Preclinical and clinical data for the fibroblast growth factor receptor (FGFR) inhibitor derazantinib and its tumor checkpoint controller, lisavanbulin, developed by Basilea Pharmaceutica, were presented at the European Society for Medical Oncology (ESMO) Virtual Congress 2020.
Derazantinib is an investigational orally administered small-molecule FGFR kinase inhibitor with strong activity against FGFR1, 2, and 3 
FGFR kinases are key drivers of cell proliferation, differentiation, and migration. FGFR genetic aberrations, e.g. gene fusions, mutations or amplification, have been identified as potentially important therapeutic targets for various cancers, including intrahepatic cholangiocarcinoma (iCCA), urothelial, breast, gastric, and lung cancers.  In these cancers, FGFR genetic aberrations are found in a range of 5% to 30%
The drug also inhibits the colony-stimulating-factor-1-receptor kinase (CSF1R).  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.  Preclinical data have shown that tumor macrophage depletion through CSF1R blockade renders tumors more responsive to T-cell checkpoint immunotherapy, including approaches targeting PD-L1/PD-1. 
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.
Derazantinib has demonstrated antitumor activity and a manageable safety profile in previous clinical studies, including a biomarker-driven Phase I/II study in iCCA patients, and has received orphan drug designation for iCCA in the United States and European Union.
Basilea is currently conducting two clinical studies with derazantinib.
The first study, FIDES-01, is a registrational phase II study in patients with inoperable or advanced iCCA. It comprises one cohort of patients with FGFR2 gene fusions and another cohort of patients with mutations or amplifications. 
The second study, FIDES-02, is a phase I/II study evaluating derazantinib alone and in combination with Roche’s PD-L1-blocking immune-checkpoint inhibitor atezolizumab (Tecentriq®; Genentech/Roche) in patients with advanced urothelial cancer, including metastatic, or recurrent surgically unresectable disease, expressing FGFR genetic aberrations. 
A preclinical study showed that treatment-specific gene expression patterns in tumor models may help to elucidate 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.
Lisavanbulin (BAL101553, the prodrug of BAL27862), an oncology drug candidate is being developed by Basilea as a potential therapy for diverse cancers.
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. The investigational drug efficiently distributes to the brain, with anticancer activity in glioblastoma models.
In preclinical studies, end-binding protein 1 (EB1) was identified as a potential response-predictive biomarker in glioblastoma models. The active moiety BAL27862 binds to the colchicine site of tubulin, with distinct effects on microtubule organization, resulting in the activation of the “spindle assembly checkpoint” which promotes tumor cell death.
Full results from a phase I study with once-daily oral lisavanbulin in adult patients with recurrent glioblastoma (rGBM), 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 II expansion study will be initiated shortly, which will use EB1-positivity as a patient selection criterion.  Lisavanbulin is dosed at the recommended phase II dose of 25 mg/day in this phase II study in patients with recurrent GBM. The prevalence of EB1-positivity in GBM is estimated at 2-5%
“The results presented at ESMO support our differentiation strategy for derazantinib, which is based on its unique kinase inhibition profile and its clinical safety profile,” Marc Engelhardt, Chief Medical Officer of Basilea Pharmaceutica said.
“The data also provide the preclinical rationale for our decision to initiate a clinical study of derazantinib alone and in combination with other therapies in patients with advanced gastric cancer. The full results from the completed phase I study with lisavanbulin underscore its potential to be developed in a targeted patient population. Our initial focus will be on glioblastoma. We may decide to explore other tumor types upon achieving clinical validation of EB1 as a response-predictive biomarker in glioblastoma,” he concluded.
* Basilea in-licensed derazantinib from ArQule, a wholly-owned subsidiary of Merck & Co., Kenilworth, N.J., U.S.A.
Phase 1/2 Study of Derazantinib (ARQ 087) in Adult Subjects With Advanced Solid Tumors With FGFR Genetic Alterations – NCT01752920
Derazantinib in Subjects With FGFR2 Gene Fusion-, Mutation- or Amplification- Positive Inoperable or Advanced Intrahepatic Cholangiocarcinoma (FIDES-01) – NCT03230318
Derazantinib and Atezolizumab in Patients With Urothelial Cancer (FIDES-02) – NCT04045613.
Microtubule-Targeted Agent BAL101553 and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma – NCT03250299
Phase 1/2a Study of BAL101553 as 48-hour Infusions in Patients With Advanced Solid Tumors or Recurrent Glioblastoma – NCT02895360
Highlights of prescribing information
Atezolizumab (Tecentriq®; Genentech/Roche)[Prescribing Information]
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Featured image: Basilea Pharmaceutica Laboratory. Photo courtesy: © 2020 Basilea Pharmaceutica.