Interim results of fight-202, a phase II, open-label, multicenter study of INCB054828 in patients (pts) with previously treated advanced/metastatic or surgically unresectable cholangiocarcinoma (CCA) with/without fibroblast growth factor (FGF)/FGF receptor (FGFR) genetic alterations

Hollebecque, Antoine; Borad, Mitesh J.; Sahai, Vaibhav; Catenacci, Daniel V.T.; Murphy, Adrian; Vaccaro, Gina M.; Paulson, Andrew Scott; Oh, Do‐Youn; Féliz, Luis; Lihou, Christine; Zhen, Huiling; Abou-Alfa, G. K.

doi:10.1093/annonc/mdy282.139

Cited by 19 publications

(22 citation statements)

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“…The efficacy seen across several early-phase clinical trials of FGFR2 inhibitors in patients with advanced refractory ICC (14,(28)(29)(30) represents a breakthrough in a disease with no FDA-approved targeted therapies to date. However, as seen with other tyrosine kinase inhibitors, the rapid emergence of resistance associated with recurrent acquired mutations in the target's kinase domain has limited the durability of benefit to ATP-competitive inhibitors.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…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%

“…Data extracted from. 139,140,[145][146][147][148][149][150][151][152][153][154] IC50 data also extracted from. 162 AEs, adverse events; CCA, cholangiocarcinoma; CR, complete response; DCR, disease control rate; FGFR, fibroblast growth factor receptor; GBC, gallbladder cancer; IC50, half maximal inhibitory concentration; iCCA, intrahepatic cholangiocarcinoma; LFTs, liver function tests; mDOR, median duration of response; mPFS, median progression-free survival; PDGFR, platelet-derived growth factor receptor; PR, partial response; ORR, objective response rate; TEAEs, treatment-emergent adverse events; TKI, tyrosine kinase inhibitor; VEGFR, vascular endothelial growth factor receptor.…”

Section: Gene Transcriptionmentioning

confidence: 99%

“…152 @ Updated data CCA cohort. 154 Multiple phase I/II clinical trials have reported a consistently high partial response rate (varying between 20.7% and 35.5%) for heavily pretreated patients with iCCA harbouring an FGFR2 fusion, [145][146][147][148][149][150][152][153][154] with a median PFS of around 6 months. 139,[145][146][147]150,154 For the majority of compounds under development, responses have been homogeneously absent for patients with other FGFR aberrations.…”

Section: Gene Transcriptionmentioning

confidence: 99%

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

Lamarca

Barriuso

McNamara

et al. 2020

Journal of Hepatology

275

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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“…Median PFS was 6.8 months. No responses were observed in cholangiocarcinomas with FGF/ FGFR alterations 8. A front-line phase III study evaluating pemigatinib versus gemcitabine plus cisplatin chemotherapy in patients with cholangiocarcinoma harboring FGFR2 rearrangements, is also underway (ClinicalTrials.gov identifier: NCT03656536).…”

mentioning

confidence: 99%