The treatment of cholangiocarcinoma welcomes new FGFR inhibitors, and currently three types of FGFR inhibitors have been approved

Cholangiocarcinoma is a highly malignant, second most common tumor in the liver derived from bile duct epithelial cells, accounting for 10%-20% of all primary liver malignancies

With the development of precision medicine, targeted drugs and immune drugs have gradually entered the public's field of vision

FGFR mutations and tumors

The full name of FGFR is Fibroblast Growth Factor Receptor.

When FGFR binds to a ligand, it induces FGFR to form dimers and catalyzes its own phosphorylation, which in turn activates four key downstream signaling pathways: RAS-RAF-MAPK, PI3K-AKT, signal transducers and transcriptional activation (STAT) and Phospholipase Cγ (PLCγ)

Refractory cholangiocarcinoma will welcome new drug--Ponatinib

Ponatinib (Ponatinib/Panatinib) is a new type of orally active multi-target TKI developed and produced by Japan's Takeda Pharmaceutical Company.

This is a multi-center, single-institution pilot study to evaluate the efficacy of ponatinib in patients with advanced refractory biliary tumors with FGFR changes

A total of 12 patients with advanced refractory biliary tumors were included in the study

For ponatinib, further large-scale clinical research will be conducted to better optimize patient selection, focusing on the combination of other molecularly targeted drugs, traditional cytotoxic chemotherapy, and a better understanding of the mechanism of treatment resistance

FGFR is currently one of the hot targets focused on "unrestricted cancer types" therapy.

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The data from the FIGH 202 study of pemigatinib second-line treatment of patients with advanced cholangiocarcinoma showed that the study included a total of 146 patients with advanced cholangiocarcinoma who had undergone ≥1 line treatment, and they were divided into 3 cohorts: A is FGFR2 fusion/rearrangement (n=107), B Other FGFR mutations (n=20), C is non-FGFR mutation (n=18), 1 patient is undecided

The results showed that the ORR of group A was 35.

The median DOR in group A was 7.

It is reported that the listing price of pemigatinib is 17,000 US dollars per course of treatment

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The approval of infigratinib is based on a phase II clinical study in which 108 patients with advanced cholangiocarcinoma who had received at least one previous treatment received 125 mg of infigratinib daily
.
The confirmed objective response rate (ORR) was 23% (95% CI 16-32%)
.
The study also showed that the median duration of response (DOR) was 5.
0 months (95% CI 3.
7-9.
3 months)
.
Common adverse reactions and detection abnormalities (> 30%) include increased creatinine, increased phosphate, decreased phosphate, nail toxicity, stomatitis, increased alkaline phosphatase, decreased hemoglobin, and taste disorders
.
The price of Infigratinib is USD 21,500 per month
.

As a popular track, there are also many domestic pharmaceutical companies deploying FGFR inhibitor drug research and development
.
For example, SY-4798, a new generation of selective FGFR4 small molecule inhibitor independently developed by First Pharmaceutical Holdings, with complete intellectual property rights and a new compound structure; FGFR 1/2/3 small molecule inhibitor developed by Sidi Medicine and Haihe Biotechnology agent --3D185; Connaught Jianhua self-developed second generation pan-FGFR inhibitor --gunagratinib the like
.

The development of FGFR inhibitors has brought the hope of targeted therapy for patients with tumors driven by FGFRs
.
In addition, it is worth mentioning that the types of FGFR inhibitors have expanded from small molecules to large molecules, and the indications have also expanded from cholangiocarcinoma and urothelial carcinoma to liver fibrosis and achondroplasia
.

Reference source:

1.
Turner N, Grose R.
Fibroblast growth factor signalling: from development to cancer.
Nat Rev Cancer.
2010 Feb;10(2):116-29.
doi: 10.
1038/nrc2780;

2.
http://innoventbio.
com/#/news/192;

3.
Basilea provides updates on efficacy data with derazantinib in bile duct cancer and on ongoing clinical programs in urothelial and gastric cancer;

4.
https:// Eswarakumar VP, Lax I, Schlessinger J.
Cellular signaling by fibroblast growth factor receptors[J].
Cytokine & growth factor reviews, 2005, 16(2): 139-149.