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

• Type of Material: Article
• Authors: Vincenzo Mazzaferro, Istituto Nazionale Tumori IRCCS; Bassel El-Rayes, Emory University; Michele Droz dit Busset, Istituto Nazionale Tumori IRCCS; Christian Cotsoglou, Istituto Nazionale Tumori IRCCS; William P. Harris, Seattle Cancer Care Alliance; Nevena Damjanov, University of Pennsylvania; Gianluca Masi, Pisa University Hospital; Lorenza Rimassa, Humanitas Cancer Center; Nicola Personeni, Humanitas Cancer Center; Fadi Braiteh, Comprehensive Cancer Centers of Nevada; Vittorina Zagonel, Veneto Institute of Oncology; Kyriakos P. Papadopoulos, South Texas Accelerated Research Therapeutics; Terence Hall, ArQule, Inc.; Yunxia Wang, ArQule, Inc.; Brian Schwartz, ArQule, Inc.; Julia Kazakin, ArQule, Inc.; Sherrie Bhoori, Istituto Nazionale Tumori IRCCS; Filippo de Braud, Istituto Nazionale Tumori IRCCS; Walid Shaib, Emory University
• Language: English
• Date: 2019-01-22
• Publisher: Springer Nature [academic journals on nature.com]: Hybrid Journals
• Publication Version: Final Published Version
• Copyright Statement: © 2018, Cancer Research UK.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41416-018-0334-0
• Title of Journal or Parent Work: British Journal of Cancer
• ISSN: 0007-0920
• Volume: 120
• Issue: 2
• Start Page: 165
• End Page: 171
• Grant/Funding Information: Kyriakos P. Papadopoulos has received funding from ArQule, Inc to START for the conduct of clinical trials.
• Keywords: METABOLISM; Life Sciences & Biomedicine; DOSE-ESCALATION; THERAPY; TRANSLOCATIONS; INHIBITOR; GROWTH-FACTOR RECEPTORS; Oncology; MUTATIONS; Science & Technology; PHASE-II; ISOCITRATE DEHYDROGENASE 1; GEMCITABINE
• Research Categories: Health Sciences, Oncology

Abstract

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).