Pemigatinib for adults with previously treated, locally advanced or metastatic cholangiocarcinoma with FGFR2 fusions/rearrangements

Walden, Daniel; Eslinger, Cody; Bekaii‐Saab, Tanios

doi:10.1177/17562848221115317

Cited by 6 publications

(7 citation statements)

References 38 publications

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“…FGFR inhibitors, erdafitinib, and pemigatinib are being used to treat urothelial carcinoma and unresectable cholangiocarcinoma respectively. 72 , 73 The observation that metastatic cSCC harbors gain of function mutation in FGFR points to the possibility of repurposing these inhibitors for treatment of advanced cSCC.…”

Section: Targeted Therapiesmentioning

confidence: 99%

Targeting receptor tyrosine kinase signaling: Avenues in the management of cutaneous squamous cell carcinoma

et al. 2023

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Section: Targeted Therapiesmentioning

confidence: 99%

Targeting receptor tyrosine kinase signaling: Avenues in the management of cutaneous squamous cell carcinoma

et al. 2023

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“…Thus, selective FGFR inhibitors have been the clinical research and testing focus. Pemigatinib, an ATP-competitive selective FGFR1-4 inhibitor, has been shown to significantly extend survival in the second-line setting to over 20 months in patients who harbor FGFR2 fusions [22]. Futibatinib, an irreversible FGFR1-4 inhibitor, has also demonstrated efficacy among previously treated patients with intrahepatic cholangiocarcinoma (iCCA) with FGFR2 fusions/rearrangements in the FOENIX-CCA2 (NCT02052778) pivotal phase 2 trial [23].…”

Section: Fgfr2 Gene Rearrangements and Their Role In Advanced Ccamentioning

confidence: 99%

“…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]. Since this medication spares FGFR4, there is a decrease in hepatotoxicity [22].…”

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

confidence: 99%

“…FGFR2 alternations have been almost exclusively isolated to intrahepatic cholangiocarcinoma, and the prevalence of this alteration ranges from 10-15% [22]. Since this medication spares FGFR4, there is a decrease in hepatotoxicity [22]. The FIGHT-202 trial enrolled 146 patients, 107 with FGFR2 alterations, and showed that 38 (35.5%) patients achieved an objective response to the treatment [34].…”

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

confidence: 99%

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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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“…Furthermore, based on the results of FOENIX trials, futibatinib was approved by FDA this year for the treatment of locally advanced or metastatic cholangiocarcinoma whose tumours harbor an FGFR2 rearrangement or fusion [ 125 ]. There is a FOENIX-CCA3 trial planned for futibatinib versus chemotherapy with gemcitabine and cisplatin as the first-line treatment in patients with FGFR2 alterations (NCT04093362) [ 126 ].…”

Section: Targeted Therapiesmentioning

confidence: 99%

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

Chmiel

Gęca²,

Rawicz‐Pruszyński³

et al. 2022

Cells

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Cholangiocarcinomas (CCAs) are rare but aggressive tumours with poor diagnosis and limited treatment options. Molecular targeted therapies became a promising proposal for patients after progression under first-line chemical treatment. In light of an escalating prevalence of CCA, it is crucial to fully comprehend its pathophysiology, aetiology, and possible targets in therapy. Such knowledge would play a pivotal role in searching for new therapeutic approaches concerning diseases’ symptoms and their underlying causes. Growing evidence showed that fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) pathway dysregulation is involved in a variety of processes during embryonic development and homeostasis as well as tumorigenesis. CCA is known for its close correlation with the FGF/FGFR pathway and targeting this axis has been proposed in treatment guidelines. Bearing in mind the significance of molecular targeted therapies in different neoplasms, it seems most reasonable to move towards intensive research and testing on these in the case of CCA. However, there is still a need for more data covering this topic. Although positive results of many pre-clinical and clinical studies are discussed in this review, many difficulties lie ahead. Furthermore, this review presents up-to-date literature regarding the outcomes of the latest clinical data and discussion over future directions of FGFR-directed therapies in patients with CCA.

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Pemigatinib for adults with previously treated, locally advanced or metastatic cholangiocarcinoma with FGFR2 fusions/rearrangements

Cited by 6 publications

References 38 publications

Targeting receptor tyrosine kinase signaling: Avenues in the management of cutaneous squamous cell carcinoma

Targeting receptor tyrosine kinase signaling: Avenues in the management of cutaneous squamous cell carcinoma

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

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

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