Derazantinib (ARQ 087) in advanced or inoperable FGFR2 gene fusion-positive intrahepatic cholangiocarcinoma

• Published in: British journal of cancer Vol. 120; no. 2; pp. 165 - 171
• Main Authors: Mazzaferro, Vincenzo, El-Rayes, Bassel F., Droz dit Busset, Michele, Cotsoglou, Christian, Harris, William P., Damjanov, Nevena, Masi, Gianluca, Rimassa, Lorenza, Personeni, Nicola, Braiteh, Fadi, Zagonel, Vittorina, Papadopoulos, Kyriakos P., Hall, Terence, Wang, Yunxia, Schwartz, Brian, Kazakin, Julia, Bhoori, Sherrie, de Braud, Filippo, Shaib, Walid L.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22.01.2019; Nature Publishing Group
• Subjects: 631/67/1059/602; 692/4028/67/1504/1329/1326; Adult; Aged; Aged, 80 and over; Alkaloids - administration & dosage; Alkaloids - adverse effects; Asthenia; Biomedical and Life Sciences; Biomedicine; Cancer Research; Chemotherapy; Cholangiocarcinoma; Cholangiocarcinoma - drug therapy; Cholangiocarcinoma - genetics; Cholangiocarcinoma - pathology; Clinical Trials as Topic; Disease control; Drug Resistance; Enzyme inhibitors; Epidemiology; Fatigue; Female; Fibroblast growth factor receptor 2; Fibroblast growth factor receptors; Gene fusion; Humans; Hyperphosphatemia; Kinases; Male; Middle Aged; Molecular Medicine; Mutation; Next-generation sequencing; Oncogene Proteins, Fusion - drug effects; Oncogene Proteins, Fusion - genetics; Oncology; Patients; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - adverse effects; Receptor, Fibroblast Growth Factor, Type 2 - genetics; Toxicity; Tumors
• ISSN: 0007-0920; 1532-1827; 1532-1827
• DOI: 10.1038/s41416-018-0334-0

Background Next-generation sequencing has identified actionable genetic aberrations in intrahepatic cholangiocarcinomas (iCCA), including the fibroblast growth factor receptor 2 (FGFR2) fusions. Derazantinib (ARQ 087), an orally bioavailable, multi-kinase inhibitor with potent pan-FGFR activity, has shown preliminary therapeutic activity against FGFR2 fusion-positive iCCA. Methods This multicentre, phase 1/2, open-label study enrolled adult patients with unresectable iCCA with FGFR2 fusion, who progressed, were intolerant or not eligible to first-line chemotherapy (NCT01752920). Subjects received derazantinib in continuous daily doses. Tumour response was assessed according to RECIST 1.1 every 8 weeks. Results Twenty-nine patients (18 women/11 men; median age, 58.7 years), 2 treatment-naive and 27 who progressed after at least one prior systemic therapy, were enrolled. Overall response rate was 20.7%, disease control rate was 82.8%. Estimated median progression-free survival was 5.7 months (95% CI: 4.04–9.2 months). Treatment-related adverse events (AE) were observed in 27 patients (93.1%, all grades), including asthenia/fatigue (69.0%), eye toxicity (41.4%), and hyperphosphatemia (75.9%). Grade ≥ 3 AEs occurred in 8 patients (27.6%). Conclusion Derazantinib demonstrated encouraging anti-tumour activity and a manageable safety profile in patients with advanced, unresectable iCCA with FGFR2 fusion who progressed after chemotherapy. A pivotal trial of derazantinib in iCCA is ongoing (NCT03230318).