Clinical Trials

Date: 2017-04-07

Type of information: Presentation of results at a congress

phase: preclinical

Announcement: presentation of results at the American Association for Cancer Research (AACR) Annual Meeting

Company: Hutchison China MediTech Limited "ChiMed" (China)

Product: fruquintinib

Action mechanism:

• tyrosine kinase inhibitor. Fruquintinib (HMPL-013) is an orally available, small molecule inhibitor of vascular endothelial growth factor receptors (VEGFRs), with potential anti-angiogenic and antineoplastic activities. Upon oral administration, fruquintinib inhibits VEGF-induced phosphorylation of VEGFRs 1, 2, and 3 which may result in the inhibition of migration, proliferation and survival of endothelial cells, microvessel formation, the inhibition of tumor cell proliferation, and tumor cell death.  It is currently under the joint development in China by Chi-Med and its partner Eli Lilly. Two late-stage, pivotal Phase III registration studies are ongoing in colorectal cancer (FRESCO) and lung cancer (FALUCA). In addition, fruquintinib is also in clinical development for gastric cancer. A new drug application (NDA) for fruquintinib to the China Food and Drug Administration (CFDA) is expected to be filed in mid-2017.

Disease: non-small cell lung cancer (NSCLC), renal cell cancer

Therapeutic area: Cancer - Oncology

Country:

Trial details:

Latest news:

• • On April 7, 2017, Hutchison China MediTech  (Chi-Med) presented pre-clinical data for fruquintinib at the American Association for Cancer Research Annual Meeting 2017 (Abstract#2089 - Evaluation of fruquintinib, a potent and selective oral VEGFR inhibitor, in combination with targeted therapies or immune checkpoint inhibitors in preclinical tumor models - Authors: Yongxin Ren et al).
• The authors have reported the evaluation of anti-tumor effect of fruquintinib in preclinical animal tumor models in combination with therapies targeting tumor driver gene alterations such as epidermal growth factor receptor (“EGFR”) and mesenchymal growth factor receptor (“c-MET”) or with immune checkpoints. In non-small cell lung cancer (NSCLC) xenograft models with EGFR activation such as activating mutations, gene amplification or protein overexpression, fruquintinib plus an EGFR tyrosine kinase inhibitor such as gefitinib or theliatinib (HMPL-309) was found to be more efficacious than either monotherapy. In PC-9 subcutaneous tumor model carrying EGFR exon 19 deletion, single agent treatment with fruquintinib at 2 mg/kg and gefitinib at 5 mg/kg produced the tumor growth inhibition (TGI) of 58% and 63%, respectively, while the combination treatment resulted in a TGI of 100% and tumor regression was observed in 11 of 16 mice treated with combinational therapy.
• In multiple xenograft models derived from lung cancer or renal cell cancer with c-MET activation (amplification or over-expression), addition of fruquintinib to a c-MET inhibitor savolitinib (AZD6094, HMPL-504) also improved the tumor growth inhibition substantially. At the end of the efficacy studies, CD31 and phosphorylation of EGFR, c-MET, protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) were analyzed with immunohistochemistry and western blotting method in tumor tissues. The results suggested that the enhanced anti-tumor effect in combination therapy could be attributed to the simultaneous blockade of cell signaling in tumor cells (EGFR or c-MET) and VEGFR suppression in the tumor microenvironment.
• Up-regulation of the immune inhibitory checkpoints induced by vascular endothelial growth factor (“VEGF”) is one of the important mechanisms for tumor cells to escape immune surveillance. In a syngeneic murine tumor model, co-administration of fruquintinib and anti-Programmed death-ligand 1 (PD-L1) antibody was found to provide improved anti-tumor effect compared to fruquintinib or anti-PD-L1 single agent alone. Studies to understand the mechanism responsible for the combination effect are underway. All combinations with fruquintinib described above were well tolerated. The efficacy observed in these models suggested that simultaneous blockade of tumor angiogenesis and tumor cell signaling or immune evasion may be a promising approach in improving treatment outcomes.

 

Is general: Yes