FGFR Inhibitors in Cholangiocarcinoma—A Novel Yet Primary Approach: Where Do We Stand Now and Where to Head Next in Targeting This Axis?

Chmiel, Paulina; Gęca, Katarzyna; Rawicz‐Pruszyński, Karol; Polkowski, Wojciech; Skórzewska, Magdalena

doi:10.3390/cells11233929

Cited by 12 publications

(3 citation statements)

References 140 publications

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“…Infigratinib is an FGFR1–3 -selective inhibitor and showed a 23% objective response rate in an open-label single-arm trial [ 75 ]. Other potential FGFR inhibitors for ICC include Futibatinib, Ponatinib, Erdafitinib, and Debio 1347 [ 76 ].…”

Section: Resultsmentioning

confidence: 99%

Molecular Profile of Intrahepatic Cholangiocarcinoma

Andraus,

Tustumi,

de Meira Junior

et al. 2023

IJMS

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Intrahepatic cholangiocarcinoma (ICC) is a relatively uncommon but highly aggressive primary liver cancer that originates within the liver. The aim of this study is to review the molecular profile of intrahepatic cholangiocarcinoma and its implications for prognostication and decision-making. This comprehensive characterization of ICC tumors sheds light on the disease’s underlying biology and offers a foundation for more personalized treatment strategies. This is a narrative review of the prognostic and therapeutic role of the molecular profile of ICC. Knowing the molecular profile of tumors helps determine prognosis and support certain target therapies. The molecular panel in ICC helps to select patients for specific therapies, predict treatment responses, and monitor treatment responses. Precision medicine in ICC can promote improvement in prognosis and reduce unnecessary toxicity and might have a significant role in the management of ICC in the following years. The main mutations in ICC are in tumor protein p53 (TP53), Kirsten rat sarcoma virus (KRAS), isocitrate dehydrogenase 1 (IDH1), and AT-rich interactive domain-containing protein 1A (ARID1A). The rate of mutations varies significantly for each population. Targeting TP53 and KRAS is challenging due to the natural characteristics of these genes. Different stages of clinical studies have shown encouraging results with inhibitors of mutated IDH1 and target therapy for ARID1A downstream effectors. Fibroblast growth factor receptor 2 (FGFR2) fusions are an important target in patients with ICC. Immune checkpoint blockade can be applied to a small percentage of ICC patients. Molecular profiling in ICC represents a groundbreaking approach to understanding and managing this complex liver cancer. As our comprehension of ICC’s molecular intricacies continues to expand, so does the potential for offering patients more precise and effective treatments. The integration of molecular profiling into clinical practice signifies the dawn of a new era in ICC care, emphasizing personalized medicine in the ongoing battle against this malignancy.

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Section: Resultsmentioning

confidence: 99%

Molecular Profile of Intrahepatic Cholangiocarcinoma

Andraus,

Tustumi,

de Meira Junior

et al. 2023

IJMS

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“…Pemigatinib was FDA-approved in 2020 for treating previously treated unrespectable advanced CCA with FGFR2 alterations. Pemigatinib is a selective inhibitor of FGFR1-3 with weak activity against FGFR4 that can be taken orally [33]. FGFR2 alternations have been almost exclusively isolated to intrahepatic cholangiocarcinoma, and the prevalence of this alteration ranges from 10-15% [22].…”

Section: Efficacy Of Alternative Treatments For Advanced Cholangiocar...mentioning

confidence: 99%

“…Futibatinib is an oral FGFR1-4 selective inhibitor that was FDA-approved in 2022 for treating locally advanced or metastatic CCA [33]. Futibatinib irreversibly binds to FGFR using covalent bonds, making it less susceptible to mutations that can cause resistance.…”

Section: Efficacy Of Alternative Treatments For Advanced Cholangiocar...mentioning

confidence: 99%

Infigratinib for the Treatment of Metastatic or Locally Advanced Cholangiocarcinoma With Known FGFR2 Gene Fusions or Rearrangements

White,

Anwar,

Jin

et al. 2023

Cureus

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Cholangiocarcinoma (CCA) is an aggressive and diverse malignancy with a poor prognosis. Related to a typical indolent course of progression, most cases of CCA are metastatic or locally advanced at the time of presentation. For patients with nonresectable tumors or metastatic disease, the mainstay of treatment is comprehensive with combination chemotherapy. The first-line chemotherapeutic combination for the treatment of CCA are cisplatin and gemcitabine-based chemotherapies. However, many locally advanced and progressive CCA cases are refractory to first-line management. Within the past few years, the increase in the incidence of metastatic CCA and its poor prognosis has brought to light the need for novel therapeutic approaches to treatment. With advancements in next-generation genome sequencing, multiple molecular pathways have been identified in the pathogenesis of CCA and have shown great potential as alternative treatments in cases of CCA refractory to surgical resection. FGFR2 fusions or rearrangements have been identified in 10-16% of all intrahepatic CCA and are thought to serve as a pathway of resistance for a number of nonresectable and refractory cases of cholangiocarcinoma. A novel therapeutic agent that has been discussed is infigratinib, a selective, ATP-competitive inhibitor of fibroblast growth factor receptor 2 (FGFR2). In a phase 1 trial, infigratinib showed a safe profile and showed remarkable clinical efficacy in advanced CCA with FGFR2 fusions or rearrangements in phase II trials. As of May 2021, the Food and Drug Administration (FDA) approved infigratinib for CCA largely based on tumor response and duration of response. As of 2021, infigratinib, futibatinib, and pemigatinib, similar novel selective FGFR inhibitors, have been approved by the FDA for the treatment of locally advanced or metastatic CCA harboring FGFR2 gene mutations. The present investigation reviews the development of infigratinib in particular and its clinical efficacy compared to other available treatment options for cholangiocarcinoma. While the side effect profile of infigratinib is minimal, particularly GI side effects, when compared with futibatinib and pemigatinib, the overall response rate (ORR) and median overall survival (mOS) for infigratinib (ORR=23.1%, mOS=3.8 months) was significantly lower than futibatinib (ORR=35.8%, mOS=21.1 months) and pemigatinib (ORR=35.5%, mOS=21.1 months). While there is ample promise for the use of infigratinib as moleculardirected therapy in the treatment of CCA harboring FGFR2 mutations, there is an appropriate concern for patient-acquired resistance. The heterogeneous nature of FGFR mutations and the emergence of different resistance mechanisms emphasize a need for more agents to inhibit FGFR rearrangements effectively.

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New Therapeutic Targets in RAS Wild-type Pancreatic Cancer

Diab

2024

Curr. Treat. Options in Oncol.

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FGFR Inhibitors in Cholangiocarcinoma—A Novel Yet Primary Approach: Where Do We Stand Now and Where to Head Next in Targeting This Axis?

Cited by 12 publications

References 140 publications

Molecular Profile of Intrahepatic Cholangiocarcinoma

Molecular Profile of Intrahepatic Cholangiocarcinoma

Infigratinib for the Treatment of Metastatic or Locally Advanced Cholangiocarcinoma With Known FGFR2 Gene Fusions or Rearrangements

New Therapeutic Targets in RAS Wild-type Pancreatic Cancer

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