Abstract B269: Pharmacodynamic and correlative biomarker analyses in clinical trials of XL184, an oral, potent inhibitor of MET, VEGFR2, and RET

Abstract

Abstract Introduction: XL184 (BMS-907351) produces balanced pharmacodynamic inhibition of MET, VEGFR2, and RET, as well as robust antiangiogenic and anti-tumor effects with oral dosing in preclinical models. Based on the encouraging preclinical activity, XL184 is being studied in multiple Phase 1 to 3 clinical studies of various tumor types. Methods: Biomarker studies from a Phase 1 trial (XL184-001, n=85) of XL184 in solid tumors enriched for a medullary thyroid carcinoma (MTC) population and from a Phase 2 trial (XL184-201, n=46) in recurrent or progressive glioblastoma multiforme (GBM) are reported here. Plasma samples were analyzed for pharmacodynamic, on-target effects of XL184 and biomarkers known to change in response to anti-angiogenic treatment. Surrogate tissue sections of skin or hair were analyzed for biomarkers of ontarget activity of XL184 using immunofluorescence. Genomic DNA isolated from archival tumor and/or fresh blood samples was analyzed for alterations in genes relevant to either GBM or MTC and/or the target profile of XL184, such as RET, MET, KIT, PTEN, and MGMT. Plasma and genotypic biomarkers were investigated for potential correlation with clinical benefit (durable stable disease or partial response). Results: Plasma biomarker data from patients (pts) in both groups receiving 175 mg oral XL184 once daily demonstrated statistically significant changes from baseline in sVEGFR2, PlGF, VEGF-A, EPO, and sKIT levels (XL184-001 n=28; XL184-201 n=22; all p<0.05), as well as regulation of sMET and HGF. Similar changes were also observed in pts in XL184-001 who received lower doses of XL184. Pts in either group who had received prior anti-angiogenic therapy showed increased baseline VEGF-A and PlGF levels (p<0.04). Preliminary analyses suggested that changes in HGF within the first four weeks of treatment may correlate with clinical benefit in some pts (XL184-001: p=0.03; XL184-201; p=0.002). Analysis of surrogate tissues from both groups demonstrated significant inhibition of the phosphorylation of MET, RET, or KIT, and of the downstream signaling proteins AKT and ERK (all p<0.05). Objective responses to XL184 in pts with GBM were observed in the presence or absence of tumor EGFR amplification, PTEN mutation, and/or MGMT promoter methylation, whereas genotyping data from pts with MTC suggested clinical benefit regardless of RET mutational status. Conclusion: Biomarker analyses in plasma and surrogate tissues confirm pharmacodynamic activity of XL184. Changes in plasma HGF may be a predictive biomarker of clinical benefit and will be further evaluated. The clinical benefit rates produced in GBM and MTC coupled with clear evidence of XL184 on-target activity, independent of tumor genotypes, suggests that the clinical benefits produced by this compound may be a result of its multitargeted profile which includes inhibition of MET, VEGFR2 and RET activity. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B269.