福巴替尼疗效如何？总缓解率竟高达42%！

What is cholangiocarcinoma?

Cholangiocarcinoma refers to a malignant tumor originating from the extrahepatic bile duct, including the bile duct from the portal area to the lower end of the common bile duct. There are many reasons for this condition, such as primary sclerosing cholangitis, bile duct stones, etc. Clinical manifestations usually include jaundice, gallbladder enlargement, and biliary hemorrhage. Currently, the main clinical treatments include surgery, radiotherapy, and chemotherapy, but the prognosis is poor.

What kind of medicine is it? How does it work?

Cholangiocarcinoma seems mysterious, but we also have corresponding countermeasures, so how to treat it? First, cholangiocarcinoma can occur both intrahepatic and extrahepatic, but 20% of patients have the intrahepatic form. Among them, 10% to 16% of patients have FGFR2 (fibroblast growth factor receptor) gene rearrangements. FGFR can activate the conduction pathways of various downstream pathways necessary for tumor growth. Therefore, the use of FGFR inhibitors can effectively block the proliferation and survival of tumor cells.

Forbatinib, as a potent FGFR inhibitor, has shown very promising efficacy in patients with previously treated, unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma. Currently, forbatinib is being evaluated under the FDA's Real-Time Oncology Review (RTOR) pilot and received accelerated approval due to its extremely promising overall response rate and duration of response, according to Taiho.

How effective is forbatinib? The overall response rate was as high as 42%!

In July 2020, "Ann Oncol" published a trial study exploring the clinical efficacy of forbatinib. The trial evaluated the efficacy of fobatinib in 103 patients with previously treated, unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma.

The primary efficacy endpoints were overall response rate (ORR) and duration of response (DoR) as determined by an independent review committee (IRC) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Trial patients received forbatinib treatment at a dose of 20 mg once daily. The median age of the trial patient population was 58 years (range: 22 to 79 years), and all patients had received at least 1 prior treatment, 30% had received 2 prior treatments, and 23% had received 3 or more prior treatments. All patients had received platinum drug treatment in the past, 91% of whom had received gemcitabine/cisplatin in the past, and the median response time was 2.5 months (range 0.7-7.4 months). The specific efficacy is shown in the figure:

Among them, the overall response rate (ORR) was 42% and the partial response rate was 43%.

The median duration of response (Median DoR) was more than one and a half years, ≥6 months in 31 people, accounting for 72% of the total number, and ≥12 months in 6 people, accounting for 14% of the total number.

Global research and development of cholangiocarcinoma drugs

For the treatment of cholangiocarcinoma, in addition to forbatinib, there are currently 143 drugs, of which 4 drugs are not under development, 2 drugs are in the drug discovery stage, 3 drugs are in the preclinical stage, 1 drug is in clinical application, and 2 drugs In early clinical phase 1, 29 drugs are in clinical phase 1, 12 drugs are in clinical phase 1/2, 39 drugs are in clinical phase 2, 2 drugs are in clinical phase 2/3, 16 drugs are in clinical phase 3, and 31 drugs have been approved for marketing. Due to space issues, the editor will introduce 3 kinds of drugs to you below. Those who are interested can pay attention to them.

Infigratinib is a new targeted drug for cholangiocarcinoma with independent intellectual property rights that can effectively inhibit FGFR. It has entered clinical trials in China and other Asian regions. After three months of treatment with this drug, the first Chinese patient's tumor-related indicators improved significantly, and the tumor shrank by more than 50%.

Pemetinib (Dabotan) was developed by Incyte Corporation and was approved for marketing by the China National Medical Products Administration in March 2022. It can be used to treat adult patients with advanced, metastatic or unresectable cholangiocarcinoma confirmed by testing to have FGFR2 fusion or rearrangement.

Ivonib (Tosuvo) is a potent oral targeted inhibitor of FGFR for the treatment of previously treated adult patients with locally advanced or metastatic cholangiocarcinoma who carry IDH1 mutations detected by an FDA-approved test.

Conclusion

Forbatinib has brought good news to patients suffering from cholangiocarcinoma, but it is not yet available in China. Due to its impressive efficacy, I believe this drug will be launched in China in the near future, bringing hope to the majority of Chinese cholangiocarcinoma patients!

References

[1]Bahleda R, Meric-Bernstam F, Goyal L, Tran B, He Y, Yamamiya I, Benhadji KA, Matos I, Arkenau HT. Phase I, first-in-human study of futibatinib, a highly selective, irreversible FGFR1-4 inhibitor in patients with advanced solid tumors. Ann Oncol. 2020 Oct;31(10):1405-1412. doi: 10.1016/j.annonc.2020.06.018. Epub 2020 Jul 2. PMID: 32622884; PMCID: PMC9743148.

[2]16. Nakatsuru Y, Ochiiwa H, Sootome H, et al. Abstract A272: intermittent treatment with TAS-120, an irreversible FGFR inhibitor, is effective in tumors harboring a FGFR gene abnormality. Mol Cancer Ther 2013;12: A272.

[3]Arai Y, Totoki Y, Hosoda F, et al. Fibroblast growth factor receptor 2 tyrosine kinase fusions define a unique molecular subtype of cholangiocarcinoma. Hepatology 2014;59:1427–1434.