Derazantinib (ARQ 087) in advanced or inoperable FGFR2 gene fusion-positive intrahepatic cholangiocarcinoma.
Adult
Aged
Aged, 80 and over
Alkaloids
/ administration & dosage
Cholangiocarcinoma
/ drug therapy
Clinical Trials as Topic
Female
Humans
Male
Middle Aged
Mutation
Oncogene Proteins, Fusion
/ drug effects
Protein Kinase Inhibitors
/ administration & dosage
Receptor, Fibroblast Growth Factor, Type 2
/ genetics
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
01 2019
01 2019
Historique:
received:
29
06
2018
accepted:
23
10
2018
revised:
19
10
2018
pubmed:
14
11
2018
medline:
21
9
2019
entrez:
14
11
2018
Statut:
ppublish
Résumé
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. 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. 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%). 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).
Sections du résumé
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).
Identifiants
pubmed: 30420614
doi: 10.1038/s41416-018-0334-0
pii: 10.1038/s41416-018-0334-0
pmc: PMC6342954
doi:
Substances chimiques
Alkaloids
0
Oncogene Proteins, Fusion
0
Protein Kinase Inhibitors
0
dercitin
115141-47-4
FGFR2 protein, human
EC 2.7.10.1
Receptor, Fibroblast Growth Factor, Type 2
EC 2.7.10.1
Banques de données
ClinicalTrials.gov
['NCT03230318']
Types de publication
Clinical Study
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
165-171Commentaires et corrections
Type : CommentIn
Références
Lancet. 2014 Jun 21;383(9935):2168-79
pubmed: 24581682
Eur J Cancer. 2009 Jan;45(2):228-47
pubmed: 19097774
Hepatology. 2014 Apr;59(4):1427-34
pubmed: 24122810
J Clin Oncol. 2018 Jan 20;36(3):276-282
pubmed: 29182496
Adv Chronic Kidney Dis. 2011 Mar;18(2):91-7
pubmed: 21406293
Hum Pathol. 2012 Oct;43(10):1552-8
pubmed: 22503487
PLoS Genet. 2014 Feb 13;10(2):e1004135
pubmed: 24550739
Nat Rev Clin Oncol. 2018 Feb;15(2):95-111
pubmed: 28994423
Clin Cancer Res. 2014 Jun 1;20(11):3012-22
pubmed: 24691021
J Gastrointest Oncol. 2017 Apr;8(2):324-336
pubmed: 28480071
J Mol Biomark Diagn. 2016 Jun;1(Suppl 2):
pubmed: 27358750
Ann Oncol. 2014 Dec;25(12):2328-2338
pubmed: 24769639
Cytokine Growth Factor Rev. 2015 Aug;26(4):425-49
pubmed: 26003532
Hum Pathol. 2014 Aug;45(8):1630-8
pubmed: 24837095
J Clin Oncol. 2017 Jan 10;35(2):157-165
pubmed: 27870574
Curr Opin Gastroenterol. 2015 May;31(3):264-8
pubmed: 25763789
PLoS One. 2016 Sep 14;11(9):e0162594
pubmed: 27627808
Nat Commun. 2015 Jan 22;6:6087
pubmed: 25608663
Dig Dis. 2017;35(4):384-386
pubmed: 28468016
JCO Precis Oncol. 2018 Nov;2:1-12
pubmed: 35135097
J Clin Oncol. 2015 Oct 20;33(30):3401-8
pubmed: 26324363
Br J Cancer. 2017 Nov 21;117(11):1592-1599
pubmed: 28972963
Curr Treat Options Oncol. 2016 Nov;17(11):58
pubmed: 27658789
Lancet Oncol. 2012 Feb;13(2):181-8
pubmed: 22192731
Cancer Discov. 2017 Mar;7(3):252-263
pubmed: 28034880
Nat Rev Drug Discov. 2016 Jan;15(1):51-69
pubmed: 26567701
J Am Coll Surg. 2013 Oct;217(4):736-750.e4
pubmed: 23890842
Oncologist. 2008 Apr;13(4):415-23
pubmed: 18448556
PLoS One. 2015 Jan 23;10(1):e0117089
pubmed: 25615698
Clin Cancer Res. 2016 Jan 15;22(2):291-300
pubmed: 26405193
Hepatobiliary Surg Nutr. 2017 Apr;6(2):91-100
pubmed: 28503556
J Bone Miner Res. 2004 Mar;19(3):429-35
pubmed: 15040831
Curr Opin Gastroenterol. 2014 May;30(3):295-302
pubmed: 24569570
Oncotarget. 2017 Feb 28;8(9):16052-16074
pubmed: 28030802
PLoS One. 2014 Dec 23;9(12):e115383
pubmed: 25536104
N Engl J Med. 2010 Apr 8;362(14):1273-81
pubmed: 20375404