Late-breaking abstract on mode of action and potential response biomarkers for FGFR/CSF1R kinase inhibitor derazantinib.
Survival advantage with monotherapy and standard-of-care combinations with tumor checkpoint controller lisavanbulin in glioblastoma models.
Basilea Pharmaceutica Ltd. (SIX: BSLN) reported today presentations of supporting preclinical data, on its clinical stage oncology drug candidates derazantinib and lisavanbulin (BAL101553), at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in Boston, USA, on October 29, 2019.
In a late-breaking abstract, novel preclinical data were presented demonstrating that derazantinib has equipotent inhibitory activity against fibroblast growth factor receptor kinases (FGFR1, 2 and 3) and the colony-stimulating factor 1 receptor (CSF1R) kinase. Structural analyses and in-cell inhibition of CSF1R activity in isolated macrophages, performed in collaboration with Dr. Paul Walker (University of Geneva), further supported CSF1R as an additional cancer target for derazantinib. As CSF1R inhibition plays a role in restoring T cell activity, thus promoting a tumoricidal immune environment, these observations support the rationale for derazantinib combination strategies with immune modulators. Furthermore, data from detailed derazantinib activity screens across a panel of urothelial cancer models were presented, providing evidence for potential response biomarkers beyond FGFR genetic aberrations that could facilitate patient selection.
Dr. Marc Engelhardt, Basilea’s Chief Medical Officer, said: “These late-breaking derazantinib data may have important clinical implications. The data support the activity of derazantinib in urothelial cancer models with genetic FGFR aberrations and highlight the dual targeting of derazantinib through FGFR and CSF1R kinase inhibition. The activity of derazantinib against CSF1R may increase the susceptibility of cancers to immunotherapy when derazantinib is combined with PD-1/PD-L1 inhibitors.”
Basilea is currently exploring derazantinib as monotherapy and in combination with Roche’s PD-L1 inhibitor atezolizumab (Tecentriq) in a multicohort phase 1/2 study in patients with advanced urothelial cancer.
A second abstract presented data obtained in collaboration with Dr. Jann Sarkaria (Mayo Clinic, Rochester), demonstrating significant survival benefits in patient-derived glioblastoma models after treatment with the microtubule-targeting tumor checkpoint controller lisavanbulin (BAL101553) as monotherapy or in combination with radiotherapy and/or standard-of-care chemotherapy, including the ‘Stupp’ regimen. Survival benefits conferred by lisavanbulin and radiotherapy combinations improved when lisavanbulin dosing continued after the radiation window, suggesting a benefit of prolonged lisavanbulin dosing.
Lisavanbulin is currently being evaluated as monotherapy in a phase 2a study in Switzerland in patients with recurrent glioblastoma and platinum-resistant ovarian cancer patients using a weekly 48-hour infusion. In the U.S., a phase 1 study is being conducted in collaboration with the Adult Brain Tumor Consortium (ABTC), in which oral lisavanbulin is evaluated in combination with radiotherapy in patients with newly diagnosed glioblastoma who have a reduced sensitivity to chemotherapy with the standard-of-care drug temozolomide. Patient recruitment into a further phase 1 study in recurrent glioblastoma or high-grade glioma with the oral formulation has just been completed with the determination of the maximum tolerated dose. In this study, daily oral lisavanbulin showed clinical antitumor activity, including one exceptional, long-lasting responder with an approximate 70% tumor area reduction.