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

Abstract

BackgroundNext-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.MethodsThis 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.ResultsTwenty-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%).ConclusionDerazantinib 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).

TAS-120 Overcomes Resistance to ATP-Competitive FGFR Inhibitors in Patients with FGFR2 Fusion–Positive Intrahepatic Cholangiocarcinoma

“…The efficacy seen across several early-phase clinical trials of FGFR2 inhibitors in patients with advanced refractory ICC (14,(28)(29)(30) represents a breakthrough in a disease with no FDA-approved targeted therapies to date. However, as seen with other tyrosine kinase inhibitors, the rapid emergence of resistance associated with recurrent acquired mutations in the target's kinase domain has limited the durability of benefit to ATP-competitive inhibitors.…”

New and Emerging Systemic Therapeutic Options for Advanced Cholangiocarcinoma

“…A multicenter, phase I-II clinical trial open-label study enrolled adult patients with unresectable iCCA with FGFR2 fusion, who progressed, were intolerant or not eligible to first-line chemotherapy. Overall response rate was 20.7%, and disease control rate was 82.8% [51]. As for the other FGFR inhibitors, the treatment was well tolerated with a manageable safety profile.…”

Gene Therapy for Liver Cancers: Current Status from Basic to Clinics

“…For this purpose, genetic analyses of liver tissues from patients with HCC for genomic medicine have provided important information about tumor initiation, progression, and chemosensitivity [168]. The findings from these studies can be used to develop personalized gene-based therapy and genome-based diagnosis in the tumor; therefore, various clinical trials to determine the disease activity and sensitivity to the specific therapy are ongoing [169][170][171][172][173]. One of the trials bridged into the phase 1/2 trial is NCT03480152, examining the effect of mRNA cancer vaccine, delivering mRNA containing epitopes from immunogenic neoantigens, predicted neoantigens, and mutations in tumor suppressor or driver genes, by intramuscular injection [159][160][161].…”

“…This study aimed to find the genes that are expressed in both the circulating white blood cells and the liver of patients, using differential gene expression analysis, with varying degrees of liver damage of different causes with or without liver cancers. These studies include a microarray analysis of gene expression patterns in liver tumors to determine new tumor and treatment markers (NCT00373737); screening of the methylation phenotype of liver cancer to predict the prognosis (NCT01786980); analysis of different gene expression patterns in liver cancer and the blood to determine genes that are expressed in both circulating white blood cells and the liver of patients with varying degrees of liver damage of different causes (NCT00160940); a genotype-guided dosing analysis of mFOLFIRINOX for primary and metastatic liver cancers (NCT01643499); phase II molecular analysis to assess how well the treatment, directed by genetic testing, works in patients with solid tumors or lymphomas that have progressed following at least one line of standard treatment, or for which no agreed treatment approach exists (NCT02465060); an analysis of the molecular mechanism of sorafenib resistance in HCC patients assessed by gene expression profiles (NCT02733809) [169]; a phase I/II study to determine fibroblast growth factor receptor (FGFR) genetic alterations treated with novel FGFR inhibitor (ARQ-087) (NCT01752920) [170]; a phase I study to determine genetic alteration of the proto-oncogene MET in patients with solid tumors, including liver cancer treated with a novel MET/CSF1R/SRC inhibitor, TPX-0022 (NCT03993873); an investigation of vascular endothelial growth factor receptor (VEGFR), promoting cell growth and metastasis in HCC (NCT01892072); an assessment the impact of IL-28B rs12979860 and rs4803217 gene polymorphisms on hepatitis C virus (HCV)-related HCC (NCT02507882) [171]; analyses of the expression of a specific set of genes and of tumor antigens in cancer tissue from patients with HCC (NCT00858000); an assessment of matrix metalloproteinase-1 genotype polymorphism as a risk factor for HCV-related HCC (NCT03722628) [172]; determination of the role of circulating tumor cells as biomarkers of prognosis and predictors of efficacy of drug therapy for patients with HCC (NCT01930383); and a phase II study comparing the efficacy and safety of SOR versus infusional 5-fluorouracil in HCC based on the information of pERK concentration, phospho VEGFR concentration, plasma proteomics, and gene expression (NCT00619541) [173] (Table 3). While the detailed information is available for 14 studies, only a few results have been reported to date and the remainder of the study is mostly under assessment ( Table 3).…”

“…While the detailed information is available for 14 studies, only a few results have been reported to date and the remainder of the study is mostly under assessment ( Table 3). NCT01752920 showed the results of anti-tumor effect and safety of Derazantinib (ARQ 087) for unresectable intrahepatic cholangiocarcinomas with FGFR genetic alterations [170]. In addition, the phase 2 trial of the combination of SOR with 5-FU showed an encouraging disease control rate and overall survival [173].…”