Foretinib (formerly GSK1363089) is a small molecule multikinase inhibitor which includes inhibition of MET and VEGFR2. The ongoing phase II study, MET111643, is evaluating the safety and efficacy of 2 dosing schedules (continuous daily dosing and intermittent 5 days on/9 days off dosing) of foretinib as a single agent in pts with metastatic GC. An additional component of the study is to collect patient plasma samples before and during treatment with foretinib, to explore the potential pharmacodynamic effect and/or the modulation by foretinib of MET and VEGFR2.

Plasma samples were collected from 42 pts on the intermittent 5 days on/9 off foretinib schedule at baseline and prior to dosing on days 5, 15, 29, and 47. The plasma levels of sMET, HGF, sVEGFR2, and VEGFA were measured using the Meso Scale Discovery platform (MSD). These marker changes from baseline were analyzed at each time point using analysis of variance and their relationships with plasma concentrations of foretinib (PK) and clinical outcome (progression free survival [PFS] and RECIST response) were also examined.

Statistically significant increases from baseline of sMET at days 5, 15, 29, and 47 (p<.0001, p =.0344, p=.0353, p<.0001 respectively), VEGFA at days 5 (p<.0001) and 47 (p<.0001), and HGF at day 47 (p<.0001) were observed. Statistically significant decreases of sVEGFR2 at days 5, 15, 29, and 47 (all p<.0001) were also observed. Plasma VEGFA levels at day 5, 15, 29 are weakly correlated with PK (p=.033, p=.0138, p=.0165, respectively). Plasma sMET levels and changes from baseline at day 47 showed significant correlation with baseline tumor SLD (sum of longest diameter, R=0.54, p=0.0042; R=0.40, p=0.0443 respectively). Plasma VEGFA levels and changes from baseline at day 47 showed significant correlation with baseline tumor SLD (R=0.55, 0.44, respectively, p<0.01) and SLD at 8 weeks (R=0.64, 0.61, respectively, p<0.01). No correlation was observed between these four markers and PFS/RECIST response.

Changes in sMET, VEGFA, and sVEGFR2 levels were observed for both intermittent and daily dosing schedules in the gastric cancer study. Although SLD at 8 weeks did not change significantly from baseline in the GC study, plasma levels of sMET and VEGFA correlated positively with the week 8 magnitude of SLD. Hence plasma levels of sMET and VEGFA may reflect biological changes following foretinib treatment.

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B210.

Copyright © 2009, American Association for Cancer Research
2009