Efficacy of TAS-120, an irreversible fibroblast growth factor receptor (FGFR) inhibitor, in cholangiocarcinoma patients with FGFR pathway alterations who were previously treated with chemotherapy and other FGFR inhibitors

Meric‐Bernstam, Funda; Arkenau, Hendrik Tobias; Tran, Ben; Bahleda, Ratislav; Kelley, Robin K.; Hierro, Cinta; Ahn, Daniel H.; Zhu, Andrew X.; Javle, Milind; Winkler, R; He, Huan; Huang, Jerry; Goyal, Lipika

doi:10.1093/annonc/mdy149

Cited by 66 publications

(64 citation statements)

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“…Similar findings have been reported for the pan‐FGFR inhibitors LY2874455 and ARQ 087 . Clinical trials are ongoing for other highly selective FGFR inhibitors in development, such as TAS‐120 and INCB054828, in which patients are screened for FGFR abnormalities using next‐generation sequencing or FISH techniques.…”

Section: Introductionsupporting

confidence: 75%

First‐in‐human phase I study of E7090, a novel selective fibroblast growth factor receptor inhibitor, in patients with advanced solid tumors

et al. 2020

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Fibroblast growth factor receptors (FGFR) are a family of transmembrane receptor tyrosine kinases involved in regulating cellular processes. FGFR mutations are implicated in oncogenesis, representing therapeutic potential in the form of FGFR inhibitors. This phase I, first-in-human study in Japan evaluated safety and tolerability of E7090, a potent selective FGFR1-3 inhibitor, in patients with advanced solid tumors.Dose escalation (daily oral dose of 1-180 mg) was carried out to assess dose-limiting toxicity (DLT), maximum tolerated dose, and pharmacokinetics. Pharmacodynamic markers (serum phosphate, fibroblast growth factor 23, and 1,25-(OH) 2 -vitamin D)were also evaluated. A total of 24 patients refractory to standard therapy or for whom no appropriate treatment was available were enrolled. No DLT were observed up to the 140-mg dose; one patient in the 180-mg cohort experienced a DLT (increased aspartate aminotransferase/alanine aminotransferase, grade 3). The maximum tolerated dose was not reached. Dose-dependent increases in the maximum concentration and area under the curve from time 0 to the last measurable concentration were observed up to 180 mg. Dose-dependent increases were observed in all pharmacodynamic markers and plateaued at 100-140 mg, indicating sufficient FGFR pathway inhibition at doses ≥100 mg. In conclusion, E7090 showed a manageable safety profile with no DLT at doses ≤140 mg. Maximum tolerated dose was not determined.The recommended dose for the follow-up expansion part, restricted to patients with tumors harboring FGFR alterations, was determined as 140 mg, once daily.

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Section: Introductionsupporting

confidence: 75%

First‐in‐human phase I study of E7090, a novel selective fibroblast growth factor receptor inhibitor, in patients with advanced solid tumors

et al. 2020

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“…129,130,133,142 Many FGFR inhibitors are currently being developed, most of which have already shown adequate safety in phase I trials and early efficacy in phase II studies in patients with refractory iCCA (Table 1). 139,140,[145][146][147][148][149][150][151][152][153][154] Activated FGFR FGF P JAK-STAT…”

Section: Key Pointmentioning

confidence: 99%

Molecular targeted therapies: Ready for “prime time” in biliary tract cancer

Lamarca

Barriuso

McNamara

et al. 2020

Journal of Hepatology

255

221

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The prognosis for patients with biliary tract cancers (cholangiocarcinoma and gallbladder cancer) is poor, while the incidence of these cancers is increasing. Most patients are diagnosed with advanced disease when treatment options are limited to palliative approaches, mainly focused on chemotherapy. In recent years, novel treatment targets of relevance to biliary tract cancers, mainly present in patients with intrahepatic cholangiocarcinoma, have been identified and are rapidly changing the field. These include fibroblast growth factor receptor (FGFR) fusions and isocitrate dehydrogenase (IDH)-1 and-2 mutations which are each present in around 10-20% of patients with intrahepatic cholangiocarcinoma. In addition, inhibition of other pathways/molecules is currently being explored, including human epidermal growth factor receptor (HER) family members, the Wnt pathway, neurotropic tyrosine kinase receptor (NTRK) fusions and BRAF mutations. The IDH1 inhibitor ivosidenib has already been tested in a phase III clinical trial in pretreated cholangiocarcinoma and showed benefit in terms of progression-free survival. Multiple FGFR inhibitors have consistently shown high response rates in phase II/III trials, especially for patients harbouring FGFR2 fusions. Herein, we provide an overview of the status of targeted therapies in biliary tract cancers, discussing the current clinical development of IDH and FGFR inhibitors in detail, as well as reviewing current caveats and future steps.

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“…TAS-120 exhibits in vitro potency at low nanomolar concentrations and high specificity against wildtype FGFR1-4 as well as against some FGFR2 kinase domain mutations (19). Preliminary results from a phase I basket study of TAS-120 in patients with refractory advanced solid tumors showed an ORR of 25% and a DCR of 78.6% in 28 patients with ICC harboring FGFR2 fusions (20), including some patients who had received prior therapy with an ATPcompetitive FGFR inhibitor.…”

Section: Introductionmentioning

confidence: 99%

TAS-120 Overcomes Resistance to ATP-Competitive FGFR Inhibitors in Patients with FGFR2 Fusion–Positive Intrahepatic Cholangiocarcinoma

et al. 2019

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ATP-competitive fi broblast 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 effi cacy in 4 patients with FGFR 2 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 profi les observed clinically for each inhibitor. Our fi ndings suggest that strategic sequencing of FGFR inhibitors, guided by serial biopsy and ctDNA analysis, may prolong the duration of benefi t from FGFR inhibition in patients with FGFR2 fusion-positive ICC. SIGNIFICANCE: ATP-competitive FGFR inhibitors (BGJ398, Debio 1347) show effi cacy 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 benefi t in patients with resistance to BGJ398 or Debio 1347 and overcomes several FGFR2 mutations in ICC models.

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Efficacy of TAS-120, an irreversible fibroblast growth factor receptor (FGFR) inhibitor, in cholangiocarcinoma patients with FGFR pathway alterations who were previously treated with chemotherapy and other FGFR inhibitors

Cited by 66 publications

References 0 publications

First‐in‐human phase I study of E7090, a novel selective fibroblast growth factor receptor inhibitor, in patients with advanced solid tumors

First‐in‐human phase I study of E7090, a novel selective fibroblast growth factor receptor inhibitor, in patients with advanced solid tumors

Molecular targeted therapies: Ready for “prime time” in biliary tract cancer

TAS-120 Overcomes Resistance to ATP-Competitive FGFR Inhibitors in Patients with FGFR2 Fusion–Positive Intrahepatic Cholangiocarcinoma

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