Abstract 8P
Background
Lenvatinib is a multiple receptor tyrosine kinase inhibitor targeting mainly vascular endothelial growth factor and fibroblast growth factor receptors. We also reported that lenvatinib has immunomodulatory activity that contributes to the antitumor activity of lenvatinib and enhances the antitumor activity in combination treatment with anti-PD-1 antibody (anti-PD-1). In this study, we investigated the characters of tumors associated with the antitumor activity of the lenvatinib plus anti-PD-1 combination treatment.
Methods
We evaluated the antitumor activities of lenvatinib (10 mg/kg, Q.D.), anti-PD-1 (200mg/head, twice weekly), and their combination in 12 mouse syngeneic tumor models. To define the characteristics of tumors, we conducted RNA-seq analysis to examine T cell inflamed GEP (GEP) score using mouse tumors before treatment. We also stained CD31 in the same tumors and calculated micro-vessel density (MVD) score by dividing CD31 positive blood vessels number by tumor area. Then, the correlation analysis among gene expression levels of GEP, IHC-based MVD score and the antitumor activity of each administration was investigated.
Results
We confirmed that lenvatinib plus anti-PD-1 inhibited tumor growth more than each single treatment in this mouse syngeneic model panel. Regarding the relationship between tumor characters and antitumor activities of each treatment, we found that antitumor activities of lenvatinib were correlated with MVD scores of pretreatment tumors. MVD-high group was significantly more sensitive to lenvatinib than MVD-low group. On the other hand, antitumor activities of anti-PD-1 were correlated with GEP score. Lenvatinib plus anti-PD-1 combination demonstrated significant enhancement of antitumor activity compared with each single agent treatment in MVD-low / GEP-high tumors.
Conclusions
In this study, we found that MVD combined with GEP might be the important predictive biomarkers reflecting the antitumor activities of lenvatinib monotherapy and lenvatinib plus anti-PD-1 combination therapy.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Eisai Co., Ltd.
Funding
Eisai Co. Ltd., Tokyo, Japan, and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Disclosure
Y. Ozawa, M. Kuronishi, Y. Kato: Financial Interests, Personal, Full or part-time Employment: Eisai Co., Ltd.