Derazantinib, an inhibitor of fibroblast growth factor receptors 1–3, increases the efficacy of paclitaxel combined with a VEGFR2-antibody in murine syngeneic tumor models

Background: Derazantinib (DZB) is an oral fibroblast growth factor receptor (FGFR) inhibitor with clinical activity in intrahepatic cholangiocarcinoma. DZB also a phase-2 trial for gastric cancer (GC), where it combined the current standard-of-care (SoC) paclitaxel and VEGFR2-antibody (Ab), ramucirumab. Kinase assays cellular vivo data indicate significant of against two other important targets oncology, CSF1R VEGFR2. Here, using three different syngeneic tumor models grown orthotopically or subcutaneously mice, we have explored efficacy tolerability combining murine VEGFR2-Ab. Materials Methods: Female Balb/c mice were used to host models: breast tumors 4T1 EMT6 both mammary fat pad, colon MC38 subcutaneously. When mean size was at least 80 mm3, treated vehicles (po, ip iv), alone (35 75 mg/kg, po, qd), (15 iv, qw) VEGFR2-Ab, DC101 (10 ip, 2qw). Treatments continued until individual reached 1500 when culled ablated formalin-fixing paraffin-embedding. Efficacy (ΔT/C) determined a) by change tumor-volume day first culling, b) median time mm3 allow longer treatment study very fast-growing MC38. The model stopped after 3-weeks quantification metastases counting lung nodules. combination interaction assessed formally as synergy/additivity/ antagonism Clarke-Combination-Index (CCI). Tolerability %-change body-weight. Results: MTD studies non-tumor bearing over 3 weeks showed that half full dose qd) could be doses (Triple-combination). In model, Triple significantly increased compared SoC paclitaxel-DC101 primary (ΔT/Cs: 0.25 0.6 respectively) reduced weight metastases. more efficacious than 0.42 0.86 respectively). CCI these indicated additive effect, gave doublets (paclitaxel-DZB DZB-Ab). still ongoing. well tolerated showing similar final body-weight changes groups including vehicle-group. Conclusions: well-tolerated VEGFR2-Ab models, shows effect orthotopic models. These support ongoing GC (FIDES-03, NCT04604132). No conflict interest.