FGFR Inhibitors Show Promise in Cholangiocarcinoma but Face Acquired Resistance

While FGFR inhibitors are a promising tool to manage cholangiocarcinoma with FGR2 fusion or rearrangement, there is the concern of acquired resistance, which needs to be studied further, according to a review published in Expert Review of Anticancer Therapy.

While surgical resection is a definitive curative treatment of cholangiocarcinoma, most patients with the disease are too advanced at initial diagnosis for the treatment. FGFR2 gene fusion or translocation is the driver of oncogenesis in 10% to 15% of intrahepatic cholangiocarcinoma. Pemigatinib is an FGFR inhibitor and the first targeted therapy approved for the FDA to treat cholangiocarcinoma.

In their review, the authors describe the FGFR pathway, its role in oncogenesis, current FGFR inhibitors, the role these inhibitors play in treatment cholangiocarcinoma, and the future of the field.

There are 4 receptor tyrosine kinases in the FGFR family. “FGFR dysfunction has been implicated in oncogenesis, and specifically, FGFR plays a role in angiogenesis, migration, and survival in tumor cells through mitotic and antiapoptotic properties,” the authors explained.

FGFR mutation or overamplification has been shown to cause breast, lung, endometrial, and gastric cancers, as well as hepatocellular carcinoma. There are currently 3 FDA-approved FGFR inhibitors: pemigatinib, futibatinib, and infigratinib.

The FDA approved pemigatinib in April 2020 based on the results of the phase 2 FIGHT 202. Among patients with FGFR2 fusions or rearrangements, the trial showed an overall response rate (ORR) of 35.5%, median duration of response of 7.5 months, median progression-free survival (PFS) of 6.9 months, and medial overall survival (OS) of 21.2 months. Among patients with other FGF/FGFR alternations or no alternations, the median PFS was 2.1 and 1.7 months, respectively, and the median OS was 6.7 and 4.0 months respectively.

The FDA approval is for pemigatinib in the second-line setting. FIGHT-302 is an ongoing randomized, open label, phase 3 trial comparing pemigatinib to gemcitabine-cisplatin in the first-line setting.

Infigratinib is also approved by the FDA to treat cholangiocarcinoma with FGFR2 fusion, but the company has decided to no longer develop it for the disease and clinical trials have been halted. In a phase 2 trial, infigratinib had an ORR of 18.8% and the disease control rate (DCR) was 83.3% among patients with FGFR2 fusion.

Futibatinib was approved by the FDA based on results of FOENIX-CCA2, a single arm, multicenter, phase 2 trial. The median ORR was 41.7%, median DCR was 82.5%, median PFS was 8.9 months, and the 12-month OS rate was 73.1%. A phase 3 trial for the drug has been halted due to enrollment issues.

Other treatments being evaluated are:

• Derazantinib: a phase 1/2 trial showed an ORR of 20.7%, DCR of 82.8% and median PFS of 5.7 months
• Erdafitinib: approved for locally advanced or metastatic urothelial carcinoma, it is in an ongoing phase 2 study in China to evaluate the objective response rate in multiple malignancies including cholangiocarcinoma
• Ponatinib: evaluated in a pilot study of 12 patients, but terminated early due to limited clinical activity

“There are no head-to-head comparisons to determine the sequence of FGFR inhibitors or if one FGFR inhibitor is better than others,” the authors noted, adding, “FGFR inhibitors have unique toxicities and need careful management to prevent dose delays and interruptions.”

An issue with current FGFR inhibitors is the development of resistance, which may be acquired through multiple mechanisms and may occur simultaneously. However, there is some research suggesting that combination therapy with treatment that inhibits the PI3K/AKT/mTOR pathways may overcome this resistance. However, it remains unclear the right sequence of treatments to overcome resistance.

“Despite what we know thus far, future trials are needed to better understand which patients with FGFR2 fusion or rearrangement will respond to treatment, methods to overcome the development of FGFR inhibitor resistance, and the role for combination FGFR inhibition and immune checkpoint inhibition,” the authors concluded.

Reference

Storandt MH, Jin Z, Mahipal A. Pemigatinib in cholangiocarcinoma with a FGFR2 rearrangement or fusion. Expert Rev Anticancer Ther. November 21, 2022. doi:10.1080/14737140.2022.2150168