Open Access Research article

Pharmacodynamic change in plasma angiogenic proteins: a dose-escalation phase 1 study of the multi-kinase inhibitor lenvatinib

Noriyuki Koyama1, Kenichi Saito2, Yuki Nishioka3, Wataru Yusa4, Noboru Yamamoto5, Yasuhide Yamada6, Hiroshi Nokihara5, Fumiaki Koizumi7, Kazuto Nishio8 and Tomohide Tamura5*

Author Affiliations

1 Oncology Medical Department, Eisai Co, Ltd, Tokyo, Japan

2 Japan Biostatistics/Biostatistics/Clinical Science, Scientific and Operational Clinical Support Core Function Unit, Eisai Co, Ltd, Tokyo, Japan

3 Japan Clinical Pharmacology/Clinical Pharmacology/Clinical Science, Scientific and Operation Clinical Support Core Function Unit, Eisai Co, Ltd, Tokyo, Japan

4 Oncology Clinical Development Section, Japan/Asia Clinical Research Production Creation Unit, Eisai Co, Ltd, Tokyo, Japan

5 Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan

6 Department of Gastrointestinal Oncology, National Cancer Center Hospital, Tokyo, Japan

7 Shien-Lab and Support Facility of Project Ward, National Cancer Center Hospital, Tokyo, Japan

8 Department of Genome Biology, Kinki University School of Medicine, Osaka, Japan

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BMC Cancer 2014, 14:530  doi:10.1186/1471-2407-14-530

Published: 21 July 2014



Lenvatinib (E7080), an oral multi-kinase inhibitor, has inhibitory action on tumor cell proliferation and tumor angiogenesis in preclinical models. We evaluated correlations between pharmacodynamic (PD) biomarkers with patient clinical outcomes in a lenvatinib phase 1 dose-escalation study.


Plasma angiogenic proteins were evaluated as potential PD biomarkers of response to lenvatinib in a dose-escalation phase 1 study. Lenvatinib was administered to 27 patients by twice-daily dosing in 3-week cycles; 2 weeks of treatment followed by 1 week of rest until discontinuation. Blood samples for plasma proteins were collected on days 1 (baseline), 8, and 15 of cycle 1, and days 1, 8, and 15 of cycle 2. Selected clinical outcomes, including tumor shrinkage and adverse events (AEs), were used for correlative analyses of pharmacokinetic parameters and PD biomarkers.


Tumor shrinkage and changes in PD biomarkers (increased vascular endothelial growth factor [VEGF] and stromal cell-derived factor 1 alpha [SDF1α] levels and decreased soluble VEGF receptor 2 [sVEGFR2] levels) significantly correlated with increasing lenvatinib exposure. Observed changes in levels of VEGF, SDF1α, and sVEGFR2 were maintained on day 15 of cycle 1, but returned to baseline during the 1-week rest period, and similar changes were induced by reinstitution of treatment in cycle 2. The worst grades of hypertension, proteinuria, and fatigue were associated with changes in VEGF and HGF at day 8 of cycle 1. Maximum tumor shrinkage was correlated with increased SDF1α levels. Decreased sVEGFR2 level was also correlated with tumor shrinkage and frequency of hypertension, proteinuria, and fatigue. Tumor shrinkage significantly correlated with the worst grade of proteinuria, but not with hypertension or fatigue.


PD biomarker changes observed in plasma angiogenic proteins are correlated with lenvatinib-induced tumor shrinkage and AEs. Our findings warrant further assessment of plasma proteins associated with angiogenesis as potential biomarkers of lenvatinib activity.

Trial registration NCT00280397 (January 20, 2006).

Lenvatinib; Angiogenesis; Pharmacodynamic biomarkers; VEGF; SDF1α; sVEGFR2; Maximum tumor shrinkage