Milestone of new drug for cholangiocarcinoma: progress in FGFR2 inhibitor research and development

Author: Chinese Snacks

The approval of the first targeted drug in 2020 adds a very important cohort to the treatment of cholangiocarcinoma: targeted FGFR inhibitors

Cholangiocarcinoma & FGFR2

Cholangiocarcinoma occurs in the bile ducts of the liver.

Figure 1 Potential targets for targeted therapy of cholangiocarcinoma

In terms of epidemiology, the incidence of cholangiocarcinoma in Europe, the United States, Australia and other places is relatively low, accounting for about 0.

At present, the choice of therapeutic drugs is extremely limited.

Figure 2 The incidence statistics of cholangiocarcinoma in 2000-2015/U.

Treatment Guidelines & FGFR2

There are no obvious symptoms in the early stage of cholangiocarcinoma, and 70% to 80% of patients are already in the advanced stage when they are diagnosed.

At present, the first-line chemotherapy for advanced cholangiocarcinoma is the combination of gemcitabine and cisplatin; based on the results of a number of phase II clinical trials, 5-fluorouracil + oxaliplatin, 5-fluorouracil + cisplatin, capecitabine + cisplatin can also be selected.

For immunotherapy, Pembrolizumab has been approved for use in patients with advanced cholangiocarcinoma showing MSI/dMMR

Targeted therapy, IDH-1, FGFR2, and NTRK are progressing relatively quickly.

Figure 3 Diagnosis and treatment strategies for cholangiocarcinoma

FGFR&target mechanism

One of the important members of the tumor microenvironment, that is, tumor-associated fibroblasts, is one of the important components of the tumor microenvironment, and its activity is regulated by the growth factors secreted by tumor cells; FGF, fibroblast growth factor, is a type of polypeptide Similar substances, the amino acid sequence homology between family members is about 25%-50%; FGFR, mainly four highly conserved transmembrane tyrosine kinase receptors FGFR1-4 play a role, and the ligand binds to the receptor It can promote receptor dimerization and activate downstream signal transduction pathways, such as PLC-γ/Ca2+, RAS/MAPK, FRS2/PI3K/AKT and PLC-γ/PKC pathways

FGFR2, as one of the isoforms of the fibroblast growth factor receptor family, is involved in regulating the basic life processes of cell proliferation, survival, migration, differentiation and metabolism

Figure 4 Schematic diagram of targeted carcinogenic signaling pathways for intrahepatic cholangiocarcinoma

2 FGFR targeted drugs already on the market

The development of FGFR targeted inhibitors is mainly focused on the selective FGFR inhibitors that have been marketed in the past 3 years.

In April 2020, the FDA accelerated the approval of pemigatinib developed by Incyte Biopharmaceuticals in the United States for use in adult patients with unresectable locally advanced or metastatic cholangiocarcinoma who have previously been treated and carry FGFR2 gene fusion or other rearrangements.

In May 2021, the FDA accelerated the approval of Infigratinib developed by QEDTherapeutic, which is an oral FGFR1-3 selective tyrosine kinase inhibitor for unresectable local treatments that have previously been treated and carry FGFR2 gene fusion or other rearrangement types.

Since both Pemigatinib and Infigratinib are pan-inhibitors of FGFR, and the indications are approved for FGFR2 subtype, the development of target drugs for FGFR2 subtype is underway

FGFR2 & global drug development situation

There are currently three main types of FGFR2 inhibitors in the world, namely, the monoclonal antibody Bemarituzumab (the highest clinical phase II) developed by Amgen and Zai Lab, the Alofanib (the highest clinical phase I) of Russian Pharmaceutical Technologies, and Relay RLY-4008 (the highest clinical phase I) developed by Therapeutics

Bemarituzumab, currently granted breakthrough therapy designation by the FDA, is used in combination with chemotherapy for the first-line treatment of patients with FGFR2b overexpression, HER2-negative locally advanced or metastatic gastric cancer and gastroesophageal junction (GEJ) adenocarcinoma.
The current main indications are For gastric cancer; in China, it has also been granted breakthrough treatment certification by CDE
.

Alofanib, a selective allosteric inhibitor of FGFR2, has a significant inhibitory effect on the phosphorylation of FRS2a in KATO-III cells induced by FGF2 (IC50<10 nM), and has an effect on FGF2-dependent FGFR1 and FGFR3 in any cell line The level of phosphorylation has no direct effect; the current clinical indications are also focused on gastric cancer
.

RLY-4008 is a highly selective irreversible oral small molecule inhibitor of FGFR2.
The current clinical trial aims to evaluate the efficacy and safety of patients with cholangiocarcinoma and other solid tumors with FGFR2 changes; the latest clinical data show that, It has good early activity in FGFR2 fusion cholangiocarcinoma patients who have not been treated with FGFR inhibitors.
3 of the 6 patients have achieved partial remission, with a tumor shrinkage of 56% to 83%, showing a certain potential for preventing drug resistance and tolerability Overall good
.

Concluding remarks

After reading the relationship between cholangiocarcinoma and FGFR/FGFR2, you may feel that the author has the same feeling: the breakthrough progress has undoubtedly pushed FGFR2 to the hottest of drug development, and it has not yet formed a fiery competition track.
For developers, there is still room
.

FGFR2 is not only making a big splash in the field of cholangiocarcinoma, it is also an extremely hot target in the field of gastric cancer, so it will undoubtedly provide a research basis for the expansion of indications, and the market will increase accordingly
.
In general, there are still opportunities for the development of FGFR family, especially FGFR2 inhibitors
.

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