Last update 01 Nov 2024

FGFR2 Mutation Cholangiocarcinoma

Last update 01 Nov 2024

Basic Info

Synonyms-

Introduction-

Drugs associated with FGFR2 Mutation Cholangiocarcinoma

TYRA-200

Target

FGFR1 x FGFR2 x FGFR3

Mechanism

FGFR1 antagonists [+2]

Active Org.

Tyra Biosciences, Inc.

Originator Org.

Tyra Biosciences, Inc.

Active Indication

FGFR2 Mutation Cholangiocarcinoma [+4]

Inactive Indication-

Drug Highest PhasePhase 1

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with FGFR2 Mutation Cholangiocarcinoma

NCT06160752 / RecruitingPhase 1

A Multicenter, Open-label, First-in-Human Study of TYRA-200 in Advanced Intrahepatic Cholangiocarcinoma and Other Solid Tumors With Activating FGFR2 Gene Alterations (SURF-201)

The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary antitumor activity of TYRA-200 in cancers with FGFR2 activating gene alterations, including unresectable locally advanced/metastatic intrahepatic cholangiocarcinoma and other advanced solid tumors.

Start Date22 Nov 2023

Sponsor / Collaborator

Tyra Biosciences, Inc.

100 Clinical Results associated with FGFR2 Mutation Cholangiocarcinoma

100 Translational Medicine associated with FGFR2 Mutation Cholangiocarcinoma

0 Patents (Medical) associated with FGFR2 Mutation Cholangiocarcinoma

Literatures (Medical) associated with FGFR2 Mutation Cholangiocarcinoma

05 Jan 2024·Clinical Cancer Research

Landscape of Clinical Resistance Mechanisms to FGFR Inhibitors in FGFR2-Altered Cholangiocarcinoma

Article

Author: Silveira, Vanessa S. ; Zhen, Yuanli ; Michel, Alexa G. ; Balasooriya, Eranga Roshan ; Wu, Qibiao ; Fece de la Cruz, Ferran ; Che, Jianwe ; Norden, Bryanna L. ; Siravegna, Giulia ; Corcoran, Ryan B. ; Ellis, Haley ; Bardeesy, Nabeel

AbstractPurpose:FGFR inhibitors are effective in FGFR2-altered cholangiocarcinoma, leading to approval of reversible FGFR inhibitors, pemigatinib and infigratinib, and an irreversible inhibitor, futibatinib. However, acquired resistance develops, limiting clinical benefit. Some mechanisms of resistance have been reported, including secondary FGFR2 kinase domain mutations. Here, we sought to establish the landscape of acquired resistance to FGFR inhibition and to validate findings in model systems.Experimental Design:We examined the spectrum of acquired resistance mechanisms detected in circulating tumor DNA or tumor tissue upon disease progression following FGFR inhibitor therapy in 82 FGFR2-altered cholangiocarcinoma patients from 12 published reports. Functional studies of candidate resistance alterations were performed.Results:Overall, 49 of 82 patients (60%) had one or more detectable secondary FGFR2 kinase domain mutations upon acquired resistance. N550 molecular brake and V565 gatekeeper mutations were most common, representing 63% and 47% of all FGFR2 kinase domain mutations, respectively. Functional studies showed different inhibitors displayed unique activity profiles against FGFR2 mutations. Interestingly, disruption of the cysteine residue covalently bound by futibatinib (FGFR2 C492) was rare, observed in 1 of 42 patients treated with this drug. FGFR2 C492 mutations were insensitive to inhibition by futibatinib but showed reduced signaling activity, potentially explaining their low frequency.Conclusions:These data support secondary FGFR2 kinase domain mutations as the primary mode of acquired resistance to FGFR inhibitors, most commonly N550 and V565 mutations. Thus, development of combination strategies and next-generation FGFR inhibitors targeting the full spectrum of FGFR2 resistance mutations will be critical.

01 Dec 2023·Investigational New Drugs

Pharmacokinetics, pharmacodynamics and efficacy of pemigatinib (a selective inhibitor of fibroblast growth factor receptor 1–3) monotherapy in Chinese patients with advanced solid tumors: a phase i clinical trial

Article

Author: Han, Xinghua ; Zheng, Shirui ; Pan, Yueyin ; Shi, Yehui ; Zhou, Hui ; Luo, Yang ; Zhang, Le ; Chen, Mingxia ; Yang, Zhaoyi ; Ba, Yi ; Deng, Ting ; Shen, Aizong ; Bai, Guiying

AbstractPemigatinib is a selective fibroblast growth factor receptor (FGFR)1–3 inhibitor and has demonstrated acceptable tolerability and clinical activity in advanced solid tumors in Western population. This phase I trial evaluated pharmacokinetics/pharmacodynamics (PK/PD) characteristics, preliminary safety and efficacy of pemigatinib in Chinese patients with advanced, solid tumors. Patients with unresectable advanced or metastatic solid tumors bearing FGF/FGFR1-3 alterations received oral pemigatinib at 13.5 mg once daily (QD) on a 2-weeks-on/1-week-off schedule. The primary endpoint was PK/PD characteristics; secondary endpoints were safety and efficacy. Twelve patients were enrolled (median age: 61 years, 58.3% males). PK data demonstrated pemigatinib (13.5 mg QD) was rapidly absorbed with a geometric mean elimination half-life of 11.3 h. The geometric mean values of maximum serum concentration and area under the plasma concentration–time curve from 0 to 24 h at steady state were 215.1 nmol/L and 2636.9 h·nmol/L, respectively. The mean clearance adjusted by bioavailability at steady state was low (11.8 L/h), and the apparent oral volume of distribution was moderate (170.5 L). The PD marker, serum phosphate level, increased on days 8 and 15 of cycle 1 (mean: 2.25 mg/dL, CV% [percent coefficient of variation]: 31.3%) and decreased to baseline post 1 week off. Three (25.0%) patients experienced grade ≥ 3 treatment-emergent adverse events. Partial response was confirmed in one patient with FGFR1-mutant esophageal carcinoma and one with FGFR2-mutant cholagiocarcinoma. Pemigatinib had similar PK/PD characteristics to Western population and demonstrated an acceptable safety profile and potential anti-cancer benefit in Chinese patients with FGF/FGFR1-3 altered, advanced, solid tumor. (ClinicalTrials.gov: NCT04258527 [prospectively registered February 6, 2020]).

01 Sep 2023·Clinical cancer research : an official journal of the American Association for Cancer Research

The Emerging Role of Circulating Tumor DNA in Non-Colorectal Gastrointestinal Cancers.

Review

Author: Kaseb, Ahmed O ; Lee, Michael S ; Pant, Shubham

Assays to detect circulating tumor DNA (ctDNA) have multiple clinically important applications in management of multiple types of gastrointestinal cancers. Different methodologies of ctDNA detection have varying sensitivities and potential applications in different contexts. For patients with localized cancers treated for curative intent, ctDNA detection is associated with prognosis in multiple cancer types, and persistent detection of ctDNA after surgical resection is highly concerning for minimal residual disease (MRD) and forebodes impending radiographic and clinical recurrence. CtDNA assays for comprehensive genomic profiling enable genotyping of cancers in the absence of tumor tissue data, and longitudinal testing can also characterize clonal evolution and emergence of putative resistance mechanisms upon treatment with targeted agents. These applications have proven instructive in patients with HER2-amplified gastric and esophageal cancers and in patients with FGFR2 fusion cholangiocarcinomas. In this review, we summarize data supporting the role of ctDNA as a novel predictive and prognostic biomarker and potential impacts on current management of patients with pancreatic, gastroesophageal, and hepatobiliary cancers.

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FGFR2 Mutation Cholangiocarcinoma

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