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
In 2021, the re-marketing of similar drugs has made the industry full of great interest in the development of FGFR inhibitors
So, what is the relationship between the dangerous advanced cholangiocarcinoma and FGFR? Why does the approved indication mention FGFR2? What is the status of global targeted drug development for FGFR/FGFR2? Is the future promising? Please read this article
Cholangiocarcinoma & FGFR2Cholangiocarcinoma & FGFR2
Cholangiocarcinoma occurs in the bile ducts of the liver.
It has a very high fatality rate and a poor prognosis.
It is a rare aggressive malignant tumor.
When diagnosed, it is often in the middle-advanced stage and loses the opportunity for surgical treatment
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.
5/100,000; the incidence of liver fluke infection in common areas (such as Thailand, China, and South Korea) is much higher; northeastern Thailand The incidence rate is the highest in the world, with an annual incidence rate of 90/100,000, accounting for more than 80% of all primary liver cancers
The ill patients are mainly under 70 years old, and the ratio of males to females is 1.
At present, the choice of therapeutic drugs is extremely limited.
Gemcitabine combined with cisplatin is the standard first-line treatment plan, but the efficacy is limited, the side effects are obvious, and the 5-year survival rate is only 9%.
It is worth noting that the study found that 15% of patients with cholangiocarcinoma~ 20% carry FGFR2 genetic variants
Figure 2 The incidence statistics of cholangiocarcinoma in 2000-2015/U.
Treatment Guidelines & FGFR2Treatment 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.
If they do not receive treatment, the overall median survival time is only 3 to 6 months
The guidelines recommend treatment options for unresectable advanced cholangiocarcinoma: 1) clinical trials; 2) systemic treatment; 3) local treatment; 4) fluorouracil combined with EBRT radiotherapy; 5) best supportive treatment
In addition, genetic testing is recommended for advanced cholangiocarcinoma to determine whether it is suitable for immunotherapy and targeted therapy
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.
Combination regimens such as platinum, capecitabine + oxaliplatin, gemcitabine + albumin combined with paclitaxel, gemcitabine + capecitabine, gemcitabine + oxaliplatin, or 5-fluorouracil, capecitabine, gemcitabine as a single agent Scheme
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.
IDH-1 and FGFR2 have been approved for the market in the past three years, especially the development of FGFR2 inhibitors, which has attracted a lot of attention
Figure 3 Diagnosis and treatment strategies for cholangiocarcinoma
FGFR&target mechanismFGFR&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
Studies have found that among 307 patients with cholangiocarcinoma, 77 (23%) of iCCA patients have FGFR2 gene fusion, and from the indications approved for targeted drugs that have been on the market in the past three years, they all point to the FGFR family FGFR2
Figure 4 Schematic diagram of targeted carcinogenic signaling pathways for intrahepatic cholangiocarcinoma
2 FGFR targeted drugs already on the market2 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.
For the indication of cholangiocarcinoma, the representative varieties are Pemigatinib, which will be marketed in 2020, and Infigratinib, which will be marketed in 2021
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.
This is the first FDA approval.
A targeted drug for cholangiocarcinoma
This species has strong inhibitory activity against FGFR1-4.
The data of phase II clinical trials conducted on patients with advanced cholangiocarcinoma who have been previously treated show that the disease control rate is more than 80%
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.
Of adult patients with advanced or metastatic cholangiocarcinoma
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 situationFGFR2 & 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 remarksConcluding 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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