for 5.1 months before progressing due to acquired FGFR2 V565L and E566A mutations, detected in cell-free DNA (PMID: 31109923; NCT02052778). 31109923
FGFR2 fusion FGFR2 K715R intrahepatic cholangiocarcinoma sensitive Debio 1347 Preclinical - Cell culture Actionable In a preclinical study, Debio 1347 treatment of intrahepatic cholangiocarcinoma cells with an FGFR2 fusion in context with FGFR2 K715R were sensitive to treatment as demonstrated by decreased cell viability and decreased activation of downstream signaling, in in vitro assays (PMID: 31109923). 31109923
FGFR2 fusion FGFR2 L618V intrahepatic cholangiocarcinoma resistant Debio 1347 Preclinical - Cell culture Actionable In a preclinical study, Debio 1347 treatment of intrahepatic cholangiocarcinoma cells with an FGFR2 fusion in context with FGFR2 L618V were resistant to treatment, as demonstrated by cell viability and downstream signaling assays (PMID: 31109923). 31109923
FGFR2 fusion FGFR2 M538I intrahepatic cholangiocarcinoma sensitive Futibatinib Preclinical - Cell culture Actionable In a preclinical study, TAS-120 treatment of intrahepatic cholangiocarcinoma cells with an FGFR2 fusion in context with FGFR2 M538I were sensitive to treatment as demonstrated by decreased cell viability and decreased activation of downstream signaling (PMID: 31109923). 31109923
FGFR2 fusion FGFR2 H683L intrahepatic cholangiocarcinoma decreased response Infigratinib Preclinical - Cell culture Actionable In a preclinical study, Infigratinib (BGJ398) treatment of intrahepatic cholangiocarcinoma cells with an FGFR2 fusion in context with FGFR2 H683L had weakened sensitivity, as demonstrated by cell viability and downstream signaling assays (PMID: 31109923). 31109923
FGFR2 fusion FGFR2 N550H intrahepatic cholangiocarcinoma decreased response Infigratinib Preclinical - Cell culture Actionable In a preclinical study, Infigratinib (BGJ398) treatment of intrahepatic cholangiocarcinoma cells with an FGFR2 fusion in context with FGFR2 N550H had weakened sensitivity, as demonstrated by cell viability and downstream signaling assays (PMID: 31109923). 31109923
FGFR2 - NRAP FGFR2 N550K intrahepatic cholangiocarcinoma resistant Futibatinib Case Reports/Case Series Actionable In a Phase I trial, a patient with intrahepatic cholangiocarcinoma, harboring an FGFR2-NRAP fusion responded to TAS-120 for 17.2 months before progressing due to an acquired FGFR2 N550K mutation, detected in cell-free DNA and the tumor biopsy (PMID: 31109923; NCT02052778). 31109923
FGFR2 fusion FGFR2 L618V intrahepatic cholangiocarcinoma resistant Infigratinib Preclinical - Cell culture Actionable In a preclinical study, Infigratinib (BGJ398) treatment of intrahepatic cholangiocarcinoma cells with an FGFR2 fusion in context with FGFR2 L618V were resistant to treatment as demonstrated by cell viability and downstream signaling assays (PMID: 31109923). 31109923
FGFR2 fusion FGFR2 H683L intrahepatic cholangiocarcinoma sensitive Futibatinib Preclinical - Cell culture Actionable In a preclinical study, TAS-120 treatment of intrahepatic cholangiocarcinoma cells with an FGFR2 fusion in context with FGFR2 H683L were sensitive to treatment as demonstrated by decreased cell viability and decreased activation of downstream signaling (PMID: 31109923). 31109923
FGFR2 - INA FGFR2 M538I FGFR2 N550H FGFR2 N550T FGFR2 L618V FGFR2 H683L intrahepatic cholangiocarcinoma resistant Debio 1347 Case Reports/Case Series Actionable In a clinical case study, a patient with intrahepatic cholangiocarcinoma harboring an FGFR2-INA fusion developed progressive disease after initial response to Debio 1347 for 11.4 months and FGFR2 H683L, L618V, N550H, N550T, M538I mutations were identified post-progression (PMID: 31109923). 31109923
FGFR2 fusion FGFR2 K660M intrahepatic cholangiocarcinoma resistant Infigratinib Preclinical - Cell culture Actionable In a preclinical study, Infigratinib (BGJ398) treatment of intrahepatic cholangiocarcinoma cells with an FGFR2 fusion in context with FGFR2 K660M were resistant to treatment as demonstrated by cell viability and downstream signaling assays (PMID: 31109923). 31109923
FGFR2 - SORBS1 FGFR2 K660M FGFR2 K715R intrahepatic cholangiocarcinoma resistant Infigratinib Case Reports/Case Series Actionable In a clinical case study, a patient with intrahepatic cholangiocarcinoma harboring an FGFR2-SORBS1 fusion developed progressive disease after initial response to Infigratinib (BGJ398) for 12.6 months and FGFR2 K660M and FGFR2 K715R were identified in the post-progression cell-free DNA (PMID: 31109923). 31109923