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

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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).

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Most cited references 24

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Fibroblast growth factor receptor 2 tyrosine kinase fusions define a unique molecular subtype of cholangiocarcinoma.

Yasuhito Arai, Yasushi Totoki, Fumie Hosoda … (2014)

Cholangiocarcinoma is an intractable cancer, with limited therapeutic options, in which the molecular mechanisms underlying tumor development remain poorly understood. Identification of a novel driver oncogene and applying it to targeted therapies for molecularly defined cancers might lead to improvements in the outcome of patients. We performed massively parallel whole transcriptome sequencing in eight specimens from cholangiocarcinoma patients without KRAS/BRAF/ROS1 alterations and identified two fusion kinase genes, FGFR2-AHCYL1 and FGFR2-BICC1. In reverse-transcriptase polymerase chain reaction (RT-PCR) screening, the FGFR2 fusion was detected in nine patients with cholangiocarcinoma (9/102), exclusively in the intrahepatic subtype (9/66, 13.6%), rarely in colorectal (1/149) and hepatocellular carcinoma (1/96), and none in gastric cancer (0/212). The rearrangements were mutually exclusive with KRAS/BRAF mutations. Expression of the fusion kinases in NIH3T3 cells activated MAPK and conferred anchorage-independent growth and in vivo tumorigenesis of subcutaneous transplanted cells in immune-compromised mice. This transforming ability was attributable to its kinase activity. Treatment with the fibroblast growth factor receptor (FGFR) kinase inhibitors BGJ398 and PD173074 effectively suppressed transformation.

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Polyclonal Secondary FGFR2 Mutations Drive Acquired Resistance to FGFR Inhibition in Patients with FGFR2 Fusion-Positive Cholangiocarcinoma.

Lipika Goyal, Supriya K. Saha, Leah Y. Liu … (2017)

Genetic alterations in the fibroblast growth factor receptor (FGFR) pathway are promising therapeutic targets in many cancers, including intrahepatic cholangiocarcinoma (ICC). The FGFR inhibitor BGJ398 displayed encouraging efficacy in patients with FGFR2 fusion-positive ICC in a phase II trial, but the durability of response was limited in some patients. Here, we report the molecular basis for acquired resistance to BGJ398 in three patients via integrative genomic characterization of cell-free circulating tumor DNA (cfDNA), primary tumors, and metastases. Serial analysis of cfDNA demonstrated multiple recurrent point mutations in the FGFR2 kinase domain at progression. Accordingly, biopsy of post-progression lesions and rapid autopsy revealed marked inter- and intralesional heterogeneity, with different FGFR2 mutations in individual resistant clones. Molecular modeling and in vitro studies indicated that each mutation led to BGJ398 resistance and was surmountable by structurally distinct FGFR inhibitors. Thus, polyclonal secondary FGFR2 mutations represent an important clinical resistance mechanism that may guide the development of future therapeutic strategies.Significance: We report the first genetic mechanisms of clinical acquired resistance to FGFR inhibition in patients with FGFR2 fusion-positive ICC. Our findings can inform future strategies for detecting resistance mechanisms and inducing more durable remissions in ICC and in the wide variety of cancers where the FGFR pathway is being explored as a therapeutic target. Cancer Discov; 7(3); 252-63. ©2016 AACR.See related commentary by Smyth et al., p. 248This article is highlighted in the In This Issue feature, p. 235.

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Fibroblast growth factor receptor 2 translocations in intrahepatic cholangiocarcinoma.

Rondell Graham, Emily G Barr Fritcher, Ekaterina Pestova … (2014)

Patients with cholangiocarcinoma often present with locally advanced or metastatic disease. There is a need for effective therapeutic strategies for advanced stage cholangiocarcinoma. Recently, FGFR2 translocations have been identified as a potential target for tyrosine kinase inhibitor therapies. This study evaluated 152 cholangiocarcinomas and 4 intraductal papillary biliary neoplasms of the bile duct for presence of FGFR2 translocations by fluorescence in situ hybridization and characterized the clinicopathologic features of cases with FGFR2 translocations. Thirteen (10 women, 3 men; 8%) of 156 biliary tumors harbored FGFR2 translocations, including 12 intrahepatic cholangiocarcinomas (12/96; 13%) and 1 intraductal papillary neoplasm of the bile duct. Histologically, cholangiocarcinomas with FGFR2 translocations displayed prominent intraductal growth (62%) or anastomosing tubular glands with desmoplasia (38%). Immunohistochemically, the tumors with FGFR2 translocations frequently showed weak and patchy expression of CK19 (77%). Markers of the stem cell phenotype in cholangiocarcinoma, HepPar1 and CK20, were negative in all cases. The median cancer-specific survival for patients whose tumors harbored FGFR2 translocations was 123 months compared to 37 months for cases without FGFR2 translocations (P = .039). This study also assessed 100 cholangiocarcinomas for ERBB2 amplification and ROS1 translocations. Of the cases tested, 3% and 1% were positive for ERBB2 amplification and ROS1 translocation, respectively. These results confirm that FGFR2, ERRB2, and ROS1 alterations are potential therapeutic targets for intrahepatic cholangiocarcinoma.

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Author and article information

Contributors

Vincenzo Mazzaferro: vincenzo.mazzaferro@istitutotumori.mi.it

Bassel F. El-Rayes: belraye@emory.edu

Journal

Journal ID (nlm-ta): Br J Cancer

Journal ID (iso-abbrev): Br. J. Cancer

Title: British Journal of Cancer

Publisher: Nature Publishing Group UK (London )

ISSN (Print): 0007-0920

ISSN (Electronic): 1532-1827

Publication date (Electronic): 13 November 2018

Publication date (Print): 22 January 2019

Volume: 120

Issue: 2

Pages: 165-171

Affiliations

[1 ]ISNI 0000 0001 0807 2568, GRID grid.417893.0, Department of Surgery and Oncology, , Istituto Nazionale Tumori IRCCS, ; Milan, Italy

[2 ]ISNI 0000 0004 1757 2822, GRID grid.4708.b, University of Milan, ; Milan, Italy

[3 ]ISNI 0000 0001 0941 6502, GRID grid.189967.8, Winship Cancer Institute, , Emory University, ; Atlanta, GA USA

[4 ]ISNI 0000 0004 0431 6950, GRID grid.430269.a, Seattle Cancer Care Alliance, ; Seattle, WA USA

[5 ]ISNI 0000 0004 1936 8972, GRID grid.25879.31, Abramson Cancer Center, , University of Pennsylvania, ; Philadelphia, PA USA

[6 ]ISNI 0000 0004 1756 8209, GRID grid.144189.1, Department of Oncology, , Pisa University Hospital, ; Pisa, Italy

[7 ]ISNI 0000 0004 1756 8807, GRID grid.417728.f, Humanitas Cancer Center, , Humanitas Clinical and Research Center, ; Rozzano, Milan, Italy

[8 ]GRID grid.452490.e, Department of Medical Biosciences, , Humanitas University, ; Pieve Emanuele, Milan, Italy

[9 ]GRID grid.428254.d, Medical Oncology, , Comprehensive Cancer Centers of Nevada, ; Las Vegas, NV USA

[10 ]ISNI 0000 0004 1808 1697, GRID grid.419546.b, Veneto Institute of Oncology IOV - IRCCS, ; Padua, Italy

[11 ]ISNI 0000 0004 0434 7503, GRID grid.477989.c, South Texas Accelerated Research Therapeutics, ; San Antonio, TX USA

[12 ]ISNI 0000 0004 0408 2410, GRID grid.459379.5, ArQule, Inc, ; Burlington, MA USA

Article

Publisher ID: 334

DOI: 10.1038/s41416-018-0334-0

PMC ID: 6342954

PubMed ID: 30420614

SO-VID: 9d9c7747-5d7c-4eef-b1ad-1474f1b64d32

License:

This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).

History

Date received : 29 June 2018

Date revision received : 19 October 2018

Date accepted : 23 October 2018

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: bile duct cancer,targeted therapies

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: bile duct cancer, targeted therapies

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