- Gene expression data may explain differences in clinical adverse event profiles of FGFR inhibitors
- Antitumor activity of derazantinib in preclinical cancer models with FGFR aberrations supports planned gastric cancer study
- Full results from the completed phase 1 study in patients with brain cancer underscores the potential for lisavanbulin to be developed in a targeted patient population using end-binding protein 1 (EB1) as a patient selection criterion
A preclinical study showed that treatment-specific gene expression patterns in tumor models may help elucidating the biological processes driving differences in the clinical adverse event profiles of FGFR inhibitors. Moreover, the results from this study may explain low rates of adverse events reported with derazantinib for retinal events, mucositis and nail toxicities.
Results from a series of preclinical efficacy models of breast, colorectal, head & neck, lung, ovarian and gastric cancer with confirmed FGFR1-3 genetic aberrations, showed that FGFR2-fusion-positive gastric cancer models were particularly sensitive to treatment with derazantinib. In addition, gastric and lung cancer models showed the strongest correlation of FGFR1-3 expression versus the anticancer activity of derazantinib. The results support the planned clinical investigation of derazantinib in gastric cancer as its next indication.
Full results from a phase 1 study with once-daily oral lisavanbulin in adult patients with recurrent glioblastoma (GBM), or high-grade glioma, showed an overall clinical benefit rate of 44% at six months at daily doses of 25-30 mg. There was an exceptional long-lasting response in a patient, whose tumor tissue was positive for end-binding protein 1 (EB1), a previously identified response predictive biomarker for lisavanbulin in preclinical studies. A phase 2 expansion study will be initiated shortly, which will use EB1-positivity as a patient selection criterion.1 Lisavanbulin is dosed at the recommended phase 2 dose of 25 mg/day in this phase 2 study in patients with recurrent GBM. The prevalence of EB1-positivity in GBM is estimated at 2-5%.
Dr.
The following e-posters were presented at | |
Presentation # | Title |
1960P | Differential induction of gene expression may explain differences in reported adverse event profiles between the FGFR-inhibitors derazantinib and erdafitinib: an analysis in safety relevant normal tissues from urothelial cancer (UC) patient-derived mouse xenograft (PDX) models. |
541P | Derazantinib (DZB), an oral Fibroblast Growth Factor Receptor inhibitor (FGFRi), shows promising activity in PDX-tumor models with aberrations in FGFR1-3 |
382P | The potential utility of end-binding protein 1 (EB1) as response-predictive biomarker for lisavanbulin: Final results from a phase 1 study of lisavanbulin (BAL101553) in adult patients with recurrent glioblastoma (GBM) |
For further information, please visit https://www.esmo.org/meetings/esmo-virtual-congress-2020
About derazantinib
Derazantinib is an investigational orally administered small-molecule FGFR kinase inhibitor with strong activity against FGFR1, 2, and 3.2 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.3 In these cancers, FGFR genetic aberrations are found in a range of 5% to 30%.4
Derazantinib also inhibits the colony-stimulating-factor-1-receptor kinase (CSF1R).2, 5 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.6 Preclinical data has shown that tumor macrophage depletion through CSF1R blockade renders tumors more responsive to T-cell checkpoint immunotherapy, including approaches targeting PD-L1/PD-1.7, 8
Derazantinib has demonstrated antitumor activity and a manageable safety profile in previous clinical studies, including a biomarker-driven phase 1/2 study in iCCA patients,9 and has received
Basilea in-licensed derazantinib from ArQule Inc, a wholly-owned subsidiary of Merck & Co., Inc.,
About lisavanbulin (BAL101553)
Basilea's oncology drug candidate lisavanbulin (BAL101553, the prodrug of BAL27862)13 is being developed as a potential therapy for diverse cancers.1, 14, 15 In preclinical studies, lisavanbulin demonstrated in-vitro and in-vivo activity against diverse treatment-resistant cancer models, including tumors refractory to conventional approved therapeutics and radiotherapy.16, 17, 18 Lisavanbulin efficiently distributes to the brain, with anticancer activity in glioblastoma models.19, 20, 21 In preclinical studies, end-binding protein 1 (EB1) was identified as a potential response-predictive biomarker in glioblastoma models.21 The active moiety BAL27862 binds to the colchicine site of tubulin, with distinct effects on microtubule organization,22 resulting in the activation of the "spindle assembly checkpoint" which promotes tumor cell death.23
About Basilea
Disclaimer
This communication expressly or implicitly contains certain forward-looking statements, such as "believe", "assume", "expect", "forecast", "project", "may", "could", "might", "will" or similar expressions concerning
For further information, please contact:
Peer Nils Schröder, PhD Head of | |
Phone | +41 61 606 1102 |
media_relations@basilea.com investor_relations@basilea.com |
This press release can be downloaded from www.basilea.com.
References
- ClinicalTrials.gov identifier: NCT02490800
- 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
- Tecentriq® ist eine eingetragene Marke von
Hoffmann-La Roche AG . - FIDES-02: ClinicalTrials.gov identifier: NCT04045613.
J. Pohlmann , F. Bachmann, A. Schmitt-Hoffmann et al. BAL101553: An optimized prodrug of the microtubule destabilizer BAL27862 with superior antitumor activity.American Association for Cancer Research (AACR) annual meeting 2011, abstract 1347;Cancer Research 2011, 71 (8 supplement)- ClinicalTrials.gov identifier: NCT03250299
- ClinicalTrials.gov identifier: NCT02895360
- A. Sharmq, A. Broggini-Tenzer, V. Vuong et al. The novel microtubule targeting agent BAL101553 in combination with radiotherapy in treatment-refractory tumor models. Radiotherapy Oncology 2017 (124), 433-438
- G. E. Duran, H. Lane, F. Bachmann et al. In vitro activity of the novel tubulin active agent BAL27862 in MDR1(+) and MDR1(-) human breast and ovarian cancer variants selected for resistance to taxanes.
American Association for Cancer Research (AACR) annual meeting 2010, abstract 4412;Cancer Research 2010, 70 (8 supplement) F. Bachmann , K. Burger, G. E. Duran et al. BAL101553 (prodrug of BAL27862): A unique microtubule destabilizer active against drug refractory breast cancers alone and in combination with trastuzumab.American Association for Cancer Research (AACR) annual meeting 2014, abstract 831;Cancer Research 2014, 74 (19 supplement)A. Schmitt-Hoffmann , D. Klauer, K. Gebhardt et al. BAL27862: a unique microtubule-targeted agent with a potential for the treatment of human brain tumors. AACR-NCI-EORTC conference 2009, abstract C233; Molecular Cancer Therapeutics 2009, 8 (12 supplement)- A. C. Mladek, J. L. Pokorny, H. Lane et al. The novel tubulin-binding 'tumor checkpoint controller' BAL101553 has anti-cancer activity alone and in combination treatments across a panel of GBM patient-derived xenografts.
American Association for Cancer Research (AACR) annual meeting 2016, abstract 4781;Cancer Research 2016, 76 (14 supplement) - R. Bergès, A. Tchoghandjian, S. Honoré et al. The novel tubulin-binding checkpoint activator BAL101553 inhibits EB1-dependent migration and invasion and promotes differentiation of glioblastoma stem-like cells. Molecular Cancer Therapeutics 2016 (15), 2740-2749
- A. E. Prota, F. Danel, F. Bachmann et al. The novel microtubule-destabilizing drug BAL27862 binds to the colchicine site of tubulin with distinct effects on microtubule organization.
Journal of Molecular Biology 2014 (426), 1848-1860 F. Bachmann , K. Burger, H. Lane. BAL101553 (prodrug of BAL27862): the spindle assembly checkpoint is required for anticancer activity.American Association for Cancer Research (AACR) annual meeting 2015, abstract 3789;Cancer Research 2015, 75 (15 supplement)
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