- Successful completion of phase 1b part of FIDES-02 exploring the safety and tolerability of combining derazantinib with PD-L1 checkpoint inhibitor atezolizumab
- Recommended phase 2 dose for the combination established at full standard doses of derazantinib and atezolizumab
- Phase 2 expansion substudies exploring derazantinib and atezolizumab combination in urothelial cancer patients now open for enrolment
Based on a safety analysis conducted for 26 patients who received increasing doses of derazantinib and atezolizumab, the Independent Data Monitoring Committee for the study determined that derazantinib and atezolizumab can be safely combined at doses of 300 mg of daily oral derazantinib and 1200 mg atezolizumab, administered intravenously once every three weeks. This RP2D corresponds to the derazantinib monotherapy dose used in the phase 2 study FIDES-01 and the standard dose for atezolizumab as a single agent in urothelial cancer. There were no dose-limiting toxicities observed. The most frequent reported adverse events were asthenia (weakness) or fatigue, nausea and diarrhoea.
Derazantinib inhibits FGFR1-3 kinases, which are key drivers of cell proliferation, differentiation and migration. In-vitro data show that it also inhibits the colony-stimulating-factor-1-receptor (CSF1R) kinase and thus has the potential to enhance the response to atezolizumab’s PD-L1 checkpoint inhibition, as CSF1R-inhibition has been shown to improve the susceptibility to PD-1/PD-L1 inhibitors, in preclinical models.2
Dr.
About derazantinib
Derazantinib is an investigational orally administered small-molecule FGFR inhibitor with strong activity against FGFR1, 2, and 3.3 FGFR kinases are key drivers of cell proliferation, differentiation and migration. FGFR genetic aberrations, e.g. gene fusions, mutations or amplifications, have been identified as potentially important therapeutic targets for various cancers, including intrahepatic cholangiocarcinoma (iCCA), urothelial, breast, gastric and lung cancers.4 In these cancers, FGFR genetic aberrations are found in a range of 5% to 30%.5
Derazantinib also inhibits the colony-stimulating-factor-1-receptor (CSF1R) kinase.3, 6 CSF1R-mediated signaling is important for the maintenance of tumor-promoting macrophages and therefore has been identified as a potential target for anti-cancer drugs.7 Preclinical data has shown that tumor macrophage depletion through CSF1R blockade renders tumors more responsive to T-cell checkpoint immunotherapy, including approaches targeting PD-1/PD-L1.8, 9
Derazantinib has demonstrated antitumor activity and a manageable safety profile in a previous biomarker-driven phase 1/2 study in iCCA patients,10 and has received
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References
- A. Chaudhry, C.N. Sternberg,
M. de Santis et al. FIDES-02: a phase 1b/2 study of derazantinib as monotherapy and combination therapy with atezolizumab in patients with surgically unresectable or metastatic urothelial cancer and FGFR genetic aberrationsJournal of Clinical Oncology 2020; 38, no. 6_suppl. TPS590. ClinicalTrials.gov identifier: NCT04045613 - X. Zheng, K. Turkowski, J. Mora et al. Redirecting tumor-associated macrophages to become tumoricidal effectors as a novel strategy for cancer therapy. Oncotarget. 2017;8(29):48436-48452
- T. G. Hall, Y. Yu, S. Eathiraj et al. Preclinical activity of ARQ 087, a novel inhibitor targeting FGFR dysregulation. PLoS ONE 2016, 11 (9), e0162594
- R. Porta, R. Borea, A. Coelho et al. FGFR a promising druggable target in cancer: Molecular biology and new drugs. Critical Reviews in Oncology/Hematology 2017 (113), 256-267
- T. Helsten, S. Elkin, E. Arthur et al. The FGFR landscape in cancer: Analysis of 4,853 tumors by next-generation sequencing.
Clinical Cancer Research 2016 (22), 259-267 - P. McSheehy, F. Bachmann, N. Forster-Gross et al. Derazantinib (DZB): A dual FGFR/CSF1R-inhibitor active in PDX-models of urothelial cancer. Molecular Cancer Therapeutics 2019 (18), 12 supplement, pp. LB-C12
- M. A. Cannarile, M. Weisser, W. Jacob et al. Colony-stimulating factor 1 receptor (CSF1R) inhibitors in cancer therapy.
Journal for ImmunoTherapy of Cancer 2017, 5:53 - Y. Zhu, B. L. Knolhoff, M. A. Meyer et al. CSF1/CSF1R Blockade reprograms tumor-infiltrating macrophages and improves response to T cell checkpoint immunotherapy in pancreatic cancer models.
Cancer Research 2014 (74), 5057-5069 - E. Peranzoni, J. Lemoine, L. Vimeux et al. Macrophages impede CD8 T cells from reaching tumor cells and limit the efficacy of anti–PD-1 treatment. Proceedings of the
National Academy of Science of the United States of America 2018 (115), E4041-E4050 - V. Mazzaferro, B. F. El-Rayes, M. Droz dit Busset et al. Derazantinib (ARQ 087) in advanced or inoperable FGFR2 gene fusion-positive intrahepatic cholangiocarcinoma.
British Journal of Cancer 2019 (120), 165-171. ClinicalTrials.gov identifier: NCT01752920 - FIDES-01: ClinicalTrials.gov identifier: NCT03230318
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