Hope of a cure for cholangiocarcinoma coming from FGFR inhibitors

Hope of a cure for cholangiocarcinoma coming from FGFR inhibitors

Last April, the Food and Drug Administration granted accelerated approval to pemigatinib for the treatment of adults with previously treated, locally advanced unresectable or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement.

Biliary tract cancer is a heterogeneous group of highly aggressive tumours, including intrahepatic cholangiocarcinoma (iCCA), extrahepatic perihilar CCA (pCCA), extrahepatic distal CCA (dCCA) and gallbladder cancer (GBC).
With incidence rates below 6/100.000 in most countries, cholangiocarcinomas are considered rare cancers. However, the incidence is increasing worldwide, mainly due to iCCA.
Unfortunately, prognosis remains poor with a 5-year survival of around 5-15%.
60-70% of patients are diagnosed with advanced, unresectable or metastatic disease due to late manifestation of clinical symptoms and absence of specific biomarkers. For that reason, only 30-40% of patients are eligible for surgical resection, the only potentially curative treatment, and the majority of them (60-65%) experience disease recurrence. For patients with advanced disease the only first line treatment option is palliative chemotherapy with gemcitabine and cisplatin. FOLFOX has been the only second line therapy available to patients progressing to CisGem until the discovery of genomic alterations with potential therapeutic implications for treating cholangiocarcinoma.

The main druggable genomic alterations have been detected in about 50% of intrahepatic cholangiocarcinoma patients. The most promising targets are IDH mutations (18-36% of patients with iCCA) and FGFR2 fusions (10-16% of patients with iCCA). These alterations seem to be mutually exclusive.
The fibroblast growth factor receptor (FGFR) family consist of four subtypes of transmembrane receptors with intracellular tyrosine kinase domains (FGFR 1-4).
Up to 22 FGF ligands have been identified, which, when linked to FGFR, activate several cellular processes: proliferation, survival, migration and angiogenesis.
FGFR genetic alterations have emerged as tumourigenic drivers in cancers such as iCCA, urothelial carcinoma, myeloid/lymphoid neoplasms and other malignancies. They have been observed in all four FGFR subtypes and include point mutations, gene amplifications and chromosomal rearrangements. Alterations identified in iCCA are mostly located in the FGFR2 gene, 85% of which are fusions. FGFR2 fusions result in constitutive, ligand-independent activation of downstream pathways, leading to tumourigenesis. The presence of FGFR2 fusions, which seems to be associated with indolent disease progression and a better prognosis, may serve as a double predictive biomarker: negative for chemotherapy and positive for FGFR inhibitors.

From interim analysis of several phase I/II and II clinical studies, a clinically meaningful benefit has been observed in iCCA patients with FGFR2 fusions treated with FGFR2 tyrosine kinase inhibitors. Objective response rates (ORR) for infigratinib, pemigatinib, derazantinib and futibatinib were 31%, 35.5%, 21% and 37.3% respectively, while median progression-free survival (mPFS) was 5.8 months, 6.9 months, 5.7 months and 7.2 months respectively. Disease control rates, between 82% and 83%, were highly comparable across all trials and FGFR-inhibitor associated toxicity profiles were manageable. No response was observed in iCCA patients with non-fusion FGFR2 alterations, but disease stabilization and a mPFS of 6.7 months were seen in some patients with FGFR2 mutations treated with derazantinib. An ORR of 17.6% was reported in patients with FGF/FGFR aberrations beyond FGFR2 fusions treated with futibatinib, which appears to overcome drug resistance driven by FGFR gatekeeper mutations in patients progressing under FGFR-inhibitor therapy.

One year after the accelerated approval of erdafitinib for chemotherapy-resistant urothelial cancers harbouring FGFR2/3 genetic alterations, last April, the FDA approved pemigatinib for the treatment of adults with previously treated, locally advanced unresectable or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement.

The results obtained in FIGHT-202, a phase II single-arm trial, were crucial for approval: in 107 patients with locally advanced or metastatic cholangiocarcinoma, whose disease had progressed on or after at least one prior chemotherapy and had an FGFR2 gene fusion or rearrangement, the ORR was 36%, with 3 complete responses, and the median DOR was 9.1 months.

The analysis of FGFR2 rearrangements can be performed with different methodologies: immunohistochemistry (IHC), fluorescent in situ hybridization (FISH), Real Time PCR and Next Generation Sequencing (NGS), but only the last one, offered by Diatech Pharmacogenetics, allows to detect both known and novel gene fusions, with all possible fusion partners in one reaction, with superior sensitivity, specificity and reproducibility. The European Society for Medical Oncology (ESMO) recommends routine use of multigene NGS to detect genomic alterations (IDH1 mutations, FGFR2 fusions, NTRK fusions) in advanced cholangiocarcinoma.


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