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

Vincenzo Mazzaferro, Bassel F El-Rayes, Michele Droz Dit Busset, Christian Cotsoglou, William P Harris, Nevena Damjanov, Gianluca Masi, Lorenza Rimassa, Nicola Personeni, Fadi Braiteh, Vittorina Zagonel, Kyriakos P Papadopoulos, Terence Hall, Yunxia Wang, Brian Schwartz, Julia Kazakin, Sherrie Bhoori, Filippo de Braud, Walid L Shaib

Research output: Contribution to journalArticle

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).

Original languageEnglish
Pages (from-to)165-171
Number of pages7
JournalBritish Journal of Cancer
Volume120
Issue number2
DOIs
Publication statusPublished - Jan 2019

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Receptor, Fibroblast Growth Factor, Type 2
Cholangiocarcinoma
Gene Fusion
Asthenopia
Hyperphosphatemia
Asthenia
Drug Therapy
Therapeutics
Disease-Free Survival
Neoplasms
Phosphotransferases
Safety

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

In: British Journal of Cancer, Vol. 120, No. 2, 01.2019, p. 165-171.

Research output: Contribution to journalArticle

Mazzaferro, V, El-Rayes, BF, Droz Dit Busset, M, Cotsoglou, C, Harris, WP, Damjanov, N, Masi, G, Rimassa, L, Personeni, N, Braiteh, F, Zagonel, V, Papadopoulos, KP, Hall, T, Wang, Y, Schwartz, B, Kazakin, J, Bhoori, S, de Braud, F & Shaib, WL 2019, 'Derazantinib (ARQ 087) in advanced or inoperable FGFR2 gene fusion-positive intrahepatic cholangiocarcinoma', British Journal of Cancer, vol. 120, no. 2, pp. 165-171. https://doi.org/10.1038/s41416-018-0334-0
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. / Derazantinib (ARQ 087) in advanced or inoperable FGFR2 gene fusion-positive intrahepatic cholangiocarcinoma. In: British Journal of Cancer. 2019 ; Vol. 120, No. 2. pp. 165-171.
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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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T1 - Derazantinib (ARQ 087) in advanced or inoperable FGFR2 gene fusion-positive intrahepatic cholangiocarcinoma

AU - Mazzaferro, Vincenzo

AU - El-Rayes, Bassel F

AU - Droz Dit Busset, Michele

AU - Cotsoglou, Christian

AU - Harris, William P

AU - Damjanov, Nevena

AU - Masi, Gianluca

AU - Rimassa, Lorenza

AU - Personeni, Nicola

AU - Braiteh, Fadi

AU - Zagonel, Vittorina

AU - Papadopoulos, Kyriakos P

AU - Hall, Terence

AU - Wang, Yunxia

AU - Schwartz, Brian

AU - Kazakin, Julia

AU - Bhoori, Sherrie

AU - de Braud, Filippo

AU - Shaib, Walid L

PY - 2019/1

Y1 - 2019/1

N2 - 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).

AB - 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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DO - 10.1038/s41416-018-0334-0

M3 - Article

VL - 120

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EP - 171

JO - British Journal of Cancer

JF - British Journal of Cancer

SN - 0007-0920

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