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AACR 2017: Mechanism of PD-1/lenvatinib combo exposed, improving CR in mouse models

Research regarding a mechanism of action that leads to increased anti-tumour activity in mouse models dosed with a combination of lenvatinib mesylate and an anti-mouse PD-1 antibody has been presented at the American Association for Cancer Research (AACR) Annual Meeting.

Lenvatinib is an orally administered multiple receptor tyrosine kinase (RTK) inhibitor with a novel binding mode that selectively inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors and fibroblast growth factor (FGF) receptors, in addition to other proangiogenic and oncogenic pathway-related RTKs involved in tumour proliferation.

The results presented at the AACR meeting showed that when syngeneic model mice inoculated with mouse liver cancer, melanoma or colon cancer cell lines were dosed with a combination of lenvatinib (10 mg/kg, once daily) and an anti-mouse PD-1 antibody (500g/mouse, twice a week), a substantial inhibitory effect on tumour growth was observed compared to individual treatments.

Additionally, an increased number of mice in the combination therapy group showed Complete Response (CR) of tumour compared to the single treatment group:

  • 7 out of 30 mice receiving the combination showed CR
    • Colon cancer models: 2/10
    • Melanoma models: 2/10
    • Liver cancer models: 3/10
  • In each single treatment group, 1 out of 30 mice showed CR
    • Colon cancer models: 1/10
    • Melanoma models: 0/10
    • Liver cancer models: 0/10

Furthermore, in the liver cancer mouse model, even when identical cancer cell lines were re-inoculated into mice with complete tumour remission, no in vivo growth was observed.

RNA analysis of the cancer tissue and other tests confirmed a reduction in immunosuppressive tumour associated macrophages, a reduction in immunosuppressive signal receptors, and an increase in the ratio of memory T cells in model mice dosed with lenvatinib.

This non-clinical research suggested synergistic anti-tumour activity when combining lenvatinib with an anti-mouse PD-1 antibody in the mouse models, based on an immunostimulatory response due to the reduction in tumour associated macrophages and the enhancement of the ratio of memory T cells by lenvatinib.

Lenvatinib was approved in combination with everolimus for the treatment of adult patients with advanced RCC following one prior vascular endothelial growth factor (VEGF) targeted therapy in Europe in August 2016, and has been launched in Europe under the brand name Kisplyx for this indication.

A phase III study of lenvatinib in separate combinations with everolimus and pembrolizumab in renal cell carcinoma is underway. and a Phase Ib/II study to investigate the agent in combination with pembrolizumab in select solid tumours including endometrial cancer, renal cell carcinoma, head and neck cancer, and urothelial cancer is also underway.

Source: ACN Newswire



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