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Targeted Therapy for Advanced or Metastatic Cholangiocarcinoma: Focus on the Clinical Potential of Infigratinib

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ONCOTARGETS AND THERAPY
卷 14, 期 -, 页码 5145-5160

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DOVE MEDICAL PRESS LTD
DOI: 10.2147/OTT.S272208

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infigratinib; cholangiocarcinoma; fibroblast growth factor receptor; FGFR inhibitors; targeted therapy

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Cholangiocarcinoma, a highly aggressive cancer, has shown promising clinical benefits with FGFR inhibitors targeting FGFR2 fusions. Infigratinib has been approved by the FDA for cholangiocarcinoma treatment and is currently being evaluated in a Phase 3 trial as a first-line therapy option. Acquired resistance to infigratinib remains a challenge that needs to be addressed in ongoing clinical trials.
Cholangiocarcinoma is one of the most aggressive cancers, with a 5-year survival rate of 11-44% after surgical resection. However, there is no established systemic therapy after failure of the gemcitabine plus cisplatin first-line therapy with exception of FOLFOX. Fibroblast growth factor receptor (FGFR) genomic aberrations have been detected in cho-langiocarcinoma, and targeting these genomic aberrations with FGFR inhibitors has shown remarkable clinical benefits in advanced cholangiocarcinoma. In this article, we provide up-to-date information on the clinical development of selective FGFR inhibitors in advanced cholangiocarcinoma, focusing on infigratinib. In a Phase 1 trial, infigratinib showed a safe profile. In a following Phase 2 trial, infigratinib showed remarkable efficacy in advanced cholangiocarcinoma with FGFR2 fusions or rearrangements, and the Food and Drug Administration (FDA) approved infigratinib for cholangiocarcinoma in May 2021 largely based on tumor response and duration of response. Currently infigratinib is on a Phase 3 trial (PROOF301) as a first-line setting compared to the GEMCIS therapy in advanced cholan-giocarcinoma. Given that the FGFR genomic aberrations including FGFR2 fusions are rarely accompanied with other targetable mutations, infigratinib and other FGFR inhibitors are continuously expected to be the novel targeted agents in cholangiocarcinoma harboring these aberrations. Acquired resistance to infigratinib was reported in several recent studies which could potentially be a barrier to overcome. Active clinical trials including PROOF301 are expected to elucidate the clinical benefits of infigratinib in this disease. Infigratinib combined with immunotherapy is also a potential future direction of investigation in

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